Reassessing the Evolutionary Importance of Inflammasomes

Abstract

Inflammasomes monitor the cytosol for microbial contamination or perturbation and, thus, are predicted to provide potent defense against infection. However, the compendium of data from murine infection models suggests that inflammasomes merely delay the course of disease, allowing the host time to mount an adaptive response. Interpretations of such results are confounded by inflammasome-evasion strategies of vertebrate-adapted pathogens. Conversely, environmental opportunistic pathogens have not evolved in the context of inflammasomes and, therefore, are less likely to evade them. Indeed, opportunistic pathogens do not normally cause disease in wild-type animals. Accordantly, the extreme virulence of two opportunistic bacterial pathogens, Burkholderia thailandensis and Chromobacterium violaceum, is fully counteracted by inflammasomes in murine models. This leads us to propose a new hypothesis: perhaps animals maintain inflammasomes over evolutionary time not to defend against vertebrate-adapted pathogens but instead to counteract infection by a plethora of undiscovered opportunistic pathogens residing in the environment.

Figure 1. Inflammasomes readily detect opportunistic microbes while vertebrate-adapted pathogens evade

Numerous pathogens evade inflammasome detection by repression or modification of ligands (yellow arrows) or by direct inhibition with specific virulence factors (red arrows). Concomitantly, the beneficial effect of inflammasomes against such pathogens is typically blunted in vivo (see Table 1). In contrast, two environmental bacteria (Chromobacterium violaceum and Burkholderia thailandensis) are potently detected by inflammasomes (green arrows), and inflammasome defense in vivo is accordingly robust. Thus, we hypothesize that inflammasomes defend against environmental pathogens with specific virulence traits and may have limited utility against vertebrate-adapted bacterial pathogens, which have evolved to evade and/or inhibit them.