Genetic diversity of Collaborative Cross mice enables the establishment of a novel Chlamydia muridarum female genital tract infection model

Abstract

Chlamydial infection in women displays wide variation in bacterial burden, persistence, and risk of upper genital tract pathology, yet the host genetic factors underlying this heterogeneity remain poorly defined. We evaluated genital tract infection with Chlamydia muridarum across 20 Collaborative Cross (CC) strains, a recombinant inbred mouse panel that captures broad genetic diversity with high within-strain reproducibility. CC strains exhibited striking differences in early bacterial burden, time to clearance, and oviduct pathology, including prolonged low-inflammatory infections and burden-pathology discordance that mirror key features of human disease. Heritability analyses demonstrated that host genetics accounted for most of the variation observed in Day 7 bacterial burden and pathological outcomes. Genome-wide scans identified suggestive quantitative trait loci associated with both traits. Genes within the burden-associated locus converged on host pathways implicated in chlamydial intracellular growth, including membrane dynamics and lipid metabolism, ubiquitin signaling, host cell survival mechanisms, and immune regulatory signaling. In contrast, genes within the pathology-associated locus were enriched for pathways regulating inflammatory cell recruitment, inflammasome activation, and tissue remodeling, processes central to genital tract damage following infection. Cervical transcriptional profiling further revealed strain-dependent innate and adaptive immune programs associated with bacterial burden and disease phenotype. Together, these findings establish the CC as a powerful platform for dissecting the genetic architecture of chlamydial immunopathogenesis, and for improving preclinical evaluation of vaccines and therapeutics.