Tularemia is caused by the bacterium Francisella tularensis, named for its discoverer, Edward Francis, and the place of its discovery, in 1911, in Tulare County, California. It had been associated with a variety of plague-like diseases in animals such as deer-fly fever, rabbit fever, and tick fever, among others, all of which are now grouped as various forms of tularemia. Humans can be infected by contact with F. tularensis in the wild, although such incidents are relatively rare, and humans do not readily transmit the resulting infection to others. Contact can result from handling of infected animals or through insect bites, but these infections are usually mild.
The most serious incidents of tularemia in humans come from inhalation of bacteria, often through handling of contaminated hay or other grains. "Inhalation tularemia" requires only a few bacteria, whereas infection through other routes usually requires exposure to millions of bacteria. If F. tularensis were to be used as a bioterrorism agent, it would almost certainly be in aerosol form. Because of the low incidence of inhalation tularemia in the United States, a large outbreak of this disease in a concentrated area would lead to an immediate suspicion of bioterrorism.
Tularemia was investigated by several countries between 1930 and 1970 as a potential biological warfare agent. The bacterium can be concentrated into a paste, which can be freeze-dried and then milled into a fine powder suitable for distribution through the air. A WHO study estimated that 50 kg of bacteria (about 110 pounds) in aerosolized form, spread over a population of 5 million people, would incapacitate about 250,000 people and cause nearly 20,000 deaths. The United States retained stocks of F. tularensis through the late 1960s, but these were destroyed in the general obliteration of such stockpiles in the early 1970s. Current military research with this microbe is restricted to defensive strategies.
Inclusion of F. tularensis by the CDC as a Category A bioterror-ism agent is due largely to its effectiveness when spread in aerosolized form. The initial signs of inhalational tularemia infection are no different from the signs accompanying most microbial infections. Most of what we know about the immune response to tularemia has been gleaned from studies of this disease in rodents. The course of infection and the resulting immune response in rats and mice appear to mimic closely the events occurring in human infection. F. tularensis, like Mycobacterium tuberculosum (chapter 6), invades and takes up residence in macrophages but manages to escape digestion and multiplies rapidly within the macrophage itself.
In the case of inhalation tularemia, the primary target is macrophages resident in the lungs, but the bacteria make their way to regional lymph nodes as well. The lung tissues become generally inflamed and can develop various forms of pharyngitis, bronchitis, and other forms of lung infection. One form or another of pneumonia is the most common cause of death in fatal cases. Tularemia is one of those diseases that have a "low index of suspicion" among doctors and laboratory personnel, which could also be a factor in its selection by bioterrorists.
Both innate and adaptive responses are mobilized in response to F. tularensis, but development of a vigorous adaptive response is absolutely essential to clearing an infection. Production of cytokines like IFN-g and TNF-a are critical during the early innate immune response and are probably provided by dendritic cells, macrophages, and perhaps NK cells. Interestingly, neutrophils are able to scavenge and kill F. tularensis; apparently the tricks used by this bug in escaping lysosomal destruction in macrophages don't work in neutrophils.
As would be expected for an intracellular parasite, B cells and antibody play little role in the ensuing adaptive response. Effective, long-term immunity is provided almost entirely by T cells, both through enhanced production of IFN-g and probably through direct T-cell-mediated killing as well, although there is little direct evidence for the latter in the current scientific literature.
There is a vaccine for tularemia, based on a live but relatively harmless strain of F. tularensis. But this vaccine is only marginally effective against inhalation tularemia, and it takes at least a week or two to build up a good level of protection after vaccination. In a bioterrorism attack using an aerosolized form of the bacterium, it is unlikely that this vaccine would be useful in protecting exposed individuals after the attack. Development of a more active vaccine, perhaps based on DNA (Chapter 7), should be a goal of those concerned with homeland security.
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