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Genes And Gene Pathways In Candida Infection

Abstract Advances in genetic technology have promoted an explosive increase in our knowledge of genes relevant to Candida infection, and our understanding of their mode of action. Although the major influence on susceptibility to systemic infection is the presence or absence of complement C5, at least two other genes, as yet unidentified, influence the severity of tissue damage. Mice in which specific genes have been deleted (geneknockout) mice are now readily available, and have been used both in the analysis of receptor interactions with Candida, and to study the role of T cell-derived cytokines in clearance of the infection and the development of host resistance, but results have not always been consistent. Gene profiling studies, in both humans and mice, will no doubt resolve some of the present anomalies

Complement And Invasive Candidiasis

Virtually the entire oro-gastrointestinal tract, from mouth to anus with the exception of the stomach, is colonised by Candida spp., detectable in more than 70 of mostly immunocompetent human beings. Another location predominantly colonised by these frequent saprophytes of mucous membranes is the vulvovaginal cavity (Odds, 1988). From the affected locations it becomes evident that both endogenic and exogenic infections may occur. At present Candida spp. represent a major cause of opportunistic fungal infection in locally or systemically immunocompromised hosts, ranging from superficial thrush to life-threatening systemic infections (Eisenstein, 1990). Candida albicans is still the most frequently isolated yeast ( 60 ), although other subspecies, which are in part more resistant against the currently applied antifungal agents, appear to be on the rise. As a first line of defence, the vulnerable physiological flora of the mucous membrane constitutes an important barrier, inhibiting...


Abstract This chapter deals with the yeast Candida, one of the increasingly important human pathogens, and addresses multiple factors that result in either immunity to or infection with this micro-organism. Factors contributing to the pathogenicity, antigenicity and type of infections caused by the genus Candida and its' species are discussed. An overview of immunity to Candida includes previous and recent data on innate and adaptive immune responses, focusing on recognition and sensing of Candida via pattern recognition receptors (Toll-like receptors, Dectin-1) and their role in directing the ensuing cascade of cytokine production, that leads to protective or non-protective immunity mediated by cellular and humoral adaptive immune responses. The disease Chronic Mucocutaneous Candidiasis (CMC), which includes a subgroup of patients with the APECED syndrome (Autoimmune PolyEndocrinopathy Candidasis Ectodermal Dystrophy), where patients show a selective susceptibility to infections with...

Wiskott Aldrich Syndrome WAS

WAS patients have poor primary antibody responses to polysaccharide antigens. T-cell immunity is also impaired and most patients cannot mount delayed hypersensitivity skin reactions to tuberculin, Candida, or streptokinase streptodornase (SK SB). A unique gene mutation has been found in WAS patients.

The organisms and special situations

The distribution of osteomyelitis is influenced dramatically by the age of the patient, the specific causative organism, and the presence or absence of any underlying disorder or situation. in infants and children, acute osteomyelitis most commonly is caused by hematogenous spread. Staphylococcus aureus is the most common causative agent, followed by b-hemolytic streptococcus, Streptococcus pneumoniae, Escherichia coli, and Pseudomonas aeruginosa 7,8 . The incidence of infection by Haemophilus influenzae has declined dramatically because of widespread HIB vaccination 8-10 . Although any bone can be affected, the most commonly involved are the metaphyses of long bones, especially the distal femur and proximal tibia, followed by the distal humerus, distal radius, proximal femur, and proximal humerus 11 . S aureus is also the most prevalent infecting organism later in life in osteomyelitis of the mature skeleton, and Gram-negative rods are found in the elderly. Fungal osteomyelitis is a...

Major Fungal Pathogens

Classic fungal infections Aspergillosis Candidiasis Candida albicans, other Candida spp. Torulopsis glabrata) were quite uncommon in the past, but are observed now more frequently, especially in patients with hematologic malignancies and recipients of bone marrow stem cell transplants (2). Both of these organisms may demonstrate resistance to fluconazole and other azole drugs. Candida parapsilosis may cause disease in neonates, oncology patients, and individuals in intensive care units, sometimes due to exogenous acquisition from indwelling catheters or other invasive devices (3). A feared emerging pathogen is Candida lusitaniae, owing to its inherent resistance to ampho-tericin B.

Regulatory Position

Ex vivo proliferation of T cells is the endpoint of surface interactions and intracellular signaling. Proliferation measurements serve two purposes. Assessment of the nonspecific proliferative capacity can be determined by exposure to mitogens such as phytohemagglutinin or concanavalin A. When the mitogens are used over a dose range, subtle decrements in proliferation can be detected. The capacity of memory T cells to proliferate can be probed by exposure to tetanus toxoid, mumps, or Candida albicans. Most subjects have memory cells directed toward one or more of these preparations.

Iron Transport in Other Fungi

As we have seen in the previous chapter, it is almost unavoidable for one particular organism to become the focus of all kinds of research, simply because of the advantages which it presents. As in bacteria with E. coli, S. cerevisiae has been the yeast of choice over the last few decades. This is certainly not unrelated to the ease of genetic manipulation of this fungal species which passes much of its life cycle in the haploid state, unlike many other fungi of pathological or economic importance, which are diploid.** Several pathogenic yeasts that cause infections in man are known (see Chapter 11). Candida albicans is responsible for a great number of oral and vaginal mucosal infections, as well as systemic infection, particularly when cellular immunity is compromised, and is genetically related to S. cerevisiae. It has a number of components in common with S. cerevisiae (Eck et al., 1999 Morrissey et al., 1996 Yamada-Okabe et al., 1996) including a ferrire-ductase and an oxidase...

Eosinophils Outside The Lung

Fungal infection of the central nervous system (CNS) has been reported to cause eosinophilic meningitis and blood eosinophilia. Patients infected with Coccid-iodes immitis that has disseminated to the CNS may demonstrate an eosinophilic pleocytosis, or eosinophilic meningitis (Ismail and Arsura 1993 Ragland et al. 1993). In cryptococcal invasion of the CNS, blood and CSF eosinophilia have been reported, and histological examination of cerebral granuloma revealed the presence of eosinophils (Anderson et al. 1985 Kamezawa et al. 2000 Gross et al. 2003). Other reports of CSF eosinophilia include a case of chronic eosinophilic meningitis associated with positive culture for Candida guillermondii, and cases of eosinophilic meningitis associated with Aspergillus sinusitis or disseminated histoplasmosis (Chan et al. 2004 Livramento et al. 1993 Paz-Sendin et al. 1999). The purpose of eosinophils in the CNS is not well understood, nor has it been extensively examined, but is felt to be...

Structural Organisation Of Human Collectins

MBL has been shown to bind clinical isolates of Candida albicans and Aspergillus fumigatus and promote C4 deposition in a concentration-dependent manner (Neth et al. 2000). MBL enhances the uptake of serum-opsonised or immunoglobulin-opsonised Cryptococcus neoformans by macrophages (Levitz et al. 1993). In addition, MBL decreases the release of TNF-a by macrophages when challenged with a cryptococcal membrane glycoprotein (Chaka et al. 1997). Curiously, interaction of C. albicans with monocytes in the presence of MBL enhances TNF-a production (Kitz et al. 1992).

Susceptibility Of Collectin Genedeficient Mice To Fungal Pathogens

Studies involving infection of SP-A- - and SP-D- - mice with P. carinii and A. fumigatus have revealed that disease susceptibility due to these gene deficiencies is valid only when these mice are immunocompromised (Atochina et al. 2004a Madan et al. 2005, unpublished). This point is amply highlighted by studies involving the challenge of MBL-A knock-out mice with C. albicans (Lee et al. 2002). In rodents, MBL is encoded by two genes- MBL-A and MBL-C. In a murine model of disseminated candidiasis, MBL-A- - mice offer resistance to challenge with C. albicans in a way similar to the WT mice and both mice have comparable survival and fungal load. It appears that functional redundancy in the mechanisms involved in the fungal clearance seem to compensate for SP-A, SP-D or MBL-A defieciency in mice. Thus, studies with double knock-out mice (SP-A and SP-D MBL-A and MBL-C) are likely to be interesting.

Streptococci Pneumococci and Enterococci

The mucous membranes of the upper respiratory tract that are exposed to air and food (nose, throat, mouth) normally display a variety of aerobic and anaerobic bacterial species gram-positive cocci (Streptococcus, Staphylococcus, and Peptostreptococcus species) gram-negative cocci (Neisseria, Moraxella, and Veillonella species) gram-positive bacilli (Corynebacterium, Propionibacterium, and Lactobacillus species) gram-negative bacilli (Haemophilus, Prevotella, and Bacteroides species) and, sometimes, yeasts (Candida species).

