Susceptibility to klebsiella pneumonaie infection in collaborative cross mice is a complex trait controlled by at least three loci acting at different time points

Abstract

BackgroundKlebsiella pneumoniae (Kp) is a bacterium causing severe pneumonia in immunocompromised hosts and is often associated with sepsis. With the rise of antibiotic resistant bacteria, there is a need for new effective and affordable control methods; understanding the genetic architecture of susceptibility to Kp will help in their development. We performed the first quantitative trait locus (QTL) mapping study of host susceptibility to Kp infection in immunocompetent Collaborative Cross mice (CC). We challenged 328 mice from 73 CC lines intraperitoneally with 104 colony forming units of Kp strain K2. Survival and body weight were monitored for 15 days post challenge. 48 of the CC lines were genotyped with 170,000 SNPs, with which we mapped QTLs.ResultsCC lines differed significantly (P < 0.05) in mean survival time, between 1 to 15 days post infection, and broad sense heritability was 0.45. Distinct QTL were mapped at specific time points during the challenge. A QTL on chromosome 4 was found only on day 2 post infection, and QTL on chromosomes 8 and 18, only on day 8. By using the sequence variations of the eight inbred strain founders of the CC to refine QTL localization we identify several candidate genes.ConclusionHost susceptibility to Kp is a complex trait, controlled by multiple genetic factors that act sequentially during the course of infection.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-865) contains supplementary material, which is available to authorized users.

Collaborative Cross Mouse Population for Studying Alveolar Bone Changes and Impaired Glucose Tolerance Comorbidity After High‐Fat Diet Consumption

“…These findings validate the power of the CC lines population for studying genetic susceptibility toward comorbidity of the two or more complex diseases simultaneously, representing, to the best of the authors’ knowledge, a novel mouse model that enables exploring co‐ and multi‐morbidity phenomena in wide aspects within a short period of time. The present findings are in agreement with previous reports using this mouse model, which demonstrated the power of the CC population for dissecting host susceptibility to complex diseases with complex etiologies 6,21,22,24,25,28‐30 …”

“…Controlled randomization was performed during the breeding process to break up large linkage disequilibrium blocks and to recombine the natural genetic variation, resulting in production of an inexhaustible source of recombinant inbred lines exhibiting a wide spectrum of phenotypic and genetic diversity 6,17‐20 . Previous studies have validated the power of CC lines to map QTLs to small genomic intervals, even <0.75 Mb 21–25 …”

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

“…However, considerable breeding difficulties were encountered (Philip et al 2011); and as of January 1, 2015, only 69 strains are listed as available on the CC website (Table 1) with a current goal of about 100 strains. Despite these difficulties, investigators have used these 69 completed strains and other incipient lines to study the genetics of infection, body weight, food intake, cancer, albuminuria, and other traits Durrant et al 2011;Foulds Mathes et al 2011;Philip et al 2011;Kelada et al 2012Thaisz et al 2012;Ferris et al 2013; Phillippi et al 2014;Rogala et al 2014;Rutledge et al 2014;Vered et al 2014).…”

Designing a QTL Mapping Study for Implementation in the Realized Collaborative Cross Genetic Reference Population

“…Full details of CC lines and their power of mapping QTL with host susceptibility to complex traits are presented in various publications (Abu‐Toamih Atamni, Mott et al., ; Abu‐Toamih Atamni, Botzman et al., ; Abu‐Toamih Atamni et al. ; Aylor et al., ; Durrant et al., ; Iraqi et al., ; Iraqi, Churchill, & Mott, ; Levy et al., ; Lorè, Iraqi, & Bragonzi, ; Molenhuis et al., ; Nashef et al., ; Philip et al., ; Vered et al., ; Welsh et al., ). The CC mouse model is the focal point in our research, having exclusive access to the CC lines produced at our laboratory at Tel Aviv University (TAU).…”