title: Actin polymerization as a key innate immune effector mechanism to control Salmonella infection.
abstract: Salmonellosis is one of the leading causes of food poisoning worldwide. Controlling bacterial burden is essential to surviving infection. Nucleotide-binding oligomerization domain-like receptors (NLRs), such as NLRC4, induce inflammasome effector functions and play a crucial role in controlling Salmonella infection. Inflammasome-dependent production of IL-1β recruits additional immune cells to the site of infection, whereas inflammasome-mediated pyroptosis of macrophages releases bacteria for uptake by neutrophils. Neither of these functions is known to directly kill intracellular salmonellae within macrophages. The mechanism, therefore, governing how inflammasomes mediate intracellular bacterial-killing and clearance in host macrophages remains unknown. Here, we show that actin polymerization is required for NLRC4-dependent regulation of intracellular bacterial burden, inflammasome assembly, pyroptosis, and IL-1β production. NLRC4-induced changes in actin polymerization are physically manifested as increased cellular stiffness, and leads to reduced bacterial uptake, production of antimicrobial molecules, and arrested cellular migration. These processes act in concert to limit bacterial replication in the cell and dissemination in tissues. We show, therefore, a functional link between innate immunity and actin turnover in macrophages that underpins a key host defense mechanism for the control of salmonellosis.
authors.affiliation: Department of Veterinary Medicine and.
authors.forename: Si Ming
authors.initials: SM
authors.lastname: Man
authors.affiliation: Sector of Biological and Soft Systems, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0ES, United Kingdom; and Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ekpenyong
authors.affiliation: Department of Veterinary Medicine and.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Tourlomousis
authors.affiliation: Sector of Biological and Soft Systems, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0ES, United Kingdom; and.
authors.forename: Sarra
authors.initials: S
authors.lastname: Achouri
authors.affiliation: Sector of Biological and Soft Systems, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0ES, United Kingdom; and.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cammarota
authors.affiliation: Department of Veterinary Medicine and.
authors.forename: Katherine
authors.initials: K
authors.lastname: Hughes
authors.affiliation: Department of Veterinary Medicine and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rizzo
authors.affiliation: Sector of Biological and Soft Systems, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0ES, United Kingdom; and Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Ng
authors.affiliation: Department of Veterinary Medicine and.
authors.forename: John A
authors.initials: JA
authors.lastname: Wright
authors.affiliation: Sector of Biological and Soft Systems, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0ES, United Kingdom; and.
authors.forename: Pietro
authors.initials: P
authors.lastname: Cicuta
authors.affiliation: Sector of Biological and Soft Systems, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0ES, United Kingdom; and Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Jochen R
authors.initials: JR
authors.lastname: Guck
authors.affiliation: Department of Veterinary Medicine and ceb27@cam.ac.uk.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Bryant
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000737:chemistry; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000382:microbiology*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009504:Neutrophils / Q000276:immunology; D058105:Polymerization; D017382:Reactive Oxygen Species / Q000378:metabolism; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium
chemical_list: D000199:Actins; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D020170:Caspase 1
keywords: ASC; ROS; caspase-1; cytoskeleton; innate immunity