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BY TOLL-LIKE RECEPTORS"
Molecular Pathology and Immunology Program
MSc, 2008, Bangalore University, India
BSc, 2006, University of Pune, India
Thesis Advisor: Dr. Padmini Salgame, Ph.D.
Department of Medicine
Monday, October 24, 2016
1:00 P.M., MSB Room B610
Innate immune recognition of mycobacterial ligands stimulates the Toll-Like receptor (TLR) signaling pathways in macrophages and dendritic cells. In this study, we sought to understand the implications of TLR signaling during (1) vaccine mediated memory response and (2) primary immune response to Mycobacterium tuberculosis (Mtb). In the first part of the study, we demonstrate that in immuno-competent mice, vaccine mediated protection to Mtb challenge is intact, despite the absence of TLR2 and TLR9 signaling. To further dissect what innate immune component of the host could ameliorate vaccine induced protection, we modulated the inflammatory milieu by blocking IL-12 signaling. We provide evidence that IL-12 deficient mice demonstrate vaccine mediated protection to Mtb challenge compared to unvaccinated mice. Furthermore, memory T cells generated in response to vaccination in an IL-12 deficient host exhibit protective functions when transferred to an IL-12 sufficient host. Nonetheless, vaccinated IL-12 deficient mice are unable to mediate long term protection to Mtb challenge emphasizing the crucial requirement for IL-12 during the effector phase of the immune response.
Next, we demonstrate that during chronic Mtb-Erdman infection, unlike what we have reported with TLR2, TLR9 does not mediate bacterial control and pulmonary inflammatory responses. Our results suggest that only the absence of TLR2 and not TLR9 impairs the lung Treg recruitment, bacterial containment and inflammation. TLR9 redundancy extends to the clinical Mtb strain, HN878.
In the final part of this dissertation, we examined the contribution of TLR2 in host resistance to clinical Mtb strains. We found that in response to infection with Mtb-HN878 and Mtb-VT-3021, TLR2 is required early during acute infection to contain bacterial replication and inflammation induced pathology. Intriguingly, this mechanism was not mediated by Treg recruitment as observed with Mtb-Erdman. The increased bacterial numbers and extensive pulmonary pathology observed in Mtb-HN878 infected TLR2 deficient mice could be reversed to a WT phenotype by blocking neutrophil entry to the lungs. This alludes to the fact that during Mtb-HN878 infection, TLR2 could modulate a chemokine niche in the lung to limit neutrophil infiltration.
Together, this study provides a novel insight into the complex role of innate immune signaling by TLRs and IL-12 in regulating vaccine mediated memory T cell responses and host resistance to Mtb infection.