Impact Of Haart On Reconstitution Of Immune Responses

The sequential loss of T-lymphocyte proliferative responses to antigens, alloantigens, and mitogens in HIV-1 infection is well described and has been found to be prognostic of disease progression independently of CD4+ T-cell counts (111,112). The recovery of T-lymphocyte proliferative responses to antigens such as CMV, MAC, Candida, and MTB following initiation of HAART has been reported by several groups (77,78,113-115). The development of new mycobacteria-specific T-cell lymphoproliferative responses has been correlated with immune inflammatory reactions in patients with unusual clinical manifestations of mycobacterial infections following the initiation of HAART (63). In general, the restoration of these responses has occurred rapidly, within the first 3 months of therapy. cyte proliferative responses after 1 year of HAART therapy (77). The selective failure of tetanus responses to increase is probably owing to the infrequency of exposure to tetanus compared with Candida, CMV, MAC,...

Natural History of HIV Disease

The spectrum of HIV-associated illnesses that eventually develops includes constitutional symptoms (e.g., weight loss, fatigue, fever, night sweats) and involvement of multiple organ systems. Opportunistic infections (OIs) are multiple and can occur throughout the body. These include fungal infections (e.g., oral or esophageal candidiasis thrush ), PCP, and mycobacterial infections (e.g., tuberculosis and Mycobacterium avium complex). Cancers, such as Kaposi's sarcoma and lymphoma, are other manifestations of severe immunosuppression. Prophylactic regimens can reduce the occurrence of many OIs in immunocompromised patients.

Intracellular Bacterial and Protozoan Pathogens

In certain infections with intracellular pathogens characterized by protective Th1 responses, such as Listeria monocytogenes,16 Chlamydia trachomatis1 or Candida albicans ,53 IL-10 KO animals demonstrate improved survival, suggesting a detrimental role for endogenous IL-10. Con-cordantly, overproduction of IL-10 by macrophages has been suggested to explain the increased susceptibility of neonatal mice to infection with Listeria.64 Furthermore, IL-10 Tg mice are highly susceptible to L. monocytogenes or Leishmania major infection,13 and administration of IL-10 to resistant strains of mice abolished protection from L. monocytogenes1

Chronic granulomatous disease CGD

Patients with the classic form of CGD develop serious infections usually within the first year of life. In most cases, infection is caused by catalase-positive bacteria, such as Staphylococcus aureus and the Gram-negative enterobacter-iaceae, Salmonella spp., Klebsiella spp., Aerobacter spp. and Serratia spp. However, infections with the fungi Aspergillus (usually fumigatus) and Candida sp. are also seen. Although severe, infection in CGD may be characterised initially only by malaise, low-grade fever and a mild leukocytosis (raised white cell count) or elevation in erythrocyte sedimentation rate. Organisms that produce H2O2 but are catalase-negative (e.g. Streptococcus sp., Pneumococcus sp., Lactobacillus sp.) are not major pathogens in CGD. This may be because the

Antifungal activity

LF and lysozyme (muramidase), either singly or in combination, are fungicidal in nature and then combined activity is synergistic. Samaranayake and co-workers (1997) examined 20 oral isolates of Candida krusei and 5 isolates of Candida albicans for their susceptibility to human apo-LF and lysozyme, either singly or in combination, using an in vitro assay system. The two species exhibited significant interspecies differences in susceptibility to LF, but not for lysozyme C. krusei was more sensitive to LF (1.4 times) than C. albicans. Both species revealed significant intraspecies differences in their susceptibility to lysozyme, but not for LF. No synergistic antifungal activity of the two proteins on either Candida species was noted. LF could inhibit the growth of C.albicans in the absence of PMNL, and anti-LF antibodies reversed both this inhibition and the PMNL activation by MP-F2, GM-CSF, and LPS. Furthermore, PMNL may be activated by relevant candidal mannoproteins, and release of...

Antibody Responses Against Different Pathogenic Fungi

Candida albicans Candida albicans is the most common fungal pathogen of humans. Although in normal individuals this microorganism is a commensal of mucosal surfaces, in patients with predisposing conditions it is able to cause a variety of infections that range from superficial (oral and vaginal) candidiasis to life threatening disseminated candidiasis. Although C. albicans remains the most frequent causative agent of candidiasis, other species have been increasingly associated with infections in an expanding population of immunocompromised patients. Morbidity and mortality rates associated with candidiasis remain unacceptably high, the main reasons being the difficulties encountered in the diagnosis and treatment of this type of infections (Banerjee et al., 1991 Pfaller et al., 1999 Pfaller et al., 1998 Viudes et al., 2002). As a result of its commensal status anti-Candida antibodies have been shown to be ubiquitous in human sera, presumably because the immune system can be...

Recognition Of Fungal Pathogens By Tolllike Receptors

Recognition of pathogen-associated molecular patterns (PAMPs) by TLRs, either alone or in heterodimerization with other TLR or non-TLR receptors, induces signals responsible for the activation of innate immune response. Recent studies have demonstrated a crucial involvement of TLRs in the recognition of fungal pathogens such as Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans. By studying fungal infections in knock-out mice deficient in either TLRs or TLR-associated adaptor molecules, it appeared that specific TLRs such as TLR2, TLR4, TLR6 and TLR9 play differential roles in the activation of the various arms of the innate immune response. In addition, stimulation of TLR2 can also induce immunological tolerance and in certain conditions offer escape mechanisms, especially through induction of antiinflamatory cytokines. These developments provide crucial information for understanding the mechanisms of fungal recognition by cells of the immune system, and...

Functional Status Complications and Causes of Death

Complications resulting from advanced neoplastic disease are frequent and may be local or systemic in nature. The development of malignant effusions in the pleural, peritoneal, and pericardial spaces is common with many solid tumors and may cause urgent therapeutic problems. Aspirated fluids may be routinely examined for cell count and differentiation, cytological study, and protein content. They may also serve as a source of material for analytical biochemical studies aimed at aiding the diagnosis or monitoring of disease progression, e.g., hyaluronan in malignant mesothe-lioma (Section Systemic complications include opportunistic infections that occur as a result of impaired host defense mechanisms or the myelosuppressive and immunosuppressive effects of chemotherapy. Mass spectrometric techniques for the rapid diagnosis and monitoring of systemic candidiasis are described in Section 5.1.6. Major causes of death from cancer include infection, organ failure, carcinomatosis,...

Multiple Intracellular Microbial Strategies

The reader should realize that the schematic subdivisions of methods of iron acquisition by microorganisms, even if useful for didactic reasons, are oversimplifications. For instance, many microbes utilize - in an apparently redundant manner - several of the outlined strategies according to their site of growth within or outside of the body. To give just two examples of very common pathogens Candida albicans can produce a hydroxamate siderophore, can lyse erythrocytes and bind haemoglobin, and can produce a ferric reductase Staphylococcus aureus can bind transferrin, can produce siderophores staphyloferrin A and B and can digest haemoglobin and haem.

Immunocompromised Hosts And Fungal Infections

Species suggest that optimal immunotherapy may require an individualized approach to each type of fungal infection. Susceptibility to a particular fungal infection is, in turn, a function of the specific immunological deficit of the host. Patients with neutropenia are at high risk for Candida and Aspergillus infections, whereas those with impaired cellular immunity are at high risk for the endemic mycosis (i.e., histoplas-mosis, coccidioidomycosis, blastomycosis, penicilliosis). Each fungal infection must be considered in the context of the immunologic deficit of the host, and therapy should be targeted at restoring or compensating for that particular immunologic impairment. An important concept is that it may be possible to use immune therapy to compensate for immunologic deficits by taking advantage of the many defense functions that comprise the immune system. For example, neutropenic mice can be protected against experimental candidiasis by administration of specific antibody,...

Nonspecific Replacement Immune Therapies

The effectiveness of granulocyte transfusions against invasive fungal infections may be lower than that against bacterial infections (10). At this time, there are not sufficient data to recommend routine granulocyte transfusions for neutropenic patients with invasive fungal infections (10). Nevertheless, several reports suggest that granulocyte transfusions can be useful for the therapy of some types of fungal infection in patients with prolonged neutropenia (15-18). Fusarium infections in neutropenic patients respond poorly to antifungal therapy, and resolution usually requires recovery of bone marrow function (16). Some patients with Fusarium infection and neutropenia have responded favorably to CSF-elicited granulocyte transfusions, and it has been suggested that this modality can buy time until recovery from myelosuppression (16). There is one report of a successful therapy of disseminated Fusarium infection using a combination of amphotericin B, granulocyte macrophage (GM)-CSF,...

Clinical Features

When the CD44 T-cell count falls below about 400 per (xl the patient may develop a constellation of constitutional symptoms (fever, night sweats, oral candidiasis, diarrhea, and weight loss) which used to be known as AIDS-related complex (ARC). Early opportunistic infections begin to be seen. At this intermediate stage of immune depletion these infections are generally not life-threatening. They particularly include infections of the skin and mucous membranes such as tinea, seborrheic dermatitis, bacterial folliculitis, warts, molluscum contagiosum, gingivitis, oral and esophageal candidiasis, oral hairy leukoplakia (Fig. 35-10D), and chronic sinusitis. Reactivation of latent herpesviruses, particularly herpes simplex and zoster, also occurs (see Chapter 20). Gastrointestinal infections, caused by any of a wide vanety of organisms, including the yeast Candida albicans and parasites such as Cryptosporidia, are common. Mycobacterial infections are also common in these patients, and this...

