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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-12, Vol.111 (49), p.17588-17593
• Main Authors: Man, Si Ming, Ekpenyong, Andrew, Tourlomousis, Panagiotis, Achouri, Sarra, Cammarota, Eugenia, Hughes, Katherine, Rizzo, Alessandro, Ng, Gilbert, Wright, John A., Cicuta, Pietro, Guck, Jochen R., Bryant, Clare E.
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; Actins; Actins - metabolism; Animals; Apoptosis Regulatory Proteins - metabolism; Bacteria; Bacterial infections; Biological Sciences; Bone Marrow Cells - cytology; Calcium-Binding Proteins - metabolism; Caspase 1 - metabolism; Cytochalasins; Cytoskeleton - metabolism; Food contamination & poisoning; Hydrogen Peroxide - chemistry; Immunity (Disease); Immunity, Innate; Infections; Inflammasomes - immunology; Inflammation - immunology; Interleukin-1beta - metabolism; Macrophages; Macrophages - cytology; Macrophages - microbiology; Mice; Mice, Transgenic; Microscopy, Confocal; Myeloid cells; Neutrophils - immunology; Polymerization; Proteins; Reactive Oxygen Species - metabolism; Salmonella; Salmonella infections; Salmonella Infections - immunology; Salmonella typhimurium; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1419925111

Significance Infectious diseases are responsible for one-third of all mortality worldwide. Innate immunity is critical for mounting host defenses that eliminate pathogens. Salmonella is a global food-borne pathogen that infects and replicates within macrophages. How inflammasomes—multimeric protein complexes that provide innate immune protection—function to restrict bacterial burden in macrophages remains unknown. We show that actin polymerization is critical for NLRC4 inflammasome activation in response to Salmonella infection. NLRC4 activation in Salmonella -infected cells prevents further uptake of bacteria by inducing cellular stiffness and antimicrobial responses, which prevent bacterial dissemination in the host. These results demonstrate a critical link between innate immunity and the actin cytoskeleton in the cellular defense against Salmonella infection. 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.