title: Host Genetic Variations and Sex Differences Potentiate Predisposition, Severity, and Outcomes of Group A Streptococcus-Mediated Necrotizing Soft Tissue Infections.
abstract: Host genetic variations play an important role in several pathogenic diseases, and we previously provided strong evidence that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive group A Streptococcus (GAS) patients, including sepsis and necrotizing soft tissue infections (NSTIs). The goal of the present study was to investigate how genetic variations and sex differences among four commonly used mouse strains contribute to variation in severity, manifestations, and outcomes of NSTIs. DBA/2J mice were more susceptible to NSTIs than C57BL/6J, BALB/c, and CD-1 mice, as exhibited by significantly greater bacteremia, excessive dissemination to the spleen, and significantly higher mortality. Differences in the sex of the mice also contributed to differences in disease severity and outcomes: DBA/2J female mice were relatively resistant compared to their male counterparts. However, DBA/2J mice exhibited minimal weight loss and developed smaller lesions than did the aforementioned strains. Moreover, at 48 h after infection, compared with C57BL/6J mice, DBA/2J mice had increased bacteremia, excessive dissemination to the spleen, and excessive concentrations of inflammatory cytokines and chemokines. These results indicate that variations in the host genetic context as well as sex play a dominant role in determining the severity of and susceptibility to GAS NSTIs.
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Karthickeyan
authors.identifier: http://orcid.org/0000-0002-4895-2495
authors.initials: K
authors.lastname: Chella Krishnan
authors.affiliation: Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Mukundan
authors.affiliation: Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Jeyashree
authors.initials: J
authors.lastname: Alagarsamy
authors.affiliation: Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Laturnus
authors.affiliation: Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA malak.kotb@med.und.edu.
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb
mesh_terms: D000818:Animals; D058491:Bacterial Load; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009336:Necrosis; D012727:Sex Characteristics; D018461:Soft Tissue Infections / Q000235:genetics* / Q000382:microbiology; D013290:Streptococcal Infections / Q000235:genetics* / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000254:growth & development / Q000472:pathogenicity*