Host Genetic Variations and Sex Differences Potentiate Predisposition, Severity, and Outcomes of Group A Streptococcus-Mediated Necrotizing Soft Tissue Infections

• Published in: Infection and immunity Vol. 84; no. 2; pp. 416 - 424
• Main Authors: Chella Krishnan, Karthickeyan, Mukundan, Santhosh, Alagarsamy, Jeyashree, Laturnus, Donna, Kotb, Malak
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.02.2016
• Subjects: Animals; Bacterial Load; Disease Models, Animal; Disease Susceptibility; Female; Genetic Predisposition to Disease; Genetic Variation; Host Response and Inflammation; Host-Pathogen Interactions; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Necrosis; Sex Characteristics; Soft Tissue Infections - genetics; Soft Tissue Infections - microbiology; Streptococcal Infections - genetics; Streptococcal Infections - microbiology; Streptococcus; Streptococcus pyogenes - growth & development; Streptococcus pyogenes - pathogenicity
• DOI: 10.1128/iai.01191-15
• ISSN: 0019-9567

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.