Nonspecific Augmentative Immune Therapies

G-CSF promotes proliferation and differentiation of PMN progenitor cells (reviewed in refs. 31 and 32). Administration of G-CSF results in an increased number of peripheral blood PMNs, including band forms (left shift). Neutrophils from individuals given G-CSF have enhanced superoxide production. Neutrophils from patients with AIDS have impaired activity against Candida albicans, which can be restored by incubation in G-CSF (35). G-CSF is used clinically to promote bone marrow recovery after chemotherapy and bone marrow transplantation and to treat chronic neutropenia, myelodysplastic syndrome, and aplastic anemia (31). G-CSF administration is also useful for treating AIDS-associated neutropenia and may reduce the incidence of infections in patients with advanced HIV infection (36). G-CSF enhances PMN antifungal activity against a variety of fungal pathogens (Table 3). Aspergillus fumigatus Candida sp. Candida albicans Candida albicans Candida albicans Cryptococcus neoformans...

Infections In The Bone Marrowstem Cell Transplant Recipient

Bone marrow transplantation is associated with a characteristic spectrum of post-transplant infectious complications that occur in relation to the time interval following transplantation (39). Although this was initially described in allogeneic transplant recipients, a similar pattern of infection, although with a decreased frequency, is found in autologous transplant recipients. The first three to four weeks after transplantation are characterized by marrow aplasia with marked neutropenia. Bacterial infections caused by common Gram-positive isolates such as S. aureus, coagulase-negative staphylococci, and a-hemolytic streptococci, and less commonly Gram-negative enteric organisms predominate in this period (40). With the administration of broad-spectrum antimicrobial agents, the normal colonizing flora, including anaerobes is ablated, and replaced by potentially more resistant bacterial isolates and fungi, especially Candida species, with subsequent infections caused by these...

Intravenous Immune Globulin

Transfer factor is an extract from lymphoid cells sensitized with antigen that can transfer cell-mediated reactivity in the form of delayed cutaneous hypersensitivity response (reviewed in ref. 60). Although many aspects of this phenomenon remain controversial, transfer factor has been used for the treatment of refractory fungal infections (60-62). Chronic mucocutaneous candidiasis in patients without HIV infection is a rare disease characterized by chronic C. albicans infections of the nails, skin, and mucous membranes (63). Several remarkable remissions of candidal infection have been reported in some patients with chronic mucocutaneous candidiasis treated with transfer factor (60). Graybill et al. (64) reported three patients with disseminated coccid-ioidomycosis who were treated with transfer factor and amphotericin B. All three patients displayed increased cellular responses to C. immitis antigens after receiving transfer factor, and two manifested significant improvement with...

Conclusion And Future Prospects

Although there is a clear need for controlled trials of immunotherapy against fungal infections, such trials are likely to be very difficult because of several factors. First, many fungal infections are relatively rare, and only multicenter studies can accumulate enough patients for meaningful studies. Second, the increasing number of reports of successful outcomes after immune therapy raises difficult ethical questions of whether such studies should be done given that conventional antifungal therapy has such a poor historical record. Third, large sample sizes may be needed since biologic differences in the patients and in the type of fungal infection could result in significant patient-to-patient variability in response and outcome. For example, the risk of fungal infection in patients with neutropenia depends on many variables, including underlying illness, antibiotic use, type of chemotherapy, and so on (reviewed in ref. 79). In addition, there is uncertainty in the classification...

Nk Cells In Fungal Infection

Scanning Electron Micrograph Adcc

The sinuses or lung is associated with decreased numbers and cytotoxic function of NK cells (Krishnaraj and Svanborg, 1993 Liodolt et al. 1989 Morrison et al. 2003). In H. capsulatum infection, NK cells have an important role (Tewari et al. 2000). Though at least one report has indicated otherwise, the beige mouse (bg bg) deficient in NK cells displays heightened susceptibility to H. capsulatum, as do perforin deficient mice (Patino et al. 1987 Suchyta et al. 1988 Zhou et al. 2001). In paracoccidioiodomycoses, the decreased function of NK cells, despite normal numbers, is associated with disease, and NK cells have been demonstrated to exhibit anti-fungal activity against C. immitis (Jimenez and Murphy, 1984 Peracoli et al. 1991). Infection with P. carinii is associated with depressed NK cell function (Bonagura et al., 1989 Staugus et al., 1988). Finally, there is extensive literature on the role of NK cells in cryptococcal infection, and the immunomodulatory effects of Candida on NK...

Water vapour absorption

Uptake thresholds and absorption kinetics are the main factors determining the physiological and ecological significance of water vapour absorption in different groups together, they determine the av range over which absorption is possible and the water deficits which can be recovered in a given time. The finding that water vapour absorption occurs in terrestrial isopods in moist environments has altered perspectives concerning its ecological significance (Wright and Machin 1993). The entire order Psocoptera possesses this ability, regardless of habitat and flight status, so the adaptive value is not readily apparent (Rudolph 1982). Recently, the common soil collembolan Folsomia Candida has been shown to absorb water vapour from the atmosphere by accumulating myo-inositol and glucose in order to raise its haemolymph osmolality above ambient av (Bayley and Holmstrup 1999). These authors point out that water vapour absorption at an av of 0.98 is as ecologically relevant for this soil...

Microbicidal activity

Lepraemurium, Candida albicans, Cryptococcus neoformans, Leishmania donovani, and Toxoplasma gondii (30-34). (a) Direct evaluation of the intracellular killing of micro-organisms by specific staining of the infected macrophages to assess the number of intracellular micro-organism (Candida) and or the number of micro-organisms per vacuole (Leishmania, Toxoplasma). (c) Counting the surviving micro-organisms as colony-forming units on solid media (Candida and bacteria). The phagocytes are challenged with the microorganisms at different efFector-to-target cell ratios for various length of time. At the end of the challenge, the killing is stopped by lysing the phagocyte and the surviving micro-organisms are plated and counted. Macrophages can kill microbes via both oxygen-dependent and -independent mechanisms. Oxygen-dependent mechanisms include the production of reactive oxygen intermediates (ROI), hydrogen peroxide, and the generation of reactive nitrogen intermediates (RNI), whereas...

Lymphoid Immunodeficiencies May Involve B Cells T Cells or Both

Immunoglobulin deficiencies are associated primarily with recurrent infections by extracellular bacteria, but those affected have normal responses to intracellular bacteria, as well as viral and fungal infections. By contrast, defects in the cellmediated system are associated with increased susceptibility to viral, protozoan, and fungal infections. Intracellular pathogens such as Candida albicans, Pneumocystis carinii, and Mycobacteria are often implicated, reflecting the importance of T cells in eliminating intracellular pathogens. Infections with viruses that are rarely pathogenic for the normal individual (such as cytomegalovirus or even an attenuated measles vaccine) may be life threatening for those with impaired cell-mediated immunity. Defects that cause decreased T-cell counts generally also affect the humoral system, because of the requirement for TH cells in B-cell activation. Generally there is some decrease in antibody levels, particularly in the production of specific...

Difficulty in swallowing dysphagia

Retrosternal chest pain experienced during swallowing, odynophagia, is characteristic of Inflammatory disorders of the oesophagus, e.g. peptic ulceration, candidiasis, herpes simplex oesophagitis. Food sticking during swallowing is an important symptom of oesophageal disease for which an explanation should always be sought. The important features in the history of dysphagia are shown in the symptom checklist Table 5.3) and some common causes of dysphagia in the box below.

Liposomal Amphotericin BAmBisome Efficacy Aspects

The marked reduction in toxicity for AmBisome, as noted above, is not associated with a loss of the drug's broad-spectrum fungicidal activity when it is tested in vitro (37,38) or in vivo. Preclinical and clinical studies have shown that AmBisome is an effective therapy for extracellular as well as intracellular fungal infections in both immunocompetent and immunosuppressed hosts. In preclinical studies, AmBisome at doses ranging from 3 to 30mg kg has been reported to have therapeutic dose-dependent responses against many different fungal infections, including pulmonary blastomycosis (39), pulmonary paracoccidioidomycosis (40), systemic and pulmonary aspergillosis (41,42), systemic candidosis (43), meningeal cryptococcosis (44), histoplasmosis (45), and fusariosis (46). High doses of AmBisome given to animals have resulted in clearance of microbes from target tissues such as the kidneys (47), liver, spleen and lungs (48), and brains (49,50). Similarly, clinical studies have supported...

Common disorders of the mouth

Mucous Patches Syphilis

This may occur in the infants of mothers who carry infection with Candida albicans in the vagina. It also occurs, particularly in the elderly, in association with febrile or debilitating diseases. It is common in patients being treated with antibiotics, corticosteroids or immunosuppressive drugs (Fig. 2.40). Fungal plaques may be seen as individual or coalescent white deposits adhering to the mucous membrane of any pan of the mouth. There is very little evidence of inflammation. Fig. 2.40 Extensive oral thrush a feature of previous a ntibiotic therapy. Fig. 2.40 Extensive oral thrush a feature of previous a ntibiotic therapy.

