title: Staphylococcus aureus sarA regulates inflammation and colonization during central nervous system biofilm formation.
abstract: Infection is a frequent and serious complication following the treatment of hydrocephalus with CSF shunts, with limited therapeutic options because of biofilm formation along the catheter surface. Here we evaluated the possibility that the sarA regulatory locus engenders S. aureus more resistant to immune recognition in the central nervous system (CNS) based on its reported ability to regulate biofilm formation. We utilized our established model of CNS catheter-associated infection, similar to CSF shunt infections seen in humans, to compare the kinetics of bacterial titers, cytokine production and inflammatory cell influx elicited by wild type S. aureus versus an isogenic sarA mutant. The sarA mutant was more rapidly cleared from infected catheters compared to its isogenic wild type strain. Consistent with this finding, several pro-inflammatory cytokines and chemokines, including IL-17, CXCL1, and IL-1β were significantly increased in the brain following infection with the sarA mutant versus wild type S. aureus, in agreement with the fact that the sarA mutant displayed impaired biofilm growth and favored a planktonic state. Neutrophil influx into the infected hemisphere was also increased in the animals infected with the sarA mutant compared to wild type bacteria. These changes were not attributable to extracellular protease activity, which is increased in the context of SarA mutation, since similar responses were observed between sarA and a sarA/protease mutant. Overall, these results demonstrate that sarA plays an important role in attenuating the inflammatory response during staphylococcal biofilm infection in the CNS via a mechanism that remains to be determined.
authors.affiliation: Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, United States of America ; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Snowden
authors.affiliation: Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Matt
authors.initials: M
authors.lastname: Beaver
authors.affiliation: Department of Microbiology and Immunology, University for Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Beenken
authors.affiliation: Department of Microbiology and Immunology, University for Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Smeltzer
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Horswill
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Tammy
authors.initials: T
authors.lastname: Kielian
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism; D018441:Biofilms / Q000254:growth & development*; D001921:Brain / Q000382:microbiology* / Q000601:surgery; D055499:Catheter-Related Infections / Q000382:microbiology*; D002552:Cerebral Ventricles / Q000382:microbiology / Q000601:surgery; D002648:Child; D006801:Humans; D007249:Inflammation / Q000382:microbiology; D008297:Male; D051379:Mice; D009154:Mutation; D010447:Peptide Hydrolases / Q000378:metabolism; D011183:Postoperative Complications / Q000382:microbiology; D013211:Staphylococcus aureus / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; C088021:SarA protein, bacterial; D015534:Trans-Activators; D010447:Peptide Hydrolases