title: GigA and GigB are Master Regulators of Antibiotic Resistance, Stress Responses, and Virulence in Acinetobacter baumannii.
abstract: A critical component of bacterial pathogenesis is the ability of an invading organism to sense and adapt to the harsh environment imposed by the host's immune system. This is especially important for opportunistic pathogens, such asAcinetobacter baumannii, a nutritionally versatile environmental organism that has recently gained attention as a life-threatening human pathogen. The emergence ofA. baumanniiis closely linked to antibiotic resistance, and many contemporary isolates are multidrug resistant (MDR). Unlike many other MDR pathogens, the molecular mechanisms underlyingA. baumanniipathogenesis remain largely unknown. We report here the characterization of two recently identified virulence determinants, GigA and GigB, which comprise a signal transduction pathway required for surviving environmental stresses, causing infection and antibiotic resistance. Through transcriptome analysis, we show that GigA and GigB coordinately regulate the expression of many genes and are required for generating an appropriate transcriptional response during antibiotic exposure. Genetic and biochemical data demonstrate a direct link between GigA and GigB and the nitrogen phosphotransferase system (PTSNtr), establishing a novel connection between a novel stress response module and a well-conserved metabolic-sensing pathway. Based on the results presented here, we propose that GigA and GigB are master regulators of a global stress response inA. baumannii, and coupling this pathway with the PTSNtrallowsA. baumanniito integrate cellular metabolic status with external environmental cues.IMPORTANCEOpportunistic pathogens, includingAcinetobacter baumannii, encounter many harsh environments during the infection cycle, including antibiotic exposure and the hostile environment within a host. While the development of antibiotic resistance inA. baumanniihas been well studied, how this organism senses and responds to environmental cues remain largely unknown. Herein, we investigate two previously identified virulence determinants, GigA and GigB, and report that they are required forin vitrostress resistance, likely comprising upstream elements of a global stress response pathway. Additional experiments identify a connection between GigA/GigB and a widely conserved metabolic-sensing pathway, the nitrogen phosphotransferase system. We propose that coordination of these two pathways allowsA. baumanniito respond appropriately to changing environmental conditions, including those encountered during infection.
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, Illinois, USA mgebhardt@uchicago.edu.
authors.forename: Michael J
authors.identifier: http://orcid.org/0000-0002-1213-8408
authors.initials: MJ
authors.lastname: Gebhardt
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Shuman
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D024881:Drug Resistance, Bacterial; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D005809:Genes, Regulator; D053858:Metabolic Networks and Pathways; D018085:Regulon; D015398:Signal Transduction; D013312:Stress, Physiological; D014774:Virulence
keywords: Acinetobacter baumannii; antibiotic resistance; nitrogen phosphotransferase system; signal transduction; stress response