Elucidating Sources and Roles of Granzymes A and B during Bacterial Infection and Sepsis

• Published in: Cell reports (Cambridge) 2014-07, Vol.8 (2), p.420-429
• Main Authors: Arias, Maykel A., Jiménez de Bagües, María P., Aguiló, Nacho, Menao, Sebastián, Hervás-Stubbs, Sandra, de Martino, Alba, Alcaraz, Ana, Simon, Markus M., Froelich, Christopher J., Pardo, Julián
• Format: Article
• Language: English
• Subjects: Animals; Bacteremia - metabolism; Brucella; Cells, Cultured; Cytokines - genetics; Cytokines - metabolism; Granzymes - genetics; Granzymes - metabolism; Killer Cells, Natural - metabolism; Liver - metabolism; Liver - pathology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Spleen - metabolism; Spleen - pathology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.06.012

During bacterial sepsis, proinflammatory cytokines contribute to multiorgan failure and death in a process regulated in part by cytolytic cell granzymes. When challenged with a sublethal dose of the identified mouse pathogen Brucella microti, wild-type (WT) and granzyme A (gzmA)−/− mice eliminate the organism from liver and spleen in 2 or 3 weeks, whereas the bacteria persist in mice lacking perforin or granzyme B as well as in mice depleted of Tc cells. In comparison, after a fatal challenge, only gzmA−/− mice exhibit increased survival, which correlated with reduced proinflammatory cytokines. Depletion of natural killer (NK) cells protects WT mice from sepsis without influencing bacterial clearance and the transfer of WT, but not gzmA−/− NK, cells into gzmA−/− recipients restores the susceptibility to sepsis. Therefore, infection-related pathology, but not bacterial clearance, appears to require gzmA, suggesting the protease may be a therapeutic target for the prevention of bacterial sepsis without affecting immune control of the pathogen. [Display omitted] •Tc-cell-associated perforin and gzmB control the bacterial pathogen Brucella microti•GzmA deficiency reduces inflammation and increases survival during sepsis•NK-cell-derived gzmA is responsible for animal death during sepsis Arias et al. provide evidence that a protease produced by natural killer cells, granzyme A (gzmA), is not necessary to control a bacterial infection, which is mediated by perforin/granzyme B. Instead, gzmA contributes to sepsis and death by inducing a proinflammatory cytokine response. Mice lacking gzmA control infection as well as normal mice, whereas their survival during a septic response is significantly improved. Our findings suggest that, during bacterial sepsis, inflammation can be selectively reduced without interfering with pathogen control.