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IMMUNE RESPONSE TO MYCOBACTERIUM TUBERCULOSIS
Julius Andrew Potian
B.A. 2000, Rutgers University
M.S. 2003, UMDNJ-Graduate School of Biomedical Sciences
Thesis Advisor: Padmini Salgame, Ph.D.
Department of Medicine
Monday, June 29, 2009
MSB B-610, 1:00 p.m.
Morbidity and mortality caused by the pulmonary pathogen Mycobacterium tuberculosis (Mtb) remains alarmingly high. It is well established that the protective immune response to Mtb is dependent on the host’s ability to initiate Th1 cellular responses. Clearly these studies provide tremendous insight into host protective mechanisms against tuberculosis (TB); nevertheless they do not take into account the affect that chronic co-endemic infectious agents may have on the development of Mtb-specific Th1 immunity in humans. Regions of the world with high incidence of TB are also endemic for helminthic diseases. Helminth infections generate a strong Th2 and T regulatory response in the host. Together with the fact that Th2/Tregulatory cytokines have suppressive effects on Th1 responses, it is highly likely that coinfections with helminths may impact on the pathogenesis of TB. In this study we test the hypothesis that parasitic infections alter host immunity to Mtb and modulate the course of tuberculosis disease. We developed a coinfection model to assess the ability of Nippostrongylus brasiliensis (Nb), a rat nematode adapted to the mouse model, to modify Th1 priming in vivo and determined the impact on acquisition of host resistance to Mtb infection. Our results showed that a comcominent Nb infection increased host susceptibility to Mtb infection. Coinfected mice displayed a transient increase in bacterial burden. In IL-4Rá -/- mice, coinfection restored bacterial burden to the level of WT Mtb-alone mice. Moreover, mice injected twice with Nb led to enhanced and exacerbated disease. The effect of Th2 cytokines was not at the level of Th1 polarization, since no difference was observed in Mtb-specific IFN- producing cells Furthermore, coinfection did not alter classical macrophage activation, but instead led to an early development of alternative activated macrophages (AAMs). In stark contrast, subsequent Nb infection during chronic Mtb infection did not lead to reactivation of disease. We conclude that Mtb-helminth coinfection leads to alternative activation of macrophages that heightens host susceptibility to Mtb infection.