Wang Chengming, Gao Dongya, Kaltenboeck Bernhard
Department of Pathobiology, Auburn University, Auburn, Alabama, USA.
J Infect Dis. 2009 Jul 15;200(2):279-87. doi: 10.1086/599796.
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.
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).
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).
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.
流行病学和病理学证据表明，高流行病原体与慢性炎症性疾病相关，如2型糖尿病。动物模型对于深入理解炎症性疾病的感染增强机制至关重要，这些疾病都以胰岛素抵抗作为核心病理生理缺陷。
我们使用小鼠模型，研究了胰岛素抵抗的进展以及感染（肺炎衣原体感染小鼠与未感染对照小鼠）、遗传背景（C57BL/6小鼠与A/J小鼠）、饮食脂肪浓度（27%与5%）和时间（接种后2、5、9或15周）的影响。
在肥胖的C57BL/6小鼠中，肺炎衣原体感染导致胰岛素抵抗显著增加，且在细菌清除后仍持续很长时间。急性肺炎衣原体肺部定植所产生的循环肿瘤坏死因子（TNF）-α加剧了胰岛素抵抗，但继发性衣原体感染期间原位释放的TNF-α则没有这种作用。阿奇霉素或抗TNF-α抗体可预防感染加剧的胰岛素抵抗，但会显著增强衣原体向心脏的扩散。接种后3周，用阿奇霉素治疗的小鼠肺部并未清除肺炎衣原体，但细菌载量（每100毫克42个基因组）明显低于对照小鼠（每100毫克219个基因组）或抗TNF-α抗体治疗的小鼠（每100毫克3090个基因组）。
鼠肺炎衣原体感染通过循环介质以遗传和营养受限的方式增强胰岛素抵抗的发展。其与当前人类糖尿病流行的相关性尚待确定，但由于全球人类肺炎衣原体感染的高患病率，这一发现可能具有重要意义。