Saccharomyces Cerevisiae

Life Cycle Saccharomyces Cerevisiae

Further insight into the S. cerevisae genome has recently been obtained from comparisons with more distantly related species. Dujon et al. (2004) sequenced four species from the hemiascomycete group, Candida glabrata, Kluyveromyces lactis, Debaryomyces hansenii, and Yarrowia lipolytica, and compared their genomes with that of S. cerevisae. A total of approximately 24200 novel genes was identified, and their translation products were classified into about 4700 families. Pairwise comparisons were made between the species to establish the degree of sequence divergence between orthologous genes. It appeared that the five yeast species together spanned a genetic diversity comparable to the entire phylum Chordata. For example, the average sequence identity between orthologous genes (translated into proteins) between S. cerevisiae and C. glabrata was 65 , between S. cerevisiae and K. lactis 60 , and between S. cerevisiae and Y. lipolytica 49 . This is less than the average sequence identity...

Get Rid Of Hesiocaeca Methanicola

Fatty acids, 147, 190, 192, 201-2, 254 fennec fox, 135 Ferns, Donald, 178 fibrinogen, 184 flamingos, 52 Folsomia candida, 253 Fontana, Felice, 100 Franklin, Sir John, 154 freeze avoidance, 157-70 in fish, 165-70 in insects, 158-65, 162 in nematodes, 163-4 in plants, 188 freeze concentration effect, 150-1, 152, 173,

Clinical Aspects Immunity

AIDS is acquired by infection with HIV, which attacks certain T cells. These cells have a specific surface attachment site, the CD4 receptor, for the virus. HIV is spread by sexual contact, use of contaminated needles, blood transfusions, and passage from an infected mother to a fetus. It leaves the host susceptible to opportunistic infections such as pneumonia caused by the protozoon Pneumocystis carinii thrush, a fungal infection of the mouth caused by Candida albicans and infection with Cryptosporidium, a protozoon that causes cramps and diarrhea. It also predisposes to Kaposi sarcoma, a once-rare form of skin cancer. It may also induce autoimmunity or attack the nervous system.

Subacute Or Chronic Meningitis

Fungal meningitis occurs primarily in individuals with immunosuppression. Crypto-coccus neoformans is the most common cause of meningitis in patients with human immunodeficiency virus (HIV) infection and in transplant patients. Other fungal infections that may occur in individuals with defects in cell-mediated immunity may include Coccidioides immites and histoplasmosis. Patients with granulocytopenia or a functional abnormality of granulocytes as is seen in diabetes mellitus are at risk of developing infections due to Candida, Aspergillus fumigatus, and Zygomycetes organisms (mucormycosis). Candida infections may also occur through central lines and in patients on broad-spectrum antibiotic therapy.

Evaluation of Suspected Immunodeficiency

Dihydrorhodamine Test

Obtaining a thorough clinical history is the appropriate starting point to direct any laboratory evaluation for immunodeficiency. For example, a history of recurrent infections with encapsulated bacteria (e.g., Haemophilus influenzae and Streptococcus pneumoniae) usually affecting the sinuses and lungs suggests an antibody deficiency (Ballow 2002). In contrast, a clinical picture of recurrent infections with opportunistic organisms (e.g., Pneumocystis jiroveci, candida species, and cytomegalovirus) should focus the initial evaluation toward a T cell abnormality (Buckley 2002). The more recent identification that persistent nontuberculous myco-bacterial (NTB) infections can be associated with defects in the IFN-y-IL-12 23 circuit has opened a new appreciation of immune deficiencies that affect the interface between the adaptive and the innate immune systems (Filipe-Santos et al. 2006). In addition, the critical role of natural killer cells in host defense has been clarified more...

Molecular adaptations of Hortaea werneckii

(Andreishcheva et al. 1999 Yoshikawa et al. 1995) but caused a decrease in phospholipid and sterol contents. In contrast, Candida membran-efaciens grown at high NaCl concentrations exhibited increased unsaturation in fatty acids and an increase in the contents of phosphatidyl-inositol (PI) and phosphatidylethanolamine (PE), resulting in slightly higher membrane fluidity (Khaware et al. 1995). The plasma membrane of the marine yeast Debaryomyces hansenii adapts to stress conditions by decreasing fluidity and increasing the sterol-to-phospholipid ratio in the presence of salt (Turk et al., submitted). Our studies have shown that salt stress does not significantly influence the total sterol content in halophilic H. werneckii, but does cause an increase in the phospholipid content. The most abundant fatty acids in phospholipids contained C16 and C18 chain lengths with a high percentage of C18 2A9,12. Salt stress also caused an increase in the fatty acid unsaturation. Halophilic fungi...

Menstrual and obstetric history

A 30-year-0ld female schoolteacher was admitted for investigation of 7 kg weight loss, tiredness and malaise of 3 months' duration. Systemic enquiry was otherwise normal. She had two children by her partner in a stable relationship of 5 years' duration. There was no history of drug use and physical examination was initially normal. The diagnosis was unclear until after complaining of a sore throat, she was found to have oral candidiasis. Suspecting an immunodeficiency disorder, a sexual history was then taken and reveaied that 2 years previously, while her partner was abroad, she had unprotected sexual intercourse with a bisexual friend. An HIV test was performed and was positive her partner and her second child were also later found to be HIV-positive.

Case 22 Severe Pneumonia

Severe Case Pneumonia

The CXR shows bilateral infiltrates and air bronchograms with a perihilar distribution. The heart size is normal. There are no Kerley B lines or evidence of upper lobe venous diversion. All these are typical features of PCP PCP is the most common life-threatening opportunistic infection in HIV disease. Generally, the most common opportunistic infection in HIV is oral candidiasis. Oral candidiasis should be looked for in any young patient with pneumonia as it may be a sign of T-cell immune deficiency. PCP can be diagnosed by sputum induction or bronchoalveo-lar lavage. Note that 10 of PCP patients could have a normal CXR.

Macrophage Evasion Mechanisms

Several reports have shown mechanisms used by Candida albicans to escape phagocytosis and killing by macrophages. C. albicans phospholipomannan, a surface glycolipid that is shed by C. albicans, was shown to mediate escape from macrophages by inducing apoptosis (Ibata-Ombetta et al., 2003a Ibata-Ombetta et al., 2003b). It has also been shown that a soluble factor from C. albicans suppresses nitric oxygen production, but does not stimulate the production of immunosuppressive cytokines (IL-10 and TGF-P) (Chinen et al., 1999). Furthermore, C. albicans p-1,2-linked mannooligosaccharides, which are part of the C. albicans cell wall, have been shown to be involved in adhesion to macrophages (Fradin et al., 1996) and inhibit NO and TNFa production (Jouault et al., 2000). Once inside the macrophage, it adapts to oxidative stress and starvation and induces morphological changes at a later stage when hyphal growth enables escape from the macrophages, it activates glycolysis and downregulates...

Clinical Manifestations 21 Orofacial Infections

Oropharyngeal Candidiasis Colonization of the oral cavity by Candida spp. increases in the elderly, although the frequency and intensity of carriage appears to be independent of denture use (16). Clinical disease may be precipitated by the use of broad-spectrum antibiotics and inadequately cleaned or ill-fitting dentures. The most common oral manifestation is pseudomembranous candidiasis (thrush), which affects about 10 of the elderly population (13). It is characterized by soft, white, slightly raised adherent plaques that can be wiped off leaving an erythematous or bleeding surface. Acute erythemic or atrophic candidiasis is characterized by painful erythematous mucosal lesions and a bald (depapillated) appearance of the tongue. Chronic atrophic candidiasis or denture-induced stomatitis is commonly found in denture wearers and elderly persons with diffuse inflammation of denture-bearing areas due to prolonged irritation. Chronic hyperplastic candidiasis is a leukoplakic or...

Esophageal Infections

The most common cause of fungal infection of the esophagus is Candida albicans. Candida esophagitis occurs most commonly in immunocompromised individuals. Physical examination may be useful if oral candidiasis is present however, upper gastrointestinal endoscopy may be necessary to confirm the diagnosis. In AIDS patients with oral candidiasis, the presence of odynophagia or dysphagia most often indicates Candida esophagitis. Therefore, therapy can be instituted without endoscopic evaluation (2). Aspergillus is the second most common cause of fungal esophagitis. It occurs most frequently in cancer patients, who usually present with severe odynophagia. Less common fungal infections include histoplasmosis and blastomycosis. These patients most often present with dysphagia. Although esophagitis with these latter pathogens is uncommon, the diagnosis should be considered in cases where presumed Candida esophagitis does not respond to therapy. Upper GI endoscopy and culture or histopathology...

