Epidemiologically characterized high and low transmission isolates of Mycobacterium tuberculosis induce distinct infection outcomes in mice

In a study of household contacts of infectious TB cases (HHC) conducted by us in Brazil, “index” cases were categorized into High (HT) and Low (LT) transmission groups based on the proportion of household contacts with a positive tuberculin skin test. In this study we wanted to determine whether Mycobacterium tuberculosis (Mtb) isolates with different transmission phenotypes diverged in their interaction with the host immune system. Initial in vitro analysis of 15 isolates from each group revealed significantly higher levels of TNF produced by macrophages infected with HT isolates. Two each of the HT and LT isolates were further characterized in vivo in the C3HeB/FeJ mice which develop lesions characteristic of human TB. Through the course of these infections, both the LT isolates exhibited a significantly higher bacterial burden and enhanced cellular recruitment to the lungs. Mice infected with the LT isolates exhibited early pulmonary inflammation that rapidly progressed to widespread consolidation of the granulomatous lesions. In contrast, mice infected with the two HT isolates formed organized cellular aggregates that contained abundant lymphocytes and foamy macrophages. Interestingly, pathological progression of the cellular aggregates into caseous fibrotic lesions, with abundant extracellular bacilli, was observed with one of the HT isolates. Furthermore, elevated levels of the pro-inflammatory cytokines IL-1β, IL-6 and IL-17 were found in the lungs of mice infected with the LT isolates. These results suggest that distinct interactions between microbe and host immunity might lead to differential trajectory in intracellular growth pattern and lung pathology that underlie differences in transmission potential.