Here we propose three tenets to consider in understanding inflammation and infectious diseases susceptibility. First, recognition of MAMPs by evolutionarily conserved PRRs does not effectively distinguish commensals from pathogens. Second, the signaling pathways induced by PRR–MAMP interactions from commensals and pathogens are similar. Third, the effectors unleashed as part of the immune response to pathogens, including reactive oxygen and nitrogen moieties, antimicrobial peptides, and bioactive lipids, can also be unleashed in response to commensal MAMPS. As discussed in the examples above, these three principles pertain to innate immunity conserved in plants and animals, irrespective of an adaptive immune system.
What then distinguishes the response of the host to commensals as compared with pathogens? We suggest that commensals respond to host signals with their own signals that “retune” the inflammatory response. Commensals that trigger canonical PRR-mediated cascades respond in turn with reciprocal alterations in their MAMPs, including release of recycled or degraded cell wall fragments or biochemical metabolites (). In concert, the microbial products create a nonhostile stance with two effects on the host: First, various changes in the host cells deescalate the inflammatory milieu, and second, the host epithelial constituents adjust to shape a welcoming anatomic and/or biochemical niche. These host changes range from alterations in surface glycosylation, such as release of fucosylated glycans, to a more dramatic morphogenesis such as induction of plant root nodules or squid light organs. The resulting niche nurtures the commensal, thus establishing conditions for healthy mucosal homeostasis. In contrast, noncommensals lack the capacity to return the dialogue, and thus are eliminated from the suddenly unfriendly niche. Those pathogens that evolve the genetic material enabling migration into compartments or tissues where the host response is muted can avoid the initial response and thereafter become virulent agents. Similarly, individual hosts that are genetically deficient in the innate recognition and/or signaling that correspond to a commensal will be incapable of maintaining its niche and therefore become susceptible to invasion by an otherwise benign colonizer.
Figure 1. Examples of pattern recognition in ancient symbioses. Cross talk between eukaryotic host cells and bacterial commensals is necessary to establish homeostasis. (A) Rhizobial Nod factors (NFs) are recognized by legume PRRs. (B) Vibrio polysaccharides are (more ...)
This model offers a different interpretation of microbial pathogenesis. Like commensals, a pathogen first activates PRRs and triggers the downstream inflammatory host cell response. In some cases pathogens such as Legionella pneumophila
are poorly recognized due to weak PRR–MAMP binding (Neumeister et al. 1998
). In other cases the pathogen’s MAMPs are recognized, but it does not reciprocate with the appropriate signal that verifies its identity as a harmless colonizer or a beneficial partner. Thus, although pathogens and commensals compete to establish interactions with host cells, pathogen signals are incapable of inducing the necessary changes to make the host compartment hospitable. One of two outcomes ensues (): expulsion of the pathogen out of the niche in favor of an appropriate, fitter commensal (i.e., avirulent “failed infection”), or, for pathogens that have acquired certain virulence factors, invasion and persistence in host tissues. In the latter case, host inflammatory output increases as the host cell continues to probe what it perceives as a wayward commensal, akin to a person shouting louder and louder but receiving no comprehensible reply.
Figure 2. Pathogens are unable to engage in host–commensal dialogue. An alternate model of host–microbial interactions. (A) Commensals express MAMPs and additional signals in response to host inflammatory mediators that limit inflammation and promote (more ...)
This model can also explain the occasional instance of invasive disease caused by organisms that are members of the mucosal flora. If innate immunity exists to recognize harmless organisms and provide them a niche, the loss of the niche can lead to tissue damage and inflammation. For example, antibiotic exposure increases the risk of infection with colonizers like Pseudomonas
, and Clostridium difficile
that are relatively antibiotic-resistant. These organisms are present in low numbers among normal human microflora, but when an antibiotic kills off the more abundant species, it leaves epithelial real estate uncontested and allows overgrowth of these potential pathogens (Sullivan et al. 2001
). Conversely, healthy tissue is rich with commensal signals and their inflammatory consequences are suppressed.
Alternatively, pathogens that are not found in normal flora, such as Mycobacterium tuberculosis
, avoid shortening the life of their host and thereby increase the odds of horizontal transmission. To limit collateral immunopathology within their “hypoinflammatory niche,” these pathogens use molecular mimicry signals that fool the host into believing that commensalism has been established (Schnappinger et al. 2006
; Vance et al. 2009
). Tuberculosis kills millions of people each year, particularly the elderly, malnourished, and immunocompromised, yet only half of those exposed become infected, and in the majority of infections the bacteria remain latent for decades inside granulomas and never cause disease. Studies in mice and in cultured macrophages show that NO production by NOS is one of the first events that occur after phagocytosis of mycobacteria. Along with interferon-γ (IFNγ), NO, hypoxia, and low pH trigger the M. tuberculosis
DosR regulon, consisting of ~50 genes controlled by a single transcription factor that accompany the latency phase of infection. Because host deficiency of IFNγ (e.g., due to HIV or immunosuppressive therapy) or pathogen loss of the DosR regulon correlates with rapid progression to disease, it is theorized that these are important components of the host–pathogen dialogue required to sustain latent infection (Schnappinger et al. 2006
Mycobacterial “reactivation” disease can therefore be considered a breach of the latency agreement, a detente that allows both parties to benefit through limited bacterial growth and limited host inflammatory response. Beyond the advantage of reducing immunopathology, it is conceivable that sequestration of latent M. tuberculosis
in granulomas, with the accompanying high levels of circulating IFNγ, might endow the host with enhanced immune killing of other infectious agents (Barton et al. 2007
). In a Mycobacterium marinum
granuloma model, superinfecting mycobacteria “home” to preexisting granulomas, suggesting that these are metabolically favorable niches for the organisms within host tissues (Cosma et al. 2004
). Unraveling the molecular signals imparted by bacteria to induce hypoinflammatory niches might lead to powerful methods for reducing excessive inflammation.