Primary Involvement of Pharynx and Peyer's Patch in Inhalational and Intestinal Anthrax

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Abstract
Bacillus anthracis causes three forms of anthrax: inhalational, gastrointestinal, and cutaneous. Anthrax is characterized by both toxemia, which is caused by secretion of immunomodulating toxins (lethal toxin and edema toxin), and septicemia, which is associated with bacterial encapsulation. Here we report that, contrary to the current view of B. anthracis pathogenesis, B. anthracis spores germinate and establish infections at the initial site of inoculation in both inhalational and cutaneous infections without needing to be transported to draining lymph nodes, and that inhaled spores establish initial infection in nasal-associated lymphoid tissues. Furthermore, we found that Peyer's patches in the mouse intestine are the primary site of bacterial growth after intragastric inoculation, thus establishing an animal model of gastrointestinal anthrax. All routes of infection progressed to the draining lymph nodes, spleen, lungs, and ultimately the blood. These discoveries were made possible through the development of a novel dynamic mouse model of B. anthracis infection using bioluminescent non-toxinogenic capsulated bacteria that can be visualized within the mouse in real-time, and demonstrate the value of in vivo imaging in the analysis of B. anthracis infection. Our data imply that previously unrecognized portals of bacterial entry demand more intensive investigation, and will significantly transform the current perception of inhalational, gastrointestinal, and cutaneous B. anthracis pathogenesis. Anthrax is caused by Bacillus anthracis, a bacterial pathogen that forms spores, dormant bacteria that are highly resistant to destruction. Infections initiate from the introduction of spores into airways or damaged skin, or from the consumption of contaminated food. Within the host, spores germinate, then bacteria secrete toxins that cripple the immune response and sheath themselves in a capsule that prevents them from being phagocytosed. We strove to determine in real space and time where and when spores introduced by these three routes of infection germinate and how bacteria subsequently disseminate in a mouse model. This was achieved through the development of light-emitting B. anthracis that could be tracked inside a living mouse. Contrary to current models, our studies indicated that spores germinated in situ in the skin, the intestines, and the nasal passages without needing to be transported to lymph nodes. Furthermore, bacteria disseminate from initial sites of infection in a similar fashion, first to the draining lymph nodes, then the spleen, and finally the lungs and blood. These findings imply that spore interactions with local sites of entry are critical in the development of systemic disease and that disruption of these interactions may offer new methods of anthrax prevention.