Infections In The Solid Organ Transplant Recipient

Chronic immunosuppressive therapy, better selection of transplant candidates, improved antimicrobial prophylaxis, and advances in surgical techniques. In the era before routine prophylaxis, the incidence of urinary tract infection following renal transplantation ranged from 35 to 80 . However, with the institution of trimethoprim-sulfamethoxazole prophylaxis, this incidence has now dropped to

Stress and the ecological niche

Ecological Niche Graph

Ecologists have invented the concept of an ecological niche to organize their thoughts about the ways in which organisms fit into their environment. The inception of this concept in the ecological literature is attributed to the American ornithologist Joseph Grinnell with his now classical paper on the California thrasher published in 1917, but the most widely used and influential elaboration of the niche concept is due to Hutchinson (1957). Hutchinson defined the niche in terms of any number of conditions and resources that limit the distribution of a species. The niche was pictured as an n-dimensional hypervolume that envelops those values of continuously varying environmental factors that allow long-term survival of the species. As an illustration of the Hutchinsonian niche concept we reproduce a two-dimensional picture of fitness in the collembolan Folsomia Candida as a function of zinc exposure and food density (Fig. 6.1 Noel et al. in press). Figure...

Diagnostic Tests 31 Urine Culture

Lower quantitative counts of organisms also occur with certain less common infecting organisms, such as Candida albicans. Patients with renal failure or receiving diuretics may also have dilute urine and lower quantitative bacterial counts. Some uncommon infecting organisms, such as Ureaplasma urealyticum or Haemophilus influenzae are not identified through routine culture methods, and urine cultures may be negative unless special cultures are requested. In the presence of complete obstruction to urinary drainage with infection proximal to the obstruction, as in ureteric

Overarching Regulatory Mechanisms

It is evident that cytokines such as TNFa and IL-1p have major roles in the orchestration of neutrophil recruitment, through the production of cytokines such as CXCL8 from other leukocytes and tissue cells. We have shown that activation of tissue cells by monocytes exposed to TLR agonists results in marked CXCL8 generation, dependent upon TLR-induced IL-ip secretion from the monocyte that drives CXCL8 production from tissue cells (Morris et al., 2005). TNFa lymphotoxin-a double knock-out mice have increased susceptibility to Candida albicans infection in a model of intra-peritoneal challenge (Netea et al., 1999). While these factors are well recognised to contribute to activation of neutrophils, these mice also demonstrated significant impairment in neutrophil recruitment, and phagocytosis of yeast, although killing of ingested yeast was not altered (Netea et al., 1999). Production of TNFa in response to fungal infection is regulated at multiple levels, as illustrated by studies of...

Exploiting Dendritic Cells As Fungal Vaccines

Either mDCs or pDCs to phagocytose and respond to Candida or Aspergillus was defective soon after allogeneic HSCT (unpublished data). In contrast, both murine and human donor mDCs and pDCs phagocytosed fungi and underwent functional maturation in response to them. However, their activation program for cytokine production was different, being IL-12 produced mainly by mDCs and IL-12,IL-10 and IFN-a produced by pDCs. This resulted in a distinct ability for T cell priming in vitro, being Th1, Th2 and Treg differently activated by the different DC subsets (Perruccio et al. 2004). More recent data have shown that the infusion of fungus-pulsed purified DCs of either subset accelerated the recovery of peripheral antifungal Th1 immunity and increased resistance to fungal infections in mice with HSCT. However, only the co-infusion of DCs of both subsets resulted in i) induction of Treg capable of a fine control over the inflammatory pathology ii) tolerization toward alloantigens and iii)...

Epidemiology and Etiology of Endophthalmitis

Endogenous endophthalmitis (EE) is relatively infrequent, and results from seeding of the eye with organisms as a complication of bacteremia or septicemia. Populations at greatest risk for EE included immunocompromised patients, those with prolonged use of indwelling devices, and intravenous drug users. Since patients with EE commonly have systemic infection, the associated mortality is relatively high. Bacillus species, Candida and Aspergillus are the most frequent causes of EE 6 .

There Are Several Phases of the DTH Response

Macrophage Receptor Cryptococcus

Intracellular bacteria Mycobacterium tuberculosis Mycobacterium leprae Listeria monocytogenes Brucella abortus Intracellular fungi Pneumocystis carinii Candida albicans Histoplasma capsulatum Cryptococcus neoformans Intracellular parasites Leishmania sp. Intracellular bacteria Mycobacterium tuberculosis Mycobacterium leprae Listeria monocytogenes Brucella abortus Intracellular fungi Pneumocystis carinii Candida albicans Histoplasma capsulatum Cryptococcus neoformans Intracellular parasites Leishmania sp.

Detection Of Fungi By Mannosebased Recognition Receptors

The outer shape and stability of fungi is largely determined by the cell wall, whose primary component is a matrix of small polysaccharides, proteins, lipids, and inorganic salts that contains chitin microfibrils. In the yeast Candida albicans the cell wall consists of 20 to 50 mannan (mannose polymers), 30 to 60 glucan (D-glucose polymers with glycosidic bonds), 1 to 2 chitin, 2 to 14 lipid, and 5 to 15 protein (McGinnis and Tyring 1996). Additionally, yeasts contain soluble peptidomannans embedded in a- and j8-glucans in their outer cell wall (McGinnis and Tyring 1996). Mannose polymers thus form an integral part of the cell wall of most fungi (Masuoka 2004).

IL10 and Innate Immunity in Infectious Diseases

In Listeria monocytogenes models, elevation of IL-10 severely compromises resistance to infection in SCID mice,6,7 while the enhanced innate response to Listeria in IL-10- - or anti-IL-10mAb-treated mice leads to rapid control of Listeria infection.8 IL-10- - mice can eliminate an intravenous inoculation with Candida albicans in experimental acute systemic candidiasis.9 Such enhancement of early innate responses also has been demonstrated in T. gondii, and T.cruzi infection.10,11 However, even normal IL-10 levels tend to limit the effectiveness of the immune response to most infectious pathogens. The suppressive effects of endogenous IL-10 can be uncovered by reducing IL-10 levels. In contrast, the effects of altering IL-10 levels manifested at different phases of an immune inflammatory response are quite complicated. In cerebral listeriosis models for example, IL-10- - mice succumbed to listeriosis quite rapidly with endogenous IL-10 required to prevent a hyperinflammatory...

HIV1 Infection Leads to Opportunistic Infections

Seroconversion Images

The first overt indication of AIDS may be opportunistic infection with the fungus Candida albicans, which causes the appearance of sores in the mouth (thrush) and, in women, a vulvovaginal yeast infection that does not respond to treatment. A persistent hacking cough caused by P. carinii infection of the lungs may also be an early indicator. A rise in the level of circulating HIV-1 (viral load) in the plasma and concomitant drop in the number of CD4+ T cells generally previews this first appearance of symptoms. Some relation between the CD4+ T-cell number and the type of infection experienced by the patient has been established (see Table 19-3). Of intense interest to immunologists are the events that take place between the initial confrontation with HIV-1 and the takeover and collapse of the host immune system. Understanding how the immune system holds HIV-1 in check during this chronic phase can lead to the design of effective therapeutic and preventive strategies. Candidiasis,...

Endocrine myopathies

Miscellaneous infections causing myopathy. It should be noted that numerous other microorganisms have been implicated as etiologic agents in myositis. Some have occurred only in immunocompromised patients. Agents found include Candida tropicalis, Mycoplasma pneumoniae, Trypanosoma cruzi, and Echinococcus alveolaris.

Combined Mechanical and Nonmechanical Disruption of Microbial Cells

A combination of enzymatic chemical lysis with mechanical disintegration has been suggested for enhancing the efficiencies of the respective methods, with savings in time and energy and facilitating subsequent processing by reducing the amount of cell debris. Pretreatment of cells with enzymes, e.g., Bacillus cereus with cellosyl, and Candida utilis and Saccharomyces cerevi-siae with zymolyase, has shown dramatically increased release of intracel-lular enzymes with fewer passes during mechanical disruption (Kula et al. 1990 Vogels and Kula 1992 Baldwin and Robinson 1990, 1994). Heat pretreatment could be another alternative for heat-stable products (Vogels and Kula 1992). Weakening of the cell wall of the gram-negative bacterium Alcaligenes eutrophus by various forms of chemical and thermal pretreat-ment, e.g., by high pH (10.5) shock, addition of SDS at 70 C, increasing monovalent cations concentration at 60 C, addition of EDTA, and lysis by

Workbook in Microbiology 7e

Microbiology Mold Slides

Gram stain Most fungi are not stained well by the Gram-stain procedure, and therefore, it is of limited use when examining specimens for fungal forms. It is generally reliable only for detecting the presence of Candida species (see colorplate 41), Sporothrix schenkii, and perhaps a few other fungi in clinical material. In Gram-stained spinal fluid specimens, Cryptococcus neoformans may appear as irregularly staining gram-positive yeast cells surrounded by an orange capsule (see colorplate 43). Yeasts. Yeasts, such as Candida species and Cryptococcus neoformans, are a heterogeneous group. Their identification is based on colonial and cellular morphology and biochemical characteristics. Morphology is used primarily to establish the genus identification, whereas biochemical tests are used to differentiate the various species. 1. Germ tube test More than 90 of yeast infections are caused by Candida albicans. The germ tube test is a rapid and inexpensive method used to identify this...

