Physiologic Factors Affecting Resistance

A great variety of physiologic factors affect resistance, the most important being the immune response, which is described in detail in Chapter 8. Little is known of many of the nonspecific factors in resistance, but age, nutrition, certain hormones, and cell differentiation play roles in a variety of viral diseases.

Viral infections tend to be most serious at the extremes of life. The high susceptibility of newborns to a number of viral infections is of considerable concern to pediatricians. It can also be exploited for the laboratory diagnosis of viral diseases. Thus the coxsackieviruses were discovered by the inoculation of suckling mice with fecal extracts, and infant mice are still useful for the isolation of arboviruses.

In laboratory animals the first few weeks of life are a period of very rapid physiologic change. For example, during this time mice pass from a stage of immunologic nonreactivily (to many antigens) to immunologic maturity. This change profoundly affects their reaction to viruses like lymphocytic choriomeningitis virus, which induces a persistent tolerated infection when inoculated into newborn mice, but an immune response in mice infected when over 1 week old. In humans, the umbrella of transplacental^ acquired maternal antibody protects the infant against many viruses for the first few months of life The importance of this cover is shown by the fact that viruses such as herpes simplex or varicella virus can cause lethal disease in infants who are born without maternal antibodies. Rotaviruses and respiratory syncytial viruses are the most striking examples of viruses that cause severe disease only in infants in the first year or so of life.

Older infants and children tend to suffer less severely from many virus infections than do premature infants or adults. For example, varicella virus, usually the cause of an uncomplicated disease in children, may produce severe pneumonia in adults, and mumps is complicated by orchitis much more often in adults than in children; poliovirus, hepatitis virus, and EB virus infections are all much more serious in adults.

Malnutrition

Malnutrition can interfere with any of the mechanisms that act as barriers to the replication or progress of viruses through the body. It has been repeatedly demonstrated that severe nutritional deficiencies will interfere with the generation of antibody and cell-mediated immune responses, with the activity of phagocytes, and with the integrity of skin and mucous membranes. However, often it is impossible to disentangle adverse nutritional effects from other factors found in deprived communities. Moreover, just as malnutrition can exacerbate viral infections, so viral infections can exacerbate malnutrition^ especially if severe diarrhea is a feature, thus creating a vicious cycle

Children with protein deficiency of the kind found in many parts of Africa are highly susceptible to measles. All the epithelial manifestations of the disease are more severe, and secondary bacterial infections cause life-threatening disease of the lower respiratory tract as well as otitis media, conjunctivitis, and sinusitis. The skin rash may be associated with numerous hemorrhages, and there may be extensive intestinal involvement with severe diarrhea, which exacerbates the nutritional deficicncy. The case-fatality rate is commonly 10% and may approach 50% during severe (amines.

Hormones and Pregnancy

There are few striking differences in the susceptibility of males and females to viral infections, except in the obvious instances of viruses with a predilection for tissues such as testis, ovaries, or mammary glands Pregnancy significantly increases the likelihood of severe disease following infection with certain viruses, an effect that was very pronounced in smallpox and is also seen in infections with hepatitis viruses, especially hepatitis E virus. Latent herpesvirus infections are often reactivated during pregnancy, contaminating the birth canal and leading to infection of the newborn.

The therapeutic use of corticosteroids exacerbates many viral infections and is contraindicated, notably in herpesvirus infections The precise mechanism is not understood, but corticosteroids reduce inflammatory and immune responses and depress interferon synthesis It is also clear that adequate levels of these hormones are vital for the maintenance of normal resistance to infection.

Fever

Almost all viral infections aie accompanied by fever. The principal mediator of the febrile response appears to be the cytokine interleukin-1 (previously known as endogenous pyrogen). InterJeukin-1 is produced in macrophages and is induced during immune responses It is found tn inflammatory exudates and acts on the temperature-regulating center in the anterior hypothalamus. hi vitro experiments have shown that antibody production and T-cell proliferation induced by interleukin-l are greatly increased when cells are cultured at 39°C rather than at 37°C

Fever profoundly disturbs bodily functions. The increased metabolic rate augments the metabolic activity of phagocytic cells and the rate at which inflammatory responses are induced, both of which might be expected to exert antiviral eflects. Exposing rabbits to high environmental temperatures greatly diminishes the severity of myxomatosis, usually a lethal disease; on the other hand, lowered environmental temperature increases the seventy of the disease produced by attenuated strains of myxoma virus.

Cell Differentiation

The replication of some viruses is determined by the state of differentiation of the cell The warts produced by papillomaviruses provide a classic example. Productive infection is not seen in the deeper layers of the epidermal tumor but occurs only when the cells become keratinized as they move to the surface layers. Basal cells contain 50-200 copies of viral DNA, but viral antigens and finally viral particles are produced only as the cells differentiate as they approach the surface of the skin Other examples involve cells of the immune system For example, measles virus, which does not replicate in normal (resting) peripheral blood lymphocyte cultures, does so after their activation by mitogen. HIV, integrated as a provirus in a resting T cell, cannot replicate until a cytokine induces synthesis of the NF-kB family of DNA-binding proteins, activating the cell to a permissive state (see Chapter 3).

