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Actin polymerization as a key innate immune effector mechanism to control Salmonella infection.


Type

Article

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Authors

Man, Si Ming 
Ekpenyong, Andrew 
Tourlomousis, Panagiotis  ORCID logo  https://orcid.org/0000-0002-6152-8066
Achouri, Sarra 
Cammarota, Eugenia 

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.

Description

Keywords

ASC, ROS, caspase-1, cytoskeleton, innate immunity, Actin Cytoskeleton, Actins, Animals, Apoptosis Regulatory Proteins, Bone Marrow Cells, Calcium-Binding Proteins, Caspase 1, Cytoskeleton, Hydrogen Peroxide, Immunity, Innate, Inflammasomes, Inflammation, Interleukin-1beta, Macrophages, Mice, Mice, Transgenic, Microscopy, Confocal, Neutrophils, Polymerization, Reactive Oxygen Species, Salmonella Infections, Salmonella typhimurium

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

111

Publisher

Proceedings of the National Academy of Sciences
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/H003916/1)
Biotechnology and Biological Sciences Research Council (BB/H021930/1)
Biotechnology and Biological Sciences Research Council (BB/K006436/1)
Wellcome Trust (108045/Z/15/Z)
European Commission (264399)
Financial support for this work was provided by a Cambridge International Scholarship (to S.M.M.), European Research Council Starting Investigator Grant “LightTouch” 282060 (to J.R.G.), Biotechnology and Biological Sciences Research Council (BBSRC) Grants BB/H003916/1 and BB/K006436/1 and BBSRC Research Development Fellowship BB/ H021930/1 (to C.E.B.)