In a study of household contacts (HHC), households were categorized into High (HT) and Low (LT) transmission groups based on the proportion of HHC with a positive tuberculin skin test. The Mycobacterium tuberculosis (Mtb) strains from HT and LT index cases of the households were designated Mtb-HT and Mtb-LT, respectively. We found that C3HeB/FeJ mice infected with Mtb-LT strains exhibited significantly higher bacterial burden compared to Mtb-HT strains and also developed diffused inflammatory lung pathology. In stark contrast, a significant number of mice infected with Mtb-HT strains developed caseating granulomas, a lesion type with high potential to cavitate. None of the Mtb-HT infected animals developed diffused inflammatory lung pathology. A link was observed between increased in vitro replication of Mtb-LT strains and their ability to induce significantly high lipid droplet formation in macrophages. These results support that distinct early interactions of Mtb-HT and Mtb-LT strains with macrophages and subsequent differential trajectories in pathological disease may be the mechanism underlying their transmission potential.

Mechanisms underlying variability in transmission of Mycobacterium tuberculosis strains remain undefined. By characterizing high and low transmission strains of M.tuberculosis in mice, we show here that high transmission M.tuberculosis strain induce rapid IL-1R-dependent alveolar macrophage migration from the alveolar space into the interstitium and that this action is key to subsequent temporal events of early dissemination of bacteria to the lymph nodes, Th1 priming, granulomatous response and bacterial control. In contrast, IL-1R-dependent alveolar macrophage migration and early dissemination of bacteria to lymph nodes is significantly impeded in infection with low transmission M.tuberculosis strain; these events promote the development of Th17 immunity, fostering neutrophilic inflammation and increased bacterial replication. Our results suggest that by inducing granulomas with the potential to develop into cavitary lesions that aids bacterial escape into the airways, high transmission M.tuberculosis strain is poised for greater transmissibility. These findings implicate bacterial heterogeneity as an important modifier of TB disease manifestations and transmission.

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The widespread emergence of antibiotic resistance including multidrug resistance in Gram negative (G-) bacterial pathogens poses a critical challenge to the current antimicrobial armamentarium. Antibody-drug conjugates (ADCs), primarily used in anti-cancer therapy, offer a promising treatment alternative due to their ability to deliver a therapeutic molecule while simultaneously activating the host immune response. The Cloudbreak® platform is being used to develop ADCs to treat infectious diseases, composed of a therapeutic targeting moiety (TM) attached via a non-cleavable linker to an effector moiety (EM) to treat infectious diseases. In this proof-of-concept study, 21 novel dimeric peptidic molecules (TMs) were evaluated for activity against a screening panel of G- pathogens. The activity of the TMs were not impacted by existing drug resistance. Potent TMs were conjugated to the Fc fragment of human IgG1 (EM) resulting in 4 novel ADCs. These ADCs were evaluated for immunoprophylactic efficacy in a neutropenic mouse model of deep thigh infection. In colistin-sensitive infections, 3 of the 4 ADCs offered similar protection as therapeutically dosed colistin while CTC-171 offered enhanced protection. The efficacy of these ADCs was unchanged in colistin-resistant infections. Together, these results indicate that the ADCs used here are capable of potent binding to G- pathogens regardless of LPS modifications that otherwise lead to antibiotic resistance and support further exploration of ADCs in the treatment of drug resistant G- bacterial infections.