Sexual Dysfunction Related to the Disease

Besides these psychological aspects, many women suffer from dyspareunia. This can be secondary to perineal disease, severe proctitis or to the presence of an inflamed segment of bowel in the pouch of Douglas, in direct contact with the posterior fornix of the vagina 135 . In these cases symptoms generally improve after resection of the inflamed bowel 135-137 . Another possible cause of dyspareunia is vaginal candidiasis, which has been frequently noticed in women affected by CD 9 .

The Lectin Pathway Originates With Host Proteins Binding Microbial Surfaces

The lectin pathway is activated by the binding of man-nose-binding lectin (MBL) to mannose residues on glyco-proteins or carbohydrates on the surface of microorganisms including certain Salmonella, Listeria, and Neisseria strains, as well as Cryptococcus neoformans and Candida albicans. MBL is an acute phase protein produced in inflammatory responses. Its function in the complement pathway is similar to that of C1q, which it resembles in structure. After MBL binds to the surface of a cell or pathogen, MBL-associated serine proteases, MASP-1 and MASP-2, bind to MBL. The active complex formed by this association causes cleavage and activation of C4 and C2. The MASP-1 and -2 proteins have structural similarity to C1r and C1s and mimic their activities. This means of activating the C2-C4 components to form a C5 convertase without need for specific antibody binding represents an important innate defense mechanism comparable to the alternative pathway, but utilizing the elements of the...

Nk And Lak Cells In Disease

Indirectly, NK cells play a role in the termination of opportunistic fungal infections in immunocompromised individuals. When Candida albicans interacts with NK cells, cytokines such as TNF, IFN-y and GM-CSF are released. These cytokines recruit and activate neutrophils that ingest and kill the fungi (Bancroft, 1993).

Intracellular pathogens and fungi

Intracellular pathogens and fungi typically require a cell-mediated response for their elimination. This is demonstrated by the fact that such infections are common in patients infected with the human immunodeficiency virus (HIV), an organism that infects and impairs the activity of the main cells involved in cell-mediated immunity (i.e. CD4+ T cells and macrophages). Although fungal infections are usually eliminated by cell-mediated immunity alone, some require more than this. For example, whilst chronic mucocandidiasis may be cured by effective cellmediated immunity, recovery from systemic infection with Candida spp. requires the activity of granulocytes, cytokines from NK cells and others, complement and possibly humoral immunity. Thus, control of certain fungal infections requires the combined activity of the innate and specific immune responses.

Classical Cytotoxictcells

Cytotoxic T cells have direct antifungal activity against Cryptococcus neoformans and Candida albicans. This direct cytotoxicity effect often parallels the development of DTH responses. In some experimental systems, generation of cytotoxic lymphocytes requires the production of IL-2. Other lymphocyte subsets (CD4+ and CD56+ cells) are also cytotoxic in some forms of the DTH reaction (Levitze al., 1995).

Mast Cells And Basophils In Allergic Fungal Disease

Immediate hypersensitivity to C. albicans is also associated with cutaneous infection. In experimental models of cutaneous candidiasis, basophils accumulated in the skin and released histamine. The mechanism by which they are attracted was not determined though, it was independent of antibody, complement or direct chemotactic effects of the fungi (Sohnle et al. 1977 Greenburg et al. 1980). Since basophils are known to express the chemokine receptor for eotaxin, this chemokine may be involved (Uguccioni et al. 1997).

Binding of Haemcontaining Compounds

Haem is the most abundant carrier of iron in vertebrates because of the high haemoglobin content of erythrocytes. It is also released by tissue damage and by desquamation of epithelial cells making it an important source of iron for bacteria colonizing the gut. A large number of mainly pathogenic bacteria can use haem (Braun et al., 1998) as an iron source (Table 11.1), employing multiple strategies for obtaining haem iron. The most obvious is for the microorganism to take up residence within the erythrocyte and to digest host-cell haemoglobin. This is the well-known case of Plasmodium sp., the protozoa that causes malaria, but may also occur with the bacterial Bartonella spp., which includes B. henselae, that causes cat scratch disease. A variant on this strategy is used by Candida albicans, which binds to erythrocytes, causes their lysis, and utilizes their haemoglobin (Manns et al., 1994). Yet another strategy is to extract iron either directly from free haemoglobin or haem, or...

Diagnostic Tests

The tuberculin skin test remains the screening intervention of choice, despite its potential for false-negative results. Negative tuberculin skin tests on initial application have been noted in up to 25 of proven cases of active TB (9). A negative reaction to tuberculin increases with age and may be partly explained due to anergy. Moreover, the booster effect of skin-test reactivity to antigen increases in prevalence in the elderly population (26). Thus, it is essential that all older persons who receive a tuberculin skin test using the standard Mantoux method with 5 tuberculin units of Tween-stabilized purified protein derivative (PPD), and results read in 48-72 h be retested within two wk of a negative response (induration of less than 10 mm) to ensure recognition of a potentially false-negative reaction. Application of the second tuberculin skin test should ideally be accompanied by common dermal control antigens (e.g., candida, mumps) to determine the presence of cutaneous anergy....


Candida Species Candida organisms are yeasts, and several species cause human disease. Candida albicans accounts for the majority of human disease, and is responsible for mucocuta-neous disease (thrush, vaginitis), as well as invasive disease. However, other Candida species are being recognized as important pathogens. Candida tropicalis is responsible for up to one fourth of systemic candidiasis and may be more virulent than C. albicans in immunocompromised patients. Candida krusei and Candida glabrata (formerly


B Lymphocytes in Candida albicans The detection of B lymphocytes and protective Abs at vaginal level indicate their involvement in local anti Candida responses (de Bernardis et al., 2000). Furthermore, women with recurrent vaginal candidiasis have normal peripheral blood B and T lymphocyte subset levels (White et al., 1997). More recently, the main role of CD4 T cells in helping vaginal B cells produce Abs, has been envisaged in an experimental model of vaginal candidiasis (Santoni et al., 2002). It has been suggested that B cells also play a role in chronic mucocuta-neous candidiasis. In particular, an impaired B cell response to pokeweed mitogen has been reported in an immunosuppressed patient with chronic mucocutaneous candidiasis (von Bernuth et al., 2002). The role of B cells in systemic candidiasis has been demonstrated in an experimental model of B cell-deficient mice. These animals are unable to resist re-infection with certain fungi, such as C. albicans, despite their...


Mast cells and basophils are important cells in the proximal events associated with immediate hypersensitivity. Many fungal diseases are associated with this type of hypersensitivity however, literature establishing a firm role for immediate hypersensitivity in fungal disease, with the exception of mast cell and basophil degranulation in rhinitis and ABPM is lacking. Future work will be required to define a role in candidiasis. Information on the contribution of mast cells and basophils to host defense against fungi is also lacking, though future investigation of mast cells in the innate response to fungi and host defense is likely to be very fruitful.

Polyene Antifungals

Amphotericin is an antifungal polyene produced by cultures of Streptomyces nodosus and contains principally the heptaene amphotericin B (Figure 3.68) together with structurally related compounds, e.g. the tetraene amphotericin A (about 10 ), which is the 28,29-dihydro analogue of amphotericin B. Amphotericin A is much less active than amphotericin B. Amphotericin is active against most fungi and yeasts, but it is not absorbed from the gut, so oral administration is restricted to the treatment of intestinal candidiasis. It is administered intravenously for treating potentially life-threatening systemic fungal infections. However, it then becomes highly protein bound resulting in poor penetration and slow elimination from the body. After parenteral administration, toxic side-effects, including nephrotoxicity, are relatively common. Close supervision and monitoring of the patient is thus necessary, especially since the treatment may need to be prolonged. A liposome-encapsulated...


Certain fungi bind fragments of C3 which may allow attachment and phagocytosis by polymorphonuclear leukocytes, e.g. C3bi, C3d and C3dg, binding to Cryptococcus neoformans. However, whilst this is essential for the phagocytosis of encapsulated cryptococci, on its own, it is not sufficient since some species that bind to these fragments are resistant to phagocytosis. Other fungi may bind directly to complement receptors on the cell surface (e.g. Candida albicans).


When the above measures have failed or when complaints and dysfunction progressively worsen, steroid therapy at low dose appears to have dramatic results and is well tolerated. Prednisone (30 mg daily tapered to 10 mg daily during a 10-day period) is satisfactory for most patients. One may then switch to an alternate-day therapeutic schedule with further tapering as the patient can tolerate. The toxicity of low-level steroid maintenance therapy for several months is not yet known. Within days of initiation of steroid therapy, however, exacerbation of mucocutaneous candidiasis and reactivation of herpes simplex are seen. Usually, these abate with steroid taper and antifungal or antiherpes regimens, respectively. There is presently no role for cytotoxic drug therapy.

