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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 well-characterized 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=33, n individuals=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=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 (P0.0001), 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.

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Acknowledgements

We are indebted to the team managing the animal facilities in the VA Medical Center and UTSHC, notably Dr Timothy Mandrell, Alfred Pointer, Rebecca Manns and colleagues.

This work was supported by grant AI40198-06 from NIH, National Institute of Allergy and Infectious Diseases (NIAID to MK), by the Research and Development Office, Medical Research Service, Department of Veterans Affairs (Merit award to MK) and the US Army Medical Research Acquisition Activity (W81XWH-05-1-0227 to MK).

Development and maintenance of the BXD Colony is partly supported by a Human Brain Project funded jointly by the NIMH, NIDA and NIAAA (P20-DA 21131), NCI MMHCC (U01CA105417), and the Biomedical Informatics Research Network (BIRN), NCRR (U01NR 105417).

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Aziz, R., Kansal, R., Abdeltawab, N. et al. 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 (2007). https://doi.org/10.1038/sj.gene.6364402

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