archives@tulane.edu / In order to develop better therapeutics and treatment strategies for tuberculosis (TB) infection, it is imperative to understand interactions that occur in the host in response to the bacilli that contribute to disease progression. Modeling of TB in simple animal models such as mice and zebrafish is often incomplete as there are evolutionary differences, as well as structural issues, that reduce the faithfulness to human TB infection. The non-human primate model of TB infection provides the added benefit of providing a long-established model of SIV infection that recapitulates HIV infection in humans and has been expanded to model TB/HIV co-infection. Here, we have sought to identify correlates of protection in TB and TB/SIV co-infection using rhesus macaques. In the first experiment, we used two strains of Mycobacterium tuberculosis (Mtb), CDC1551 and Erdman, to investigate strain-specific mechanisms of virulence. As increased virulence of Mtb Erdman was associated with excess inflammatory responses, we sought to evaluate a host-directed therapeutic in a lethal challenge model of Mtb CDC1551 infection. We found that use of a type I interferon antagonist significantly improved host survival in the absence of antibiotic treatment and survival was associated with the presence of increased levels of granzyme B producing T cells. A major producer of granzyme B, mucosal-associated invariant T (MAIT) cells was investigated in Mtb/SIV co-infection, but was found to not contribute to protection in TB or TB/SIV. In order to further expand our model of Mtb/SIV co-infection, we co-infected latent Mtb-infected rhesus macaques with a non-pathogenic strain of SIV, SIVmac239ΔGY, and administered a CD4-depleting antibody, CD4R1, in place of SIVmac239 co-infection. Using SIVΔGY, we found that virulent viral replication was necessary for TB reactivation. Using both SIVΔGY and antibody-mediated CD4+ T cell depletion, we found that immune responses are disregulated in Mtb/SIV reactivators in a divergent manner, illustrating the presence of SIV-dependent factors that contribute to TB/SIV reactivation. Overall, these results indicate that immune mechanisms, especially those of inflammation, are significant in determining host outcomes. Developing ways to better control inflammation are necessary to supplement antibiotic treatment and cure TB. / 1 / Allison Bucsan
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_87914 |
| Date | January 2018 |
| Contributors | Bucsan, Allison (author), Kaushal, Deepak (Thesis advisor), School of Medicine Biomedical Sciences Graduate Program (Degree granting institution) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | electronic, pages: 222 |
| Rights | No embargo, Copyright is in accordance with U.S. Copyright law. |
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