Phagocytic cells

Phagocytes have been shown to be particularly important in the control of some fungal infections. Normal, healthy individuals rarely suffer from fungal infections since such organisms are poorly invasive and their spread is limited by the innate immune response until they are eliminated by the adaptive response. Neutrophils may be particularly involved in this control of fungal infections they are thought to be primarily responsible for preventing the tissue invasion by, and the dissemination of, Candida spp.

Fungal arthritis

Candidiasis causes hematogenous septic arthritis in immunosuppressed hosts. Two-thirds of patients present acutely, 40 have multiple joint involvement, and 65 have evidence of osteomyelitis. 2. Treatment of blastomycosis, coccidioidomycosis, histoplasmosis, and sporotrichosis can be successful with oral imidazoles. Candidiasis is treated with IV amphotericin B. Surgical debridement is often necessary to eradicate fungal infection.

Fungal Endocarditis

Fungal endocarditis (FE) is rare and predominately occurs in hospitalized patients, in immunocompromised patients, in patients with prosthetic valves, or IVDA (50-53). Candida spp. and Aspergillus spp. cause the majority of FE however, other non-albi- cans Candida, Cryptococcus spp., Histoplasma spp., and Coccidiomyces spp. may be etiologic (51,53). Despite available antifungal therapy, mortality remains between 56 and 94 (51). Factors predisposing patients to the development of FE include widespread and prolonged use of antibiotics, invasive diagnostic procedures, previous bacterial endocarditis (BE), chemotherapy, and open-heart surgery (51-53). The current recommendations for the treatment of FE are surgical replacement of the involved valves with adjunctive antifungal therapy (50,52). Amphotericin B (AmB) is the antifungal agent of first choice, and many advocate the concomitant use of flucytosine or rifampin as synergistic agents. Intravenous fluconazole is used infrequently...

C CFU assay

1 Add 0.1 ml of Candida suspension (containing 1 x 10 yeasts) to wells containing washed monocytes macrophages (effector-to-target ratio 10 l)a and to six wells not containing macrophages to be used as control cultures. 3 Incubate the plates containing macrophages and Candida for 3 h at 37 C. 5 Stop the intracellular Candida killing by lysing the phagocytic cells with 20 xl well of a solution of 10 Triton X-100 in water. 9 Express the results as the percentage of anti-Candida activity according to the formula Protocol 9 describes a method for assessment of extracellular killing of Candida (hyphal form) using the (3-(4,5-dimethy MTT colorimetric assay.

The Nrampl Gene

The first gene to be discussed is Nramp1. This acronym describes 'natural resistance-associated macrophage protein 1'. This gene was formerly known as the Bcg gene, because it confers resistance to Mycobacterium bovis (Bcg strain) in inbred mice during the initial phase of infection (Gros etal., 1981). Subsequently, when it was found that the same gene controls innate resistance susceptibility not only to several Mycobacteria species but also to other intracellular pathogens, such as Salmonella typhimurium and Leishmania donovani, the gene was renamed Bcg Ity Lsh. More recently, the same gene in the mouse was found to control, at least to some extent, resistance to infection caused by some other microorganisms as well, as shown in Table 11.3. It should be noted that Mycobacterium tuberculosis does not belong to this list (North and Medina, 1998). When a candidate for this gene was found on the mouse chromosome 1, it was designated Nramp1. It encodes a 548 amino-acid protein with 10 to...

Primary Pyodermas

Superficial skin infections, also called primary pyodermas, are the most common skin infections occurring in all age groups. These include impetigo, folliculitis, furuncles, carbuncles, and paronychia. Most of these infections are caused by group A streptococci or by Staphylococcus aureus. Pseudomonas aeruginosa is a cause of hot tub folliculitis, an infection associated with recreational use of contaminated whirlpools and hot tubs resulting in a self-limited pruritic papular eruption in a characteristic bathing suit distribution. Some cases of folliculitis and paronychia are caused by Candida albicans. pyoderma Group A streptococci Candida spp.


The new azole drugs represent an exciting advance for the treatment of serious fungal diseases (29,30). For the first time, oral agents with reliable efficacy are now available for the treatment of several of the fungal diseases. Fluconazole is a relatively nontoxic drug that has good efficacy in the treatment of Candida and some other fungal infections. It is available in both an oral and an intravenous form. Itraconazole has a broader spectrum of activity, including activity against some Aspergillus organisms, as well as Candida, Blastomyces, and Histoplasma. New azole drugs such as voriconazole appear promising. Azoles have effects on the P450 system, and other medications should always be reviewed to prevent adverse drug interactions. Candidiasis Guidelines for the treatment of mucocutaneous candidiasis have been published by the American Academy of Dermatology (21). Thrush due to Candida spp. can be treated with many different agents, including clotrimazole troches, nystatin...


This fungus attacks members of the mustard family of plants and is known as a white rust. Both asexual and sexual reproduction occur. In asexual reproduction, chains of multinucleated sporangia are cut off from the end of a hypha and are dispersed in the air. When the sporangia break open, each nucleus emerges as a biciliated spore. Note that rather than dispersing spores directly, Albugo Candida disperses sporangia. The spores are ciliated when they emerge from the sporangium, but soon lose their cilia, come to rest, and develop into new mycelia. Figure 18-7 Albugo Candida. In asexual reproduction, chains of sporangia break away from the hyphae. When mature, the sporangium ruptures, releasing zoospores, which swim about for a time, lose their cilia and grow into a new mycelium. In sexual reproduction, fertilization occurs when the male gamete of the antheridium penetrates the oogonium to fertilize the egg cell. The zygospore thus formed produces...


Bacterial vaginosis (BV) and candidiasis are not sexually transmitted infections, but may arise in older women because of the changes in the vaginal microflora that occur in the postmenopausal state. Because these conditions are not STDs, they are not discussed further here, but the reader is referred to the STD Treatment Guidelines for discussion on the diagnosis and treatment (10). Trichomoniasis, caused by Trichomonas vaginalis, is an STD, which in women can infect the vagina, cervix, urethra or bladder. Trichomoniasis is not a reportable disease, so accurate data on the incidence of this infection in older women are not available. Common signs due to trichomonia-sis include abnormal discharge, which is often discolored and or frothy, vaginal erythema, and punctate cervical hemorrhages. Symptoms include discharge, itching, or burning of the vagina or vulva, but occasionally women will present with predominantly urethral complaints, such as frequency, urgency, or dysuria....

The Clinical Problem

Cytomegalovirus, HTLV-1, others Fungal (Candida, Aspergillus, others) Non-infectious Involving eye alone Pars planitis Idiopathic vitritis Idiopathic retinal vasculitis Idiopathic multifocal retinochoroiditis Sympathetic ophthalmia White dot syndromes Histoplasmosis-like disease Associated with systemic disease Behfet's disease Sarcoidosis

Gram Negative Fungus

Fungal UTI, an increasingly frequent problem, is generally limited to hosts with an obvious predisposing factor such as diabetes mellitus, antibiotic therapy, and or indwelling bladder catheter use (53). Candida species predominate overwhelmingly as the causative agents, with Aspergillus and other fungi only rarely causing UTI, and then only in profoundly immunocompromised hosts. The great majority of fungal UTIs are asymptomatic and, like catheter-associated UTI (which many fungal UTIs are), require no specific diagnostic testing or antifungal therapy B (53-57). Although the morbidity and mortality associated with funguria are considerable, this is due primarily to the comorbid conditions that are commonly present in patients who develop funguria (53,54). Complications attributable to fungal UTI per se are rare (53,58). When treatment is judged to be necessary because of clinical manifestations of infection, fluconazole is usually the treatment of choice A (53,59-61). It should be...


DC-SIGN (CD209) is a type II CLR that contains one CRD (Geijtenbeek et al. 2000a). It functions as both cell adhesion and pathogen receptor, is mainly expressed by immature DCs, but can also be detected on tissue resident alveolar and decidual macrophages (Soilleux et al. 2002) and on macrophages in normal lymph nodes (Granelli-Piperno et al. 2005). DC-SIGN mediates contact between T lymphocytes and DCs by binding to ICAM-3 (Geijtenbeek et al. 2000a) and between DCs and neutrophils by interacting with CD11b CD18 (van Gisbergen et al. 2005). Furthermore, DC-SIGN mediates rolling of DCs on endothelial cells by binding to ICAM-2 (Geijtenbeek et al. 2000b). As pathogen receptor, it recognises various microorganisms such as HIV, Mycobacterium tuberculosis, Helicobacter pylori, Leishmania mexicana, Schistosoma mansoni, Candida albicans and Aspergillus fumigatus (reviewed in Cambi et al. 2005). DC-SIGN achieves ligand specificity not only by binding primary mannose groups, but also by...

Suspected Discitis

When an unusual infection is considered (i.e., tuberculosis or a fungus), the use of an automated biopsy becomes even more compelling. Yu et al.16 described two cases in which automated biopsy results were used to diagnose unusual infections. They described two patients, one of whom was diagnosed with Candida discitis and the other with tuberculosis. Their article emphasized the large sample obtained with the automated biopsy, allowing histological identification of both infections by microscopy, and the initiation of specific therapy without having to wait for cultures. These authors also stressed the usefulness of automated biopsy for the debridement and treatment of infected discs. Both patients received immediate symptomatic relief after removal of large amounts of infected disc material.


Nemunaitis and collaborators (45,46) used M-CSF in doses ranging from 100 to 2000 g m2 day as an adjunct to antifungal therapy in 24 patients with bone marrow transplants complicated by invasive fungal infections. Of these patients, 25 resolved their infection, 50 could not be evaluated for judging the efficacy of the intervention, and 25 did not respond (45). In a larger follow-up study, bone marrow transplant patients with fungal infections treated with M-CSF and antifungal therapy had significantly improved long-term survival compared with historical controls treated with antifungal therapy alone (46). The results suggest that benefits of adjunctive M-CSF therapy occur primarily in the subset of patients with Candida infections (46). This encouraging study suggests the need for


Fungal superinfections commonly occur in the vagina, mouth, and anal and genital areas. Symptoms include lesions of the mouth or tongue, vaginal discharge, and anal or vaginal itching. Pseudomembranous colitis is a common bacterial superinfection candidi-asis or moniliasis is a common type of fungal superinfection.


Aspergillus Candida Cryptococcus Pseudomonas aeruginosa Immunosuppressed individuals are at risk for developing fungal infections of the skin and soft tissue. Ecthyma gangrenosum, a rapidly developing necrotic ulcer, is most often due to bacteremic P. aeruginosa infection and occurs predominantly in neutropenic patients. Occasionally, Aeromonas, Candida spp, and other Gram-negative bacilli can produce similar lesions.

Extreme physiology

Springtails (collembola) are common inhabitants of soil. They have very permeable cuticles which show little resistance to water loss. As the soil dries out, the springtail is at risk of losing water and of dying, since only a few springtails can survive anhydrobiotically. Folsomia candida is a common soil collembolan that can tolerate prolonged exposure to soils at 98.2 per cent relative humidity. The animal would be expected to lose water in soils below 100 per cent relative humidity. The springtail prevents this by producing high concentrations of glucose and myoinositol (a sugar alcohol). This raises its internal osmotic concentration sufficiently to arrest water loss to the environment. The springtail then starts to reabsorb water from the surrounding atmosphere. This enables it to remain active in the root zone of plants through a similar range of drought intensities tolerated by the plants themselves.


Miconazole is contraindicated in patients with known hypersensitivity to the drug. The drug is given cautiously in cases of chronic or recurrent candidiasis. With recurrent or chronic candidiasis the patient may have underlying diabetes. Recurrent or chronic candidi-asis requires an evaluation for diabetes. The drug is used cautiously during pregnancy (Category C). If used during pregnancy, a vaginal applicator may be con-traindicated. Manual insertion of the vaginal tablets may be preferred. Because small amounts of these drugs may be absorbed from the vagina, the drug is used during the first trimester only when essential.

Types Of Infections

Candidiasis Candida spp. can cause superficial (mucocutaneous) or deep infections (17). Candi-dal infections are extremely common, ranging from oral thrush to disseminated disease. Thrush most often occurs in patients on steroids or chronic antibiotics and in immunocompromised patients, especially those with HIV infection. In addition to the classic creamy white coating of the tongue and oral mucosa, oral candidiasis can present as an atrophic form, as angular cheilitis, or as Candida leukoplakia. In immuno-compromised patients, Candida esophagitis can occur and usually presents with odynophagia. In HIV patients, painful swallowing can often be treated with an empiric course of antifungal therapy, reserving diagnostic workup for patients who fail. Candida vaginitis is an extremely common condition up to 70 of women will experience a yeast infection at some time in their lives (see Chapter 11, this volume). Severe and or recurrent disease may signal underlying diabetes mellitus or HIV...

Medical Management

Patients who have evidence of purulent secretions at surgery are advised to take a broad-spectrum antibiotic with anaerobic cover for 2 weeks, unless a culture suggests a different spectrum of sensitivity. Patients are advised that they may have loose stools toward the end of the course of treatment. Women are warned that they may get vaginal thrush toward the end of treatment and require an antifungal pessary. They are also warned that antibiotics can interfere with the absorption of the contraceptive pill.


A) Schematic representation of phagocytosis. Engaging of phagocytic receptors leads to particle binding and signalling for cytoskeletal rearrangements. This leads to the formation of a so called phagocytic cup that results in membrane engulfment of the particle. Once a phagosome is formed it matures by fusion and fission with early endosomes, late endosomes and lysosomes, sequentially. During this process the pH of the phagosome is lowered from 6 to around 4.5. Phagocytic signalling cascades also stimulate secretion of H2O2, NO and TNFa. B) Candida albicans phagocytosis by RAW264.7 macrophages. The cells were stained for actin with TRITC phalloidin (red) and for endosomes and lysosomes with LAMP-1 (green). The first yeast is taken up in a phagosome where the lysosomes have fused (asterisk). The second yeast is in the process of being phagocytosed and there is a clear phagocytic cup present (arrow) (See Color Section.) Figure 2. Phagocytosis. A) Schematic...

Cd8 Lymphocytes

CD8 Response in Candida albicans The role of CD8 T cells has been studied particularly in mucosal C. albicans infections. In vaginal candidiasis, the importance of CD8 T cells in participating to local immune response is not clear. Indeed it has been suggested that CD8 cells could play a marginal role in anti-Candida immunity at the vaginal level (Santoni et al., 2002). Moreover, a considerable and persistent increase of CD8 T cells in vaginal candidiasis has been observed, but their role has not yet been defined (Ghaleb et al., 2003). A controversial role for CD8 T cells has been reported in oropharyngeal candidiasis, in a mouse experimental model and in HIV positive subjects. In the mouse experimental model, depletion of CD4, but not CD8, prolonged infection in the compromised host (Farah et al., 2001 Farah et al., 2002). Human studies in HIV positive and negative subjects provide convincing evidence on the important role of CD8 T cells in mucosal host defense against...

The lips

Angular stomatitis, consisting of painful inflamed cracks at the corners of the mouth, is often caused by ill-fitting dentures allowing saliva to dribble out of the mouth, followed by infection with Candida albicans. Angular stomatitis may also be due to deficiency of iron or riboflavine.

Cd4 Lymphocytes

T helper immune response in Candida albicans response in systemic candidiasis, appears to apply mainly to the development of resistance to re-infection (Mencacci et al., 1998b Mencacci et al., 1998a). Local infection. The role of T cells in local candidiasis is often controversial and not well defined. Regarding vaginal infections, studies by Fidel's group illustrated a lack of a protective role of T cells against C. albicans vaginitis. This assertion was due to the evidence that most T cell-immunodeficient or knockout mice had a vaginal fungal burden similar to that of wild-type strains (Wormley et al., 2003). In support of the missing T cell involvement at vaginal level, they demonstrated that following intravaginal challenge with Candida Ag in adult women, there was no evidence of local immune stimulation, including changes in Th (Fidel et al., 2003). A role for oral and vaginal epithelial cells in retarding or arresting the growth of C. albicans, has been described...


C., and Kozinn, P. J. (1976) Candida esophagitis. A prospective study of 27 cases. Gastroenterology 71, 715-719. 25. Wise, G. J., Goldberg, P., and Kozinn, P. J. (1976) Genitourinary candidiasis diagnosis and treatment. J. Urol. 116, 778-780.


Staphylococcus aureus is the predominant pathogen in right-sided IE, both in IVDA and other patients. Candida spp. have also been implicated as etiologic agents in both groups of patients. Gram-negative IE occurs more frequently in IVDA (2,4,7,9). In contrast, left-sided valvular structures are most often targeted by streptococci, especially S. viridans. S. aureus and enterococci are also frequently isolated pathogens. Enterococci are most likely among elderly patients (1,2,7,8,12,19). Recently, antibiotic-resistant microorganisms have emerged as an important cause of IE. The pathogens that have been particularly problematic are S. aureus, S. pneumoniae, Enterococcus spp., and Candida spp. Rates of penicillin resistant pneumococci have dramatically increased during the 1990s, and resistance levels of more than 40 are now reported in most regions of the United States (31). Although pneumococci are not a predominant cause of IE, mortality associated with infection is high (32).


A fungus that infects the vulva and vagina is Candida albicans, causing candidiasis. There is vaginitis, a thick, white, cheesy discharge, and itching. Pregnancy, diabetes mellitus, and use of antibiotics, steroids, or birth control pills predispose to infection. If the infection is recurrent, the patient's partner should be treated to prevent reinfections. Antifungal agents (mycostatics) are used in treatment.

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