Multivariate Analyses of Disease Outcomes of Chlamydial Infections in Cattle and Mice

Abstract

In humans, Chlamydia pneumoniae infection is implicated in 10 ~ 15% of bronchitis and community-acquired pneumonia, and 50 ~ 70% of adults have antibodies to Chlamydia pneumoniae. In livestock animals, ubiquitous C. abortus infection is a major, if underestimated, factor influencing subclinical infertility and abortion of farm animals. Numerous factors, including population density of the host and dietary influences on immunity, influence the ultimate manifestation of any infectious disease. Only occasionally chlamydial infections manifest themselves as clinical disease. The research presented in this dissertation addresses the question of causal involvement of chlamydial infection in a prospective study of fertility in cattle, the natural host of Chlamydophila abortus, in association with challenge with this organism. In a second approach, the effect of dietary components with known influence on the immune response, protein and antioxidants, on chlamydial infection was studied by analyzing lung disease in a murine respiratory challenge model with C. pneumoniae. The first study determined the effects of controlled re-infection on the fertility of cattle naturally pre-exposed to Chlamydophila abortus. Virgin heifers were estrus synchronized, artificially inseminated 2 to 3 days later, and challenged immediately by intrauterine administration of C. abortus or through indirect exposure by contact with their previously challenged cohorts. Uterine inoculum dose and cohort challenge (or, alternatively, negative pregnancy outcome = infertility) correlated highly significantly with a rise in postchallenge anti-C. abortus IgM levels over prechallenge levels. These data proved that local and systemic infection with C. abortus suppressed fertility in cattle. The second study investigated in a balanced multivariate experimental design major factors known to influence C. pneumoniae disease: i) host genetic background; ii) pre-challenge immunity against C. pneumoniae; iii) duration of the infection; iv) dietary protein; and v) dietary antioxidants. C57BL/6 mice previously immunized against C. pneumoniae and fed a low-protein & low-antioxidant diet showed on day 10 post challenge inoculation severe disease due to a pronounced Th1 response as indicated by significantly (p < 0.05) upregulated transcripts such as those of IFN-?, TNF-a, or IL-6. In contrast, immune A/J mice showed lowest disease outcome with Th2-biased immunity and reduced inflammation. This pattern was opposite in the early response on day 3 after inoculation. Immune C57BL/6 mice on LL diet showed a strongly