The stage of the mitotic cycle may affect susceptibility. Autonomously replicating parvoviruses replicate only in cells that are in late S phase Most vulnerable are the rapidly dividing cells of bone marrow, gut, and the developing fetus. The human parvovirus B19 produces lytic infection ol dividing cells, the most sensitive target being the erythroid precursor cells. The arrest of erythrocyte production is not clinically apparent in hematologically normal individuals, but in persons with a shortened red cell survival time this arrest results in the transient profound anemia of aplastic crisis. Infrequently, this virus has also been recovered from stillborn edematous fetuses (hydrops fetalis)

Role of Interferons in Recovery from Viral Infection

Interferons arc cellular proteins that are induced in virus-infected cells and were first recognized because they interfered with the replication of viruses, although they are now known to have a variety of other physiologic effects. Their properties and mode of action were described in Chapter 5; here we consider the role of interferons in the body. It is difficult to determine which cell types, or even which tissues and organs, are responsible for most interferon production in vivo. Extrapolating from findings with cultured cells, one can probably assume that most cells in the body are capable of producing interferons in response to viral infection Certainly, interferons can he found in the mucus bathing epithelial surfaces such as the respiratory tract, and interferon is produced by most or all cells of mesenchymal origin. Lymphocytes, especially T cells and NK cells, as well as macrophages, produce large amounts of interferon « and y, and Ihey are probably the principal source of circulating interferon in viral infections characterized by a viremic stage

There are data supporting a central role for inteiferons in the recovery (if experimental animals and humans following at least some viral infections. Telling evidence that interferon can indeed be instrumental m deciding the fate of the animal following natural viral infection was provided in the early 1970s by Gresser and colleagues, who showed that mice infected with any of several nonlethal viruses, or with sublethal doses of more virulent viruses, die if anti-interferon serum is administered. More recent support is given by the elegant work on the Mx gene and the susceptibility of mice to influenza virus described in Chapter 5. Perhaps the most persuasive evidence, however, comes from a more recent study with transgenic mice. Mice transfected with the gene for human interferon 3 displayed enhanced resistance to pseu-dorabies virus, in proportion to the resulting concentration of circulating interferon. Serum from the transgenic mice also protected nontransgenic mice against the unrelated vesicular stomatitis virus, and this protection was abrogated by anti-interferon serum.

Although it is widely thought that interferons constitute the first line of defense in the process of recovery from viral infections, it would be naive to believe that it is (he most important factor in recovery. If this were so, one might expect that a systemic infection with any virus, or immunization with a live vaccine, might protect an individual, for a period at least, against challenge with an unrelated virus, yet this cannot be demonstrated. The evidence is somewhat stronger thai infection of the upper rcspiiatory tract with one virus will provide temporary and strictly local protection against others. Perhaps this distinction provides the clue that the direct antiviral effect of interferons is limited in both time and space. The main antiviral role of interferons may be to protect cells in the immediate vicinity of (he initial focus of infection for the crucial first few days.

Natural Inhibitors of Attachment of Virions to Cells

Blood, mucus, milk, and other body fluids contain a wide range of substances, some of which can coal particular viruses and impede their attachment to cells For example, influenza virions can be neutralized by mannose-binding lectins (conglutinin and "mannose-binding protein," MBP) found in the plasma of a number of animal species including humans, and in the lungs as pulmonary surfactant proteins, as well as by sialylated glycoproteins found in plasma and respiratory mucus Cytomegalovirus is often coaled with ^-microglobulin, as is HIV which also hinds HLA-DR (« and |3 chains) and CD4 found in soluble form in plasma as well as on lymphocytes. Antiviral fatty acids derived from lipids in breast milk have also been described 11 is not yet clear whether these observations relate to biologically important phenorn-

ena If they do, they may represent the tip of an iceberg of innate natural defense mechanisms which could, with the advent of recombinant DNA technology, be exploited for chemotherapeutic purposes.

Dual Infections

Viral infections at the respiratory tract often lower resistance to bacterial superinfection, notably in measles and influenza. Experimental studies in mice have shown that Staphylococcus aureus produces a protease which increases the virulence of influenza virus, presumably by cleavage of the HA molecule. Rotavirus infection of the murine gut is more severe in the presence of an enterotoxigenic strain of Escherichia coli.

Even more important are the secondary infections that complicate infections with immunosuppressive viruses. HIV, for example, so profoundly depletes the CD4+ cell population and damages cells of the monocyte lineage that AIDS patients usually die from any of a number of uncontrollable secondary infections These may be otherwise rare parasites such as Pneumocystis carimi and Toxoplasma gondii, or mycobacteria, including atypical mycobacteria and Mycobacterium avium Numerous other organisms, including rare fungi, the yeasts Candida albicans and Cryptococcus iieoformans, and herpesviruses, papillomaviruses, adenoviruses, and hepatitis viruses, are frequently isolated from these unfortunate individuals.

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