An Unbiased Systems Genetics Approach to Mapping Genetic Loci Modulating Susceptibility to Severe Streptococcal Sepsis

Abstract

Striking individual differences in severity of group A streptococcal (GAS) sepsis have been noted, even among patients infected with the same bacterial strain. We had provided evidence that HLA class II allelic variation contributes significantly to differences in systemic disease severity by modulating host responses to streptococcal superantigens. Inasmuch as the bacteria produce additional virulence factors that participate in the pathogenesis of this complex disease, we sought to identify additional gene networks modulating GAS sepsis. Accordingly, we applied a systems genetics approach using a panel of advanced recombinant inbred mice. By analyzing disease phenotypes in the context of mice genotypes we identified a highly significant quantitative trait locus (QTL) on Chromosome 2 between 22 and 34 Mb that strongly predicts disease severity, accounting for 25%–30% of variance. This QTL harbors several polymorphic genes known to regulate immune responses to bacterial infections. We evaluated candidate genes within this QTL using multiple parameters that included linkage, gene ontology, variation in gene expression, cocitation networks, and biological relevance, and identified interleukin1 alpha and prostaglandin E synthases pathways as key networks involved in modulating GAS sepsis severity. The association of GAS sepsis with multiple pathways underscores the complexity of traits modulating GAS sepsis and provides a powerful approach for analyzing interactive traits affecting outcomes of other infectious diseases.

Genetic Control of Survival and Weight Loss during Pneumonic Burkholderia pseudomallei (Bp) Infection

“…A set of studies by Miyairi and associates revealed that susceptibility to Chlamydia psittaci is a simple trait that is controlled by a single host locus that encodes p47 GTPases [74,100]. Another study revealed that differential susceptibility to group A Steptococci is also controlled by a single host genetic locus [122]. In contrast, a study by Yadav and colleagues [121] and the present study revealed that susceptibility to the bacterial pathogens Yersina pestis and Bp, respectively, involve multiple host loci.…”

“…These findings are not surprising in light of findings that genetic factors play a key role in susceptibility to a wide range of other infectious diseases. Published findings have identified host genetic factors that are critical for variable susceptibility to intracellular parasites [115], viruses [116][117][118][119][120], and both intracellular [74,100,121] and extracellular [122] bacterial pathogens. Moreover, recent genome-wide studies have established novel associations between common polymorphisms and susceptibility to several infectious diseases that are responsible for significant morbidity and/or mortality in humans [73,100,123,124].…”

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

“…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).…”

“…RI and ARI strains have been successfully used to map quantitative trait loci (QTLs) associated with various phenotypes and diseases (Hardy et al, 2001;Grizzle et al, 2002;Chesler et al, 2005;Miyairi et al, 2007;Abdeltawab et al, 2008). RI and ARI strains of mice are the progeny of two ancestral inbred strains.…”

“…We employed genome-wide association studies (GWAS) adopting systems genetics approach as discussed in chapters 2 and 3. Using these genome-wide association studies, we identified interleukin 1 and prostaglandin pathways as candidate pathways associated with modulation of differential susceptibility to severe GAS sepsis (chapter 3 and Abdeltawab et al 2008). In this chapter, we sought to characterize and further dissect genetic and soluble biomarkers associated with differential susceptibility to GAS sepsis.…”