Elucidating sources and roles of granzymes A and B during bacterial infection and sepsis.

Abstract

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.

• Authors: Maykel A Arias, María P Jiménez de Bagües, Nacho Aguiló, Sebastián Menao, Sandra Hervás-Stubbs, Alba de Martino, Ana Alcaraz, Markus M Simon, Christopher J Froelich, Julián Pardo
• Journal: Cell reports (Cell Rep) Vol. 8 Issue 2 Pg. 420-9 (Jul 24 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 25017060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Granzymes
• Gzmb protein, mouse
• granzyme A, mouse

Topics

• Animals
• Bacteremia (metabolism)
• Brucella
• Cells, Cultured
• Cytokines (genetics, metabolism)
• Granzymes (genetics, metabolism)
• Killer Cells, Natural (metabolism)
• Liver (metabolism, pathology)
• Macrophages (metabolism)
• Mice
• Mice, Inbred C57BL
• Spleen (metabolism, pathology)