Abstract
Innate immunity plays a central role in resolving infections by pathogens. Host survival during plague, caused by the Gram-negative bacterium Yersinia pestis, is favored by a robust early innate immune response initiated by IL-1β and IL-18. These cytokines are produced by a two-step mechanism involving NF-κB-mediated pro-cytokine production and inflammasome-driven maturation into bioactive inflammatory mediators. Because of the anti-microbial effects induced by IL-1β/IL-18, it may be desirable for pathogens to manipulate their production. Y. pestis type III secretion system effectors YopJ and YopM can interfere with different parts of this process. Both effectors have been reported to influence inflammasome caspase-1 activity; YopJ promotes caspase-8-dependent cell death and caspase-1 cleavage, whereas YopM inhibits caspase-1 activity via an incompletely understood mechanism. However, neither effector appears essential for full virulence in vivo Here we report that the sum of influences by YopJ and YopM on IL-1β/IL-18 release is suppressive. In the absence of YopM, YopJ minimally affects caspase-1 cleavage but suppresses IL-1β, IL-18, and other cytokines and chemokines. Importantly, we find that Y. pestis containing combined deletions of YopJ and YopM induces elevated levels of IL-1β/IL-18 in vitro and in vivo and is significantly attenuated in a mouse model of bubonic plague. The reduced virulence of the YopJ-YopM mutant is dependent on the presence of IL-1β, IL-18, and caspase-1. Thus, we conclude that Y. pestis YopJ and YopM can both exert a tight control of host IL-1β/IL-18 production to benefit the bacteria, resulting in a redundant impact on virulence.
Highlights
Loss of YopJ alone results in reduced IL-1/ IL-18 secretion (Fig. 1B) and caspase-1 activation (Fig. 1A), despite an increase in pro-IL-1 and pro-caspase-1. Loss of both YopM and YopJ leads to a further increase in ASC/ caspase-1-dependent IL-1 and IL-18 secretion but an insignificant increase in caspase-1 activation compared with loss of YopM alone (Fig. 1, A, B, and D)
We found that YopE may play a part in triggering the IL-1 release that is inhibited by YopM (Fig. 1C)
IL-1 secretion is minimally altered by the absence of YopM unless YopJ is absent (Fig. 5B). These results suggest that the bacterial regulation of IL-1 release in dendritic cells (DCs) is markedly different from macrophages and neutrophils
Summary
T3SS, type III secretion system; NLR, NOD-like receptor; MOI, multiplicity of infection; BMDM, bone marrow-derived macrophage; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; TCR, T-cell receptor. Y. pestis YopM and YopJ Inhibit IL-1/IL-18 Production by a NOD-like receptor (NLR), such as NLRP3, NLRC4, or the non-NLR protein AIM2. This leads to recruitment and oligomerization of the adaptor protein ASC, which in turn recruits pro-caspase-1 dimers to be autoproteolyzed into the catalytically active p20 form. This process is normally accompanied by an inflammatory form of cell death called pyroptosis. We found a strain lacking both effectors to be significantly attenuated in a bubonic plague model in an IL-18/ IL-1/caspase-1-dependent fashion, suggesting that tuning down inflammasome activity and IL-1/IL-18 release are key features of Y. pestis pathogenesis
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