Clinical isolates of Mycobacterium tuberculosis associated with different transmission phenotypes induce differential activation of the host immune response

In a Household contact (HHC) study conducted in Brazil, we have categorized “index” cases into High (HT) and Low (LT) transmission groups based on the number of their household contacts testing positive for the tuberculin skin test. A balanced induction of lipid mediators (Leukotriene B4, Prostaglandin E2 and Lipoxin A4) and Tumor necrosis factor (TNF) is essential for host defenses. Virulent Mycobacterium tuberculosis (Mtb) strains induce an imbalance in host lipid mediators to result in increased TNF production and activation of pro-necrotic pathway in macrophages. As necrosis is associated with increased growth of extracellular bacilli, we hypothesize that Mtb isolates derived from HT index cases exploit the TNF/necrotic axis in macrophages to increase the infectiousness in the index case, while LT isolates reduced necrosis but enhanced intracellular replication. Consistent with this, preliminary analysis of eight isolates confirms significantly higher TNF expression in human monocyte-derived macrophages infected with HT isolates in comparison to LT isolates. All isolates induced similar expression of IL-1β, IL-8 and IL-10. Ongoing experiments are evaluating the lipid mediator response, induction of pro-necrotic pathway, and bacterial growth in cells infected with HT and LT Mtb isolates. Together, the findings will provide insight into the role of Mtb strain variation and the resultant differing host immune response that contributes to their transmission phenotype.