Mast cells in bacterial infections

Sammanfattning: Mast cells are implicated in immunity towards bacterial infection, but the molecular mechanisms by which mast cells contribute to the host response are only partially understood. Previous studies have examined how mast cells react to purified bacterial cell wall components, such as peptidoglycan and lipopolysaccharide. To investigate how mast cells react to live bacteria we co-cultured mast cells and the gram-positive bacteria Streptococcus equi (S. equi) and Staphylococcus aureus (S. aureus). Gene array analysis showed that mast cells upregulate a number of genes in response to live bacteria. Many of these corresponded to pro-inflammatory cytokines, but also numerous additional genes, including transcription factors, signaling molecules and proteases were upregulated. The release of cytokines was confirmed on the protein level by antibody-based cytokine/chemokine arrays and/or ELISA. Granzyme D, a protease mainly expressed in cytotoxic T cells, was one of the genes that were upregulated by S. equi. We showed that granzyme D is expressed by murine mast cells and that its level of expression correlated positively with the extent of mast cell maturation. Granzyme D expression was also induced by stem cell factor, IgE receptor cross-linking and calcium ionophore stimulation. Previous studies investigating the role of mast cells in bacterial infection in vivo have used mice that are mast cell deficient due to mutations in Kit-signaling. However, these mutations also influence other cell types than mast cells. Thus, to study the role of mast cells during in vivo infection with S. aureus we used the newly developed Mcpt5-Cre+ x R-DTA mice whose expression of diphteria toxin under the Mcpt5 promoter selectively depletes mast cells. S. aureus was injected intraperitoneally into Mcpt5-Cre+ x R-DTA mice using littermate mast cell-sufficient mice as controls. We did not observe any difference between mast cell-deficient and control mice in regard to weight loss, bacterial clearance, inflammation or cytokine production. We conclude that, despite mast cells being activated by S. aureus in vitro, mast cells do not influence the in vivo manifestations of S. aureus intraperitoneal infection. However, to make more general conclusions about the role of mast cells in bacterial infections, more studies in the new mast cell-deficient mice are needed using other bacterial strains and other routes of administration.

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