Mycobacterium tuberculosis Cell Wall Fragments Released upon Bacterial Contact with the Human Lung Mucosa Alter the Neutrophil Response to Infection

Abstract

In 2016, the World Health Organization reported that one person dies of tuberculosis (TB) every 21 s. A host environment that Mycobacterium tuberculosis (M.tb) finds during its route of infection is the lung mucosa bathing the alveolar space located in the deepest regions of the lungs. We published that human lung mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e., interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release, and does not induce cytotoxicity. Unexpectedly, these ALF fragment-derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site.

Underestimated Manipulative Roles of Mycobacterium tuberculosis Cell Envelope Glycolipids During Infection

“…Nevertheless, these M. tuberculosis cell envelope glycolipid modifications also result in the release of M. tuberculosis cell envelope fragments to the milieu (164). Their implications in M. tuberculosis pathogenesis are starting to be elucidated, but studies have shown that these fragments further assist macrophages in controlling M. tuberculosis infection by further increasing phagosome-lysosome fusion events in an IL-10dependent manner (179), as well as drive neutrophils to control M. tuberculosis infection better by increasing their oxidative response (180).…”

Immune Responses to Bacillus Calmette–Guérin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?

“…All of these components are associated with the lung alveolar lining fluid (ALF) (199, 200). Studies from our laboratory have shown that some ALF components (i.e., hydrolytic enzymes or hydrolases) are capable of altering the cell wall of M.tb with two distinct outcomes, modifications on the M.tb cell wall exposing “ de novo ” motifs on the bacterium cell surface and the release of M.tb cell wall fragments to the lung milieu (201–204). The interaction of M.tb with human ALF reduces the amount of ManLAM and TDM by ~65 and ~40%, respectively, from the M.tb cell wall surface (201).…”

“…It is likely that as M.tb is deposited in the alveolar space it will encounter ALF hydrolases that will modify its cell wall prior to encountering host cells. These M.tb cell wall alterations consequently alter M.tb recognition by human phagocytes (201–204) with subsequent impact on Ag processing and presentation. One question that remains is whether these human lung mucosa-induced alterations to the M.tb cell wall during its natural path of infection could explain the reason why the protective immune response generated by BCG vaccination is inadequate against PTB.…”

A lung-on-chip model reveals an essential role for alveolar epithelial cells in controlling bacterial growth during early tuberculosis

“…The exact mechanisms of surfactant-mediated attenuation remain to be elucidated, but this work demonstrates a direct physical interaction that is a two-way street: Mtb surface lipids are actively removed while surfactant lipids coat the bacterial surface. These interactions are independent of the action of hydrophilic SP-A and SP-D proteins that have previously shown to interact with 10 Mtb surface lipids (39)(40)(41), and enzymes shown to modify the Mtb capsule (9,10), none of which are components of Curosurf. These components have been shown to be potent adjuvants for intranasal influenza vaccines (42), suggesting the possibility that pulmonary surfactant could be harnessed to generate improved therapeutics and host-directed therapies against the spread of TB.…”

“…The 'first contact' with a naïve host is therefore by default a single-cell interaction, where heterogeneous outcomes may determine the future course of 15 infection. Potential sources of heterogeneity include cell-to-cell differences in macrophage populations (5,6), infection of alveolar epithelial cells (7), and the action of pulmonary surfactant (8)(9)(10). These factors have not been characterized completely within the native setting in the lung, primarily because experiments in animal models (11) cannot provide information about the dynamics of host-Mtb interactions at this stage with sufficient spatiotemporal 20 resolution (12,13).…”