Genetic analysis of susceptibility to Chlamydia trachomatis in mouse

Abstract

Chlamydia trachomatis is a bacterial pathogen that is a major cause of blindness and infertility in diverse populations across the world. In an effort to model genetic complexities that are observed in human populations and to identify novel genes involved in susceptibility to C. trachomatis, we have adapted a murine model of systemic infection for use in genetic analysis. In this model, chlamydial colonization and replication is measured in the spleens of mice shortly after intravenous delivery of C. trachomatis L2. Here, we show that C57BL/6J and C3H/HeJ inbred mice are differentially susceptible to this systemic infection. Additionally, fibroblasts cultured from C57BL/6J and C3H/HeJ embryos are differentially permissive for chlamydial replication. We have taken advantage of this natural variation to map quantitative trait loci on Chromosomes 2, 3, and 11 that segregate with the bacterial load in F2 cross progeny during the acute phase of C. trachomatis infection in vivo. To validate our mapping results, we also generated mice that are congenic for a portion of Chromosome 11 from the susceptible parent. This congenic interval confers increased susceptibility to C. trachomatis, both in vivo and in vitro, suggesting that our screen identified at least one gene that is involved in cellular resistance to C. trachomatis replication.

The p47 GTPases Igtp and Irgb10 map to the Chlamydia trachomatis susceptibility locus Ctrq-3 and mediate cellular resistance in mice

“…We previously showed that congenic MEFs carrying Ͼ30 megabases of chromosome 11 around Ctrq-3 from C3H on a B6 background are more susceptible to C. trachomatis L2 than noncongenic B6 MEFs; this effect is observed only upon pretreatment of the MEFs with IFN-␥ (14). To further localize this in vitro effect, we derived three subcongenic lines from the large-interval B6.C3H congenic.…”

“…WT B6 mice for experiments and breeding were obtained from The Jackson Laboratory (Bar Harbor, ME). The initial B6.C3H congenic used for derivation of the subcongenic lines was described previously (14). The Igtp knockout was described previously (27).…”

“…In genetic crosses involving inbred mice that are relatively resistant [C57BL͞6J (B6)] and susceptible [C3H͞HeJ (C3H)] to Chlamydia spp. (11)(12)(13)(14), we recently identified three quantitative trait loci (QTL) that segregate with the splenic bacterial load in F 2 progeny shortly after i.v. delivery of C. trachomatis L2 (14).…”

“…(11)(12)(13)(14), we recently identified three quantitative trait loci (QTL) that segregate with the splenic bacterial load in F 2 progeny shortly after i.v. delivery of C. trachomatis L2 (14). These QTL map to chromosomes 2, 3, and 11 and have been called Ctrq-1, Ctrq-2, and Ctrq-3, respectively.…”

Immune-mediated control of Chlamydia infection

“…Furthermore, the increased susceptibility of some mouse strains to C. trachomatis infection has been attributed to reduced expression of a member of the p47 family of IFN-ginducible GTPases. These GTPases are capable of limiting C. trachomatis replication in mice and in primary cells through mechanisms that are yet to be elucidated (Nelson et al, 2005;Bernstein-Hanley et al, 2006). The effects of the IFN-g-inducible GTPases appear to be limited to models where human serovars of C. trachomatis are used to infect mice.…”