Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids

Abstract

The evolutionary survival of Mycobacterium tuberculosis, the cause of human tuberculosis (TB), depends on its ability to invade the host, replicate, and transmit infection. At its initial peripheral infection site in the distal lung airways, M. tuberculosis infects macrophages which transport it to deeper tissues1. How mycobacteria survive in these broadly microbicidal cells is an important question. Here we show that M. tuberculosis, and its close pathogenic relative Mycobacterium marinum, preferentially recruit and infect permissive macrophages while evading microbicidal ones. This immune evasion is accomplished by using cell surface associated phthiocerol dimycoceroserate (PDIM) lipids2 to mask underlying pathogen-associated molecular patterns (PAMPs). In the absence of PDIM, these PAMPs signal a toll-like receptor (TLR)-dependent recruitment of macrophages that produce microbicidal reactive nitrogen species. Concordantly, the related phenolic glycolipids (PGL)2, promote recruitment of permissive macrophages via a host chemokine receptor 2 (CCR2)-mediated pathway. Thus, we have identified coordinated roles for PDIM, known to be essential for mycobacterial virulence3 and PGL, which (along with CCR2) is known to be associated with human TB4,5. Our findings also suggest an explanation for the longstanding observation that M. tuberculosis initiates infection in the relatively sterile environment of the lower respiratory tract, rather than in the upper respiratory tract, where resident microflora and inhaled environmental microbes may continually recruit microbicidal macrophages through TLR-dependent signaling.

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

“…Studies performed in zebrafish model showed that the environment induced by mycobacterial infection stimulates the recruitment of highly motile macrophages in a matrix metalloproteases (MMP)-dependent manner, which is known to enhance the pathogenesis [43,44]. On the basis of these observations, we investigated whether cmMTB influences human monocyte-macrophages migration in different 3D environments that mimic tissues [45].…”

Characterization of the inflammatory phenotype of Mycobacterium avium subspecies paratuberculosis using a novel cell culture passage model

“…Our data suggest that MAP changes its phenotype during the stages of intracellular infection, and that these changes involve the alteration of whole cell-and cell wall-associated lipids. These changes are pertinent, as MAP has an abundant reliance on its lipid-rich cell wall for virulence and survival (Bansal-Mutalik & Nikaido, 2014;Cambier et al, 2014;Ehrt & Schnappinger, 2007). The upregulated genes we identified in this study are involved in a number of lipid-related processes.…”

Virulence Factors and Pathogenicity of Mycobacterium

“…PI3P is essential for phagosomes to acquire lysosomal constituents; it is involved in the docking of rab effector proteins early endosomal autoantigen 1 (EEA1) and hepatocyte growth factor-regulated tyrosine kinase (HRS) substrate, which are important for phagosome maturation [89]. Disruption of sapM in MTB resulted in a highly attenuated strain with an impaired ability to grow in the THP-1 macrophages as well as in the guinea pig tissues [33].…”

“…PDIM and PLG are major virulence factors of mycobacteria. PDIM and PGL are molecules required for bacterial duplication during the acute phase [33]. PDIM is involved in mycobacterial resistance to detergents, and also is linked with the permeability and envelope solidity [34].…”

“…However, non-opsonic phagocytosis of MTB results in higher intracellular survival, although it is difficult to assess if the engagement of specific receptor determines the course of infection [86]. MTB uses PDIM lipids to evade detection by TLRs, thereby preventing mycobacterial delivery into microbicide macrophages expressing iNOS [33]. Moreover, MTB actively blocks the phagosome maturation by their cell wall components or through the secretion of various macromolecules that interferes with this process, which enables bacterial survival in a non-acidified intracellular compartment [12].…”