Contained Mycobacterium tuberculosis infection induces concomitant and heterologous protection

Abstract

Progress in tuberculosis vaccine development is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although the M72/ASOE1 trial yielded encouraging results (54% efficacy in subjects with prior exposure to Mtb), a highly effective vaccine against adult tuberculosis remains elusive. We show that in a mouse model, establishment of a contained and persistent yet non-pathogenic infection with Mtb ("contained Mtb infection", CMTB) rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge. Protection is associated with elevated activation of alveolar macrophages, the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtbspecific T cells to the lung parenchyma. Systems approaches, as well as ex vivo functional assays and in vivo infection experiments, demonstrate that CMTB reconfigures tissue resident alveolar macrophages via low grade interferon-γ exposure. These studies demonstrate that under certain circumstances, the continuous interaction of the immune system with Mtb is beneficial to the host by maintaining elevated innate immune responses.

DNA methylomes derived from alveolar macrophages display distinct patterns in latent tuberculosis - implication for interferon gamma release assay status determination

“…While being a risk factor for developing active TB, LTBI has been shown to convey protection against M. tuberculosis reinfection, partly explained by heterologous immunity and the concomitant activation of the innate immune system 51,52 . The protective mechanisms of LTBI were associated with activation of alveolar macrophages and accelerated recruitment of M. tuberculosis -specific T cells to the lung and enhanced cytokines production 52 , compatible with our results where we showed an overrepresentation of pathways involved in TGF-β, NOD-like receptor (NLR) and chemokine signaling. The activation of the NLRP3 inflammasome, activated via NLRP3 promotor demethylation, has previously been identified as an important regulatory function in TB 53 .…”

T‐cell memory in tissues

“…This epigenetic programming allows the respective innate leucocytes to respond more rapidly to reencounters of the same or closely related immunogenic stimuli including reinfection. Such innate protection often lasts for months and is mediated by tissue‐resident immune cells, either long‐lived myeloid or innate lymphoid cell populations, that are already in the tissue, or innate leucocytes, such as NK cells and monocytes, that acquire tissue residency during the primary immune response [12–14] ( Fig . ).…”

Diagnosis of latent tuberculosis infection is associated with reduced HIV viral load and lower risk for opportunistic infections in people living with HIV

“…Chronic Herpes virus infection primes the murine immune system to provide antigen-independent beneficial effects [8]. Contained MTB infection itself protects against MTB rechallenge and heterologous challenges (L. monocytogenes and Melanoma metastases) through low-grade cytokinaemia and an augmented innate immune response [9].…”