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

Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis, is a major public health challenge facing the world. During infection, M.tbis 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.tbencounters 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.tbcell 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.tbinfection by human macrophages. Specifically, macrophages exposed to fragments derived from the exposure of M.tbto 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 interleukin-10 (IL-10) production but also involves the STAT3 signaling pathway in an IL-10-independent manner. Collectively our data indicate that M.tbfragments released upon contact with lung mucosa hydrolases participate in the host immune response to M.tbinfection through innate immune modulation.