Abstract
For many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional responses to wild-type Mycobacterium tuberculosis (Mtb) and mutants that fail to damage the phagosomal membrane. We identified a set of genes with enhanced expression in response to the mutants. These genes represented a late component of the TLR2-dependent transcriptional response to Mtb, distinct from an earlier component that included Tnf. Expression of the later component was inherent to TLR2 activation, dependent upon endosomal uptake, and enhanced by phagosome acidification. Canonical Mtb virulence factors that contribute to phagosomal membrane damage blunted phagosome acidification and undermined the endosome-specific response. Profiling cell survival and bacterial growth in macrophages demonstrated that the attenuation of these mutants is partially dependent upon TLR2. Further, TLR2 contributed to the attenuated phenotype of one of these mutants in a murine model of infection. These results demonstrate two distinct components of the TLR2 response and identify a component dependent upon endosomal uptake as a point where pathogenic bacteria interfere with the generation of effective inflammation. This interference promotes tuberculosis (TB) pathogenesis in both macrophage and murine infection models.
Highlights
Innate immune recognition of invading pathogens, typically driven by the interaction of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs), requires recognition of microbial products at multiple subcellular sites
Principles elucidated with LPS and TLR4 are broadly thought to hold for other PAMP/PRR interactions, to date we have less insight into subcellular sites of signaling by other PRRs, the contribution of compartment-specific signaling in the response to complex microorganisms, and the pathogenic strategies employed to evade such compartmentalized signaling events
We compared the response to wild-type Mycobacterium tuberculosis (Mtb) with the response to phthiocerol dimycocerosate (PDIM) and ESX-1 mutants, with the goal of identifying facets of the macrophage response to Mtb impacted by phagosomal membrane damage
Summary
Innate immune recognition of invading pathogens, typically driven by the interaction of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs), requires recognition of microbial products at multiple subcellular sites. While some PRRs recognize PAMPs at a single site within the cell, other PRRs have the potential to bind PAMPs and initiate signaling from multiple sites. The mechanisms through which one PRR can recognize and respond distinctly to PAMPs at different subcellular sites is best understood for TLR4/LPS interactions [1,2,3,4,5]. Principles elucidated with LPS and TLR4 are broadly thought to hold for other PAMP/PRR interactions, to date we have less insight into subcellular sites of signaling by other PRRs, the contribution of compartment-specific signaling in the response to complex microorganisms, and the pathogenic strategies employed to evade such compartmentalized signaling events. TLR2, a receptor for bacterial cell wall lipoproteins, has been suggested to signal from the plasma membrane and endosomes, similar to TLR4. TLR2 activation has been described to induce a type I interferon (IFN) transcriptional response from endosomes [7,8,9,10]
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