title: A group A Streptococcus ADP-ribosyltransferase toxin stimulates a protective interleukin 1β-dependent macrophage immune response.
abstract: The M1T1 clone of group A Streptococcus (GAS) is associated with severe invasive infections, including necrotizing fasciitis and septicemia. During invasive M1T1 GAS disease, mutations in the covRS regulatory system led to upregulation of an ADP-ribosyltransferase, SpyA. Surprisingly, a GAS ΔspyA mutant was resistant to killing by macrophages and caused higher mortality with impaired bacterial clearance in a mouse intravenous challenge model. GAS expression of SpyA triggered macrophage cell death in association with caspase-1-dependent interleukin 1β (IL-1β) production, and differences between wild-type (WT) and ΔspyA GAS macrophage survival levels were lost in cells lacking caspase-1, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), or pro-IL-1β. Similar in vitro findings were identified in macrophage studies performed with pseudomonal exotoxin A, another ADP-ribosylating toxin. Thus, SpyA triggers caspase-1-dependent inflammatory cell death in macrophages, revealing a toxin-triggered IL-1β-dependent innate immune response pathway critical in defense against invasive bacterial infection.
  
  
  OBJECTIVE
  Group A Streptococcus (GAS) is a leading human pathogen capable of producing invasive infections even in healthy individuals. GAS bacteria produce a toxin called SpyA that modifies host proteins through a process called ADP ribosylation. We describe how macrophages, frontline defenders of the host innate immune system, respond to SpyA by undergoing a specialized form of cell death in which they are activated to release the proinflammatory cytokine molecule interleukin 1β (IL-1β). Release of IL-1β activates host immune cell clearance of GAS, as we demonstrated in tissue culture models of macrophage bacterial killing and in vivo mouse infectious-challenge experiments. Similar macrophage responses to a related toxin of Pseudomonas bacteria were also shown. Thus, macrophages recognize certain bacterial toxins to activate a protective immune response in the host.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Federico C
authors.initials: FC
authors.lastname: Beasley
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Keller
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollands
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Urbano
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Troemel
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.affiliation: vnizet@ucsd.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D017353:Gene Deletion; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D014774:Virulence
chemical_list: D053583:Interleukin-1beta; D036002:ADP Ribose Transferases