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"Household Contact Study to understand Mycobacterium tuberculosis transmission dynamics and protection against infection"

by
Sheetal Verma
Infection, Immunity and Inflammation Track
M.S. 2010, Case Western Reserve University, OH
B.Tech. 2006, Allahabad Agricultural Institute, India




Thesis Advisor: Padmini Salgame, PhD
Professor
Department of Medicine

Monday, February 27, 2017
1:30 P.M., MSB Room B610


Abstract

Infection with Mycobacterium tuberculosis (Mtb) causes divergent outcomes, leading to early resolution in some exposed individuals, while the majority of infected people remain asymptomatic (with “latent” bacilli) and about 5-10% of exposed individuals progress towards active tuberculosis (TB) disease. These latently infected individuals maintain the infectious foci and continue the cycle of infection-to-transmission.

In a study of 731 household contacts (HHC) of 124 infectious TB cases, we found heterogeneity of Mtb transmission within households. Index cases (with active TB disease) were categorized into high (HT) and low (LT) transmission groups based on the proportion of household contacts with a positive tuberculin skin test. The aims in this project leverage this already-established household contact study and allow investigation of the primary immunological responses induced during Mtb infection.

In the first part of this study, we demonstrated that Mtb strains coming from index cases with HT and LT profiles, exhibit distinct patterns of bacterial growth and lung pathology in mice. Further, we observed significant correlation between in vitro induction of eicosanoid derivatives and the transmission profile of the tested HT and LT Mtb strains. Additionally, using in vitro immune mediators as biomarkers we were able to predict the transmission outcome of the strains through a statistical regression model. These findings demonstrate that distinct early interactions between microbe and host innate immunity determine infection outcome. Our access to a collection of epidemiologically defined Mtb strains provides a rational framework for side-by-side comparison of the causal immune mechanisms that contribute to transmission.

Recognition of Mtb antigens by immune cells leads to the activation of innate antibacterial mechanisms and eventual induction of the adaptive immune response. Recently infected individuals (TST-converters) as well as those with latent TB, test positive for antigen reactivity on tuberculin skin test (TST) and the Interferon Gamma Release Assay (IGRA). Relevant to this study, there is also a sub-set of individuals who despite continuous exposure to Mtb remain persistently TST negative. In the second aim of this project, we outlined the key innate and adaptive inflammatory signaling pathways that are induced in the TST-negative and TST-converter groups, using a systems biology approach. Varied clinical outcomes during infection and limited understanding of early host response, add to the lack of accurate biomarkers that correlate with susceptibility to Mtb infection. Through this aim, we intend to address this knowledge gap and provide insights into host resistance mechanisms as seen in certain subsets of Mtb-exposed population. In turn, these correlates of protection may offer future relevance in terms of new treatments, targeted interventions and vaccine strategies.


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