Mycobacterium tuberculosis cell wall released fragments by the action of the human lung mucosa modulate macrophages to control infection in an IL-10-dependent manner

Abstract

Mycobacterium tuberculosis (M.tb) , the causative agent of tuberculosis, is a major public health challenge facing the world. During infection, M.tb is deposited in the lung alveolar space where it comes in contact with the lung mucosa, known as alveolar lining fluid (ALF), an environment that M.tb encounters at different stages of the infection and disease. ALF is abundant in homeostatic and antimicrobial hydrolytic enzymes, also known as hydrolases. Here we demonstrate that ALF hydrolases, at their physiological concentrations and upon contact with M.tb, release M.tb cell envelope fragments into the milieu. These released fragments are bioactive, but non-cytotoxic, regulate the function of macrophages, and thus are capable of modulating the immune response contributing to the control of M.tb infection by human macrophages. Specifically, macrophages exposed to fragments derived from the exposure of M.tb to ALF were able to control the infection primarily by increasing phagosome-lysosome fusion and acidification events. This enhanced control was found to be dependent on fragment induced IL-10 production but also involves the STAT3 signaling pathway in an IL-10 independent manner. Collectively our data indicate that M.tb fragments released upon contact with lung mucosa hydrolases participate in the host immune response to M.tb infection through innate immune modulation.

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

“…Mtb infection induces the production of immunosuppressive cytokines including IL-10 to affect STAT3 activation. 66 After Mtb infection, IL-10 levels and STAT3 and pSTAT3 expression levels increase significantly in the first week. The production of IL-10 is strongly correlated with the expression of STAT3 and pSTAT3 proteins.…”

“…The inhibitory activity of Mtb would be reversed when IL-10 is neutralized through the addition of soluble IL-10 receptor. 66 The interaction of Mtb with differentiating monocytes rapidly activates the STAT pathway, which likely participates in IL-10 gene expression. 69 STAT3 activation leads to the inhibition of cytokines IL-6, IFN-γ, TNF-α and MIP-1β (macrophage inflammatory protein-1β).…”

Checks and Balances between Autophagy and Inflammasomes during Infection

“…Studies indicate that autophagy could also be subverted by M.tb to reside into an autophagosome that is not acidified [164]. Overall, the autophagy process depends on the activation status of Ser/Thr kinase Tor [165].…”

Integrating Lung Physiology, Immunology, and Tuberculosis

“…The importance of human ALF as a whole in determining the outcome of M.tb droplet deposition and subsequent M.tb infection is still uncertain. Recent studies indicate that M.tb exposed to human ALF is controlled more effectively by host phagocytes [30–32], potentially reducing tissue damage. This improved control is due to ALF-derived modifications of the M.tb cell wall during ALF exposure [30,32].…”

“…Recent studies indicate that M.tb exposed to human ALF is controlled more effectively by host phagocytes [30–32], potentially reducing tissue damage. This improved control is due to ALF-derived modifications of the M.tb cell wall during ALF exposure [30,32]. Human ALF contains a variety of homeostatic hydrolases secreted by resident alveolar host cells [6], including those producing surfactant [33], that resemble but are distinct from lysosomal enzymes [34].…”