Abstract
Pathogenic mycobacteria reside in macrophages where they avoid lysosomal targeting and degradation through poorly understood mechanisms proposed to involve arrest of phagosomal maturation at an early endosomal stage. A clear understanding of how this relates to host defenses elicited from various intracellular compartments is also missing and can only be studied using techniques allowing single cell and subcellular analyses. Using confocal imaging of human primary macrophages infected with Mycobacterium avium (Mav) we show evidence that Mav phagosomes are not arrested at an early endosomal stage, but mature to a (LAMP1+/LAMP2+/CD63+) late endosomal/phagolysosomal stage where inflammatory signaling and Mav growth restriction is initiated through a mechanism involving Toll-like receptors (TLR) 7 and 8, the adaptor MyD88 and transcription factors NF-κB and IRF-1. Furthermore, a fraction of the mycobacteria re-establish in a less hostile compartment (LAMP1-/LAMP2-/CD63-) where they not only evade destruction, but also recognition by TLRs, growth restriction and inflammatory host responses that could be detrimental for intracellular survival and establishment of chronic infections.
Highlights
Both Mycobacterium tuberculosis (Mtb) and pathogenic non-tuberculous mycobacteria like M. avium (Mav) have developed mechanisms to hijack the normal trafficking of phagosomes and use macrophages as a natural habitat and tools of spread in the host [1,2,3]
We present three key findings: 1) M. avium phagosomes are not arrested at an early endosomal stage, but rather mature normally into phagolysosomes from where a fraction of the bacteria escape and re-establish
Mice deficient in Myeloid differentiation primary response gene 88 (MyD88) are susceptible to infections with either Mtb or Mav [25,26], and we have recently demonstrated that negative regulation of inflammatory signaling by a cellular stress sensor, Keap1, facilitates intracellular growth of Mav in human primary macrophages [27]
Summary
Both Mycobacterium tuberculosis (Mtb) and pathogenic non-tuberculous mycobacteria like M. avium (Mav) have developed mechanisms to hijack the normal trafficking of phagosomes and use macrophages as a natural habitat and tools of spread in the host [1,2,3]. The process begins with the engagement of pathogen-recognition receptors (PRR) like Toll-like receptors (TLRs) and C-type lectins at the plasma membrane, initiating inflammatory signaling followed by phagocytosis and the gradual maturation of the phagosome into a phagolysosome, where bacteria are attempted digested [6]. TLR-ligand complexes are bridged by sorting adaptors like toll-interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP) or TRIF-related adaptor molecule (TRAM) to signaling adapter molecules such as Myeloid differentiation primary response gene 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF) in raft domains of various sub-cellular membranes. Signaling cascades culminate in the nuclear translocation of transcription factors like nuclear factor (NF)-κB and interferon regulatory factors (IRFs) and subsequent production of inflammatory mediators, type I interferons (IFNs) and antimicrobial programs [6,23,24]
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