title: Mast cells as rapid innate sensors of cytomegalovirus by TLR3/TRIF signaling-dependent and -independent mechanisms.
abstract: The succinct metaphor, 'the immune system's loaded gun', has been used to describe the role of mast cells (MCs) due to their storage of a wide range of potent pro-inflammatory and antimicrobial mediators in secretory granules that can be released almost instantly on demand to fight invaders. Located at host-environment boundaries and equipped with an arsenal of pattern recognition receptors, MCs are destined to be rapid innate sensors of pathogens penetrating endothelial and epithelial surfaces. Although the importance of MCs in antimicrobial and antiparasitic defense has long been appreciated, their role in raising the alarm against viral infections has been noted only recently. Work on cytomegalovirus (CMV) infection in the murine model has revealed MCs as players in a novel cross-talk axis between innate and adaptive immune surveillance of CMV, in that infection of MCs, which is associated with MC degranulation and release of the chemokine CCL5, enhances the recruitment of protective CD8 T cells to extravascular sites of virus replication, specifically to lung interstitium and alveolar epithelium. Here, we have expanded on these studies by investigating the conditions for MC activation and the consequent degranulation in response to host infection. Surprisingly, the data revealed two temporally and mechanistically distinct waves of MC activation: an almost instant indirect activation that depended on TLR3/TRIF signaling and delayed activation by direct infection of MCs that did not involve TLR3/TRIF signaling. Cell type-specific Cre-recombination that yielded eGFP-expressing reporter virus selectively originating from MCs identified MC as a new in vivo, first-hit target cell of productive murine CMV infection.
authors.affiliation: Institute for Immunology, Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Becker
authors.affiliation: Institute for Virology, Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Niels A W
authors.initials: NA
authors.lastname: Lemmermann
authors.affiliation: Institute for Virology, Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ebert
authors.affiliation: Institute for Immunology, Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Pamela
authors.initials: P
authors.lastname: Baars
authors.affiliation: Institute for Virology, Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Angelique
authors.initials: A
authors.lastname: Renzaho
authors.affiliation: Institute for Virology, Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Podlech
authors.affiliation: Institute for Immunology, Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stassen
authors.affiliation: Institute for Virology, Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Reddehase
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000821:virology; D005260:Female; D019426:Integrases / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051196:Toll-Like Receptor 3 / Q000502:physiology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D019426:Integrases; D051196:Toll-Like Receptor 3; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C045073:Cre recombinase