An emerging role for the innate immune system in Mycobacterium tuberculosis infection and disease

Tuberculosis (TB) remains the main cause of death from a single infectious agent (Mycobacterium tuberculosis, MTB) and the 10th leading cause of death overall worldwide. Multidrug resistance is rising globally. Understanding natural immunity against MTB is paramount to develop novel host directed approaches for the treatment of TB. T cell responses are used routinely for the diagnosis of MTB infection. However, the diagnostic value of specific T cells in peripheral blood is surprisingly poor in the context of active disease. The underlying mechanism for this clinical phenomenon is the recruitment of effector T cells from the peripheral circulation to the site of infection. These observations suggest that active TB disease is associated with a strong local T cell response, leading to the hypothesis that the interface between innate and adaptive immunity is defective during active TB. Therefore, we set out to investigate the role of the innate immune system in the context of MTB infection and active TB. In a novel in vivo MTB infection model, we discovered that the innate immune system is unable to recognize MTB early enough to prevent establishment of infection: instead of a pro-inflammatory response, MTB infection induces an anti-oxidant response governed by the transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2) in alveolar macrophages in vivo. The lack of an appropriate inflammatory response allows the pathogen to establish an infection within the host. Perturbing NFR2 lead to changes in the disease phenotype, suggesting that the early response to infection contributes to the outcome of infection. Next, we discovered that natural immunity against MTB in a model of contained MTB infection is associated with changes in the innate immune system leading to increased protection. Protection was associated with an early recruitment of specific effector cells to the parenchyma and early control of bacterial growth. These experiments showed that asymptomatic MTB infection provides concomitant immunity, a phenomenon typically ascribed to parasitic infections such as Malaria and Leishmania. Mechanistically, protection is mediated in part by low grade cytokinemia which rewires the transcriptional landscape of tissue resident macrophages and allows the host to respond faster to the re-infection with MTB. Independently, low grade cytokinemia provides protection against heterologous challenges, suggesting that the relationship between the host and MTB may have symbiotic aspects. Finally, we were able to increase the efficacy of antimicrobial agents by targeting innate cells. Every cell requires efflux pumps to maintain membrane fluidity and to respond to xenobiotic substances. For the first time, we discovered increased expression and activity of efflux pumps in the context of inflammation. By inhibiting the efflux pump expressed by the macrophage with the old antimalarial chloroquine, the effectivity of tuberculostatic treatment increases, without direct antimicrobial effects. In sum, these studies emphasize the central role of the innate immune system in the patho-physiology of active TB and potential therapeutic targets for the treatment of one of the most important infectious agents, MTB.