bHost 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.
Streptococcus pyogenes or group A streptococci (GAS) are the causative agents of a multitude of human diseases ranging from nonsevere strep throat, pharyngitis, and impetigo to lifethreatening necrotizing soft tissue infections (NSTIs) and streptococcal toxic shock syndrome (STSS) (1-12). The multifaceted nature of invasive GAS infections requires several modes of pathogenic adaptation to evade host immune defenses to successfully colonize and survive in host niches. In addition to the plethora of pathogenic factors contributing to disease severity, variations in the host genetic context play an equally important role in manipulating disease severity, manifestations, and outcomes.The emergence of virulent strains of GAS bacteria in the early 1980s coincided with a remarkable resurgence of severe and often deadly forms of invasive infections associated with STSS and NSTIs (5,6,12,13). One particular strain that emerged during that time is the clonal M1T1 strain that disseminated globally and continues to be one of the most prevalently isolated strains from patients with invasive and/or noninvasive GAS infections (12,(14)(15)(16)(17). This strain produces many secreted and surface-bound virulence factors; most of them are adapted to evade human host defense mechanisms (12, 18). However, previous studies from our laboratory characterized indistinguishable, invasive M1T1 isolates from patients with starkly different disease severity and outcomes (19). These findings underscored the contribution of host factors to the stark differences in severity and outcomes of invasive GAS infections.Indeed, ensuing ...