Host-bacterial interactions determining the spectrum of Mtb transmission

Halting tuberculosis (TB) transmission by active case finding is challenging, requires substantial resources and is unaffordable in many countries with a high burden of TB. Host-directed therapeutics or prevention of infection (POI) vaccines that prevent Mycobacterium tuberculosis (Mtb) from establishing infection in exposed contacts could be potentially powerful tools to break the transmission cycle of Mtb and accelerate TB elimination. Significant gaps exist in our understanding of the biology of the spectrum of Mtb infection in exposed contacts. A household contact (HHC) study conducted by our group found that the transmissibility of Mtb from the index case was heterogenous using Interferon-Gamma Release Assay (IGRA) and tuberculin skin test (TST) positivity to infer infection. Households (HH) were categorized into High (HT), and Low (LT) transmission groups based on the proportion of HH contacts (HHC) with a positive (IGRA) and/or TST. Mtb strains from index cases of the HT and LT households were designated Mtb-HT and Mtb-LT, respectively. In susceptible mice, Mtb-HT and Mtb-LT strains induced distinct in vivo immunopathological responses. Furthermore, Mtb-HT and Mtb-LT strains induced distinct metabolic reprogramming of THP1 cells (preliminary data). Individuals who remain IGRA negative despite long-term and intense exposure to Mtb, are considered to have either resisted infection or cleared it and are referred to as ‘resisters’. Several immune mechanisms have been associated with resister phenotype, including responses mediated by macrophages, T cells and B cells. In preliminary studies, we found that a significant proportion of IGRA- HHCs were from LT-HH and had evidence of non-canonical antigen-specific T cell (NCAT) activation (measured as increased expression of activation markers) that was interferon (IFN) independent. This suggests that the current binary classification of exposed contacts as IGRA+ or IGRA- does not capture the complexity of the Mtb infection spectrum. Moreover, NCAT activation in IGRA- may be a protective phenotype as most TB arises from IGRA+ individuals. Epidemiological studies have shown a substantial association between human genetic variations and bacterial genotypes and the development of TB. Our overarching hypothesis is that Mtb-HT and Mtb-LT strains are phenotypically and genetically diverse, and the contribution of this inter-strain variability is at least as consequential to infection outcome in exposed individuals as is the contribution of inter-individual variability. Findings from our study will provide insights into mechanisms that regulate resistance to Mtb infection. Identification of mechanisms of resistance may lead to novel approaches for immunomodulatory therapy targeting host macrophage anti-microbial pathways and identifying genomic signatures segregating Mtb-HT and Mtb-LT may provide novel Mtb targets for developing POI vaccines that induce T-cell responses that activate macrophages or “train” the innate immune system to eliminate Mtb.