Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

Abstract

Variation in responses to pathogens is influenced by exposure history, environment and the host's genetic status. We recently demonstrated that human leukocyte antigen class II allelic differences are a major determinant of the severity of invasive group A streptococcal (GAS) sepsis in humans. While in-depth controlled molecular studies on populations of genetically wellcharacterized humans are not feasible, it is now possible to exploit genetically diverse panels of recombinant inbred BXD mice to define genetic and environmental risk factors. Our goal in this study was to standardize the model and identify genetic and nongenetic covariates influencing invasive infection outcomes. Despite having common ancestors, the various BXD strains (n strains ¼ 33, n individuals ¼ 445) showed marked differences in survival. Mice from all strains developed bacteremia but exhibited considerable differences in disease severity, bacterial dissemination and mortality rates. Bacteremia and survival showed the expected negative correlation. Among nongenetic factors, age -but not sex or weight -was a significant predictor of survival (P ¼ 0.0005). To minimize nongenetic variability, we limited further analyses to mice aged 40-120 days and calculated a corrected relative survival index that reflects the number of days an animal survived post-infection normalized to all significant covariates. Genetic background (strain) was the most significant factor determining susceptibility (Pp0.0001), thus underscoring the strong effect of host genetic variation in determining susceptibility to severe GAS sepsis. This model offers powerful unbiased forward genetics to map specific quantitative trait loci and networks of pathways modulating the severity of GAS sepsis.

Systems Biology Approach to Identifying Host Interactive Pathways Modulating the Severity of Streptococcal Sepsis

“…Another interesting observation was that, in general, susceptible strains survival was better correlated with bacterial load in blood and spleen than resistant strains. Together, these findings confirm that there is more than one mechanism modulating differential susceptibility or resistance to severe GAS sepsis (Aziz et al, 2007).…”

“…Our initial studies (Aziz et al, 2007) demonstrated that there is considerable variability among BXD strains with respect to susceptibility to severe GAS sepsis. To quantify differences among strains in this study, we used three main quantitative traits, namely animal survival, bacteremia, and bacterial dissemination to spleen.…”

“…Moreover, the bacteria produce a number of additional, important virulence factors that must also participate in the pathogenesis of GAS sepsis. The overall aim of my study was to identify additional host factors modulating susceptibility to severe GAS sepsis and to identify host genes and pathways involved in this disease (Aziz et al, 2007;Abdeltawab et al, 2008).…”

“…Recombinant inbred (RI) strains have been successfully used to map quantitative trait loci (QTLs) associated with various phenotypes and diseases (Hardy et al, 2001;Rosen and Williams, 2001;Grizzle et al, 2002;Peirce et al, 2003;Chesler et al, 2005;Mountz et al, 2005;Aziz et al, 2007;Miyairi et al, 2007). We used the BXD panel of ARI mice derived from C57BL/6J (B6) and DBA/2J (D2) strains and consisting of homozygous, inbred BXD lines, each of which is genetically distinct.…”

“…Our laboratory provided direct evidence that the highly polymorphic human  Source: Reprinted with permission. Aziz, R.K., Kansal, R., Abdeltawab, N.F., Rowe, S.L., Su, Y., Carrigan, D., Nooh, M.M., et al (2007) Susceptibility to severe Streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors. Genes Immun 8: 404-415. leukocyte antigen (HLA) genes confer high risk or protection in rheumatic heart disease as well as in streptococcal toxic shock (STSS) and necrotizing fasciitis (NF) Kotb et al, 2003).…”