Manipulation of interleukin-1β and interleukin-18 production by Yersinia pestis effectors YopJ and YopM and redundant impact on virulence
| Autor: | Robyn Marty-Roix, Egil Lien, Megan K. Proulx, Jon D. Goguen, M. Pontus A. Orning, Kristian K. Starheim, Dmitry Ratner |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Chemokine Yersinia Infections Inflammasomes Yersinia pestis Interleukin-1beta Mutant Immunology Virulence Real-Time Polymerase Chain Reaction Biochemistry Type three secretion system Microbiology Mice 03 medical and health sciences Bacterial Proteins medicine Animals Molecular Biology Cells Cultured Innate immune system biology Effector Macrophages Interleukin-18 Inflammasome Cell Biology biology.organism_classification Immunity Innate 030104 developmental biology biology.protein Additions and Corrections Bacterial Outer Membrane Proteins medicine.drug |
| Zdroj: | The Journal of biological chemistry. 291(31) |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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