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.
Highlights
Despite the strides made in the tuberculosis (TB) research field over the years, TB remains a major public health concern (1, 2)
While we observed a trend in decreased IL-8 release by neutrophils exposed to alveolar lining fluid (ALF)-M.tb fragments at all multiplicity of exposure (MOE) tested, the significance observed at an MOE of 20:1 and 40:1 prompted us to utilize the MOE 20:1 for all our subsequent studies
In contrast to these findings, ALF fragments failed to induce significant differences in tumor necrosis factor (TNF), IL-6, or IL-10 compared to 0.9% NaCl fragments over background levels of protein produced by naïve neutrophils
Summary
Despite the strides made in the tuberculosis (TB) research field over the years, TB remains a major public health concern (1, 2). Mycobacterium tuberculosis (M.tb) is transmitted primarily via the aerosol route and is delivered into the distal lung space. Our lab has shown that the lung microenvironment plays a role in altering the interaction between M.tb and host cells in the alveolar space (3, 4). We showed that the human lung mucosa, or alveolar lining fluid (ALF), contains hydrolases that significantly alter the M.tb cell wall surface (4). We have demonstrated that cell surface alterations on M.tb after exposure to human ALF enhance the killing capacity of phagocytes (3, 4). In addition to altering the M.tb bacterial surface, M.tb exposure to ALF releases M.tb cell wall fragments into the lung milieu (4). It is plausible that these released M.tb cell wall fragments may contact host cells in the lung space both prior to and during M.tb infection
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