Immunomodulation of alveolar epithelial cells by Mycobacterium tuberculosis phosphatidylinositol mannosides results in apoptosis

Abstract

During intracellular residence in macrophages, mycobacterial lipids, namely phosphatidylinositol mannosides (PIM) and lipoarabinomannans, are expelled in the lung milieu to interact with host cells. PIM include a group of essential lipid components of Mycobacterium tuberculosis (M. tb) cell wall. Given that PIM function as mycobacterial adhesins for binding to host cells, the present study explored the consequences of interaction of M. tb PIM with alveolar epithelial cells (AEC). A 24-h PIM exposure at a concentration of 10 μg/mL to AEC conferred cytolysis to AEC via induction of apoptosis, suggesting their potential to alter alveolar epithelium integrity. The results also reflected that type I like AEC are more sensitive to cytolysis than type II AEC. PIM-treated AEC exhibited significant production of reactive oxygen species (ROS) and an immunosuppressive cytokine transforming growth factor-β (TGF-β) in the culture supernatants. Although AEC displayed constitutive mRNA transcripts for toll-like receptors (TLR2 and 4) as well as chemokines (IL-8 and MCP-1), no significant change in their expression was observed upon PIM treatment. Collectively, these results offer insights into PIM potential as M. tb virulence factor that might promote mycobacterial dissemination by causing cytolysis of AEC via increased production of ROS and TGF-β.

The Mycobacterial Cell Envelope--Lipids

“…Inside the cells, Mtb releases significant amounts of proteins and lipids, among them TMM, TDM, PIM, PGL, PE, phosphatidylglycerol, CL, and ManLAM, that traffic within the cell and may be released through exocytosis (Russell et al 2002;Russell 2011). These molecules are not only taken up by bystander antigen-presenting cells, they also act as modulators of the function of the host cell and surrounding tissue, impacting the secretion of pro-and anti-inflammatory cytokines (e.g., PGL, TDM, mycolic acids, SL, PIM, LM, ManLAM, and lipoproteins), apoptosis (lipoproteins, PIM, ManLAM, and TDM), T-cell functions (ManLAM, DAT, and PAT), the induction of foamy macrophages (oxygenated mycolates and TDM), and granuloma formation (TMM, TDM, and ManLAM) (Daffé and Draper 1998;Jackson et al 2007;Gilleron et al 2008;Peyron et al 2008;Guenin-Macé et al 2009;Neyrolles and Guilhot 2011;Rajni et al 2011;Russell 2011;Vander Beken et al 2011;Li et al 2012;Sakamoto et al 2013;Vir et al 2013). Importantly, several Mtb lipids, including diacylated forms of SL, PIM, ManLAM, MPM, and mycolyl lipids, represent themselves as antigens for immune recognition and are presented to T lymphocytes by MHC-I-like molecules of the CD1 family (Matsunaga and Sugita 2012;Arora et al 2013;Ly et al 2013;Van Rhijn et al 2013).…”

Alveolar Epithelial Cells in <b><i>Mycobacterium tuberculosis</i></b> Infection: Active Players or Innocent Bystanders?

“…While most reports have focused on M.tb -induced necrosis in ATs [2;4;8;9;11;17;18], recent work has shown that infection of ATs may also result in apoptosis [17;19]. M.tb infection can result in the expression of apoptotic cell markers leading to efferocytosis by resident macrophages [20], which would help to resolve excess inflammation and control further infection.…”

“…In particular, the M.tb cell wall lipids and lypoglycans [specifically phosphatidyl- myo -inositol mannosides (PIMs) and mannose-capped lipoarabinomannan (ManLAM)] have been shown to result in epithelial cytotoxicity [19]. It is interesting to note that ManLAM induces expression of the antimicrobial peptide HβD-2, showcasing two vastly different immune responses following antigen exposure [27].…”

“…It is interesting to note that ManLAM induces expression of the antimicrobial peptide HβD-2, showcasing two vastly different immune responses following antigen exposure [27]. Additionally, PIM exposure induces AT cytotoxicity and TGF-β production [19]. …”

“…In sharp contrast, M.tb uptake and compartmentalization into ATII vesicles reach full maturity and phenotypically resemble late rather than early endosomes. Although M.tb does not block phagosome maturation in ATIIs, M.tb -containing late endosomes within ATIIs fail to acidify thereby allowing M.tb to evade destruction and replicate [12;19]. Autophagy has also been suggested as an outcome following M.tb internalization by ATs; however, autophagy has been shown to promote M.tb growth within infected ATIIs suggesting that M.tb may have evolved to utilize AT cellular machinery to avoid elimination [12].…”