Background: Epidemiological and pathological evidence links highly prevalent pathogens to chronic inflammatory diseases, such as type 2 diabetes. Animal models contribute critically to the mechanistic understanding of infectious enhancement of inflammatory diseases, which share insulin resistance as the central pathophysiological defect.
Methods: With use of a mouse model, we examined insulin resistance progression and the influence of infection (Chlamydia pneumoniae-infected vs. uninfected control mice), genetic background (C57BL/6 vs. A/J mice), dietary fat concentration (27% vs. 5%), and time (2, 5, 9, or 15 weeks after inoculation).
Results: In obese C57BL/6 mice, C. pneumoniae infection induced significantly increased insulin resistance that persisted long after bacterial clearance. Circulating tumor necrosis factor (TNF)-alpha produced in response to acute C. pneumoniae lung colonization exacerbated insulin resistance but not TNF-alpha released in situ during secondary chlamydial infection. Azithromycin or anti-TNF-alpha antibody prevented infection-exacerbated insulin resistance but significantly enhanced chlamydial dissemination to the heart. Azithromycin-treated mice did not eliminate C. pneumoniae from lungs by 3 weeks after inoculation but had significantly lower loads (42 genomes per 100 mg) than did control mice (219 genomes per 100 mg) or anti-TNF-alpha antibody-treated mice (3090 genomes per 100 mg).
Conclusions: Murine C. pneumoniae infection enhanced insulin resistance development in a genetically and nutritionally restricted manner via circulating mediators. The relevance for the current human diabetes epidemic remains to be determined, but this finding is potentially important because of the high prevalence of human C. pneumoniae infection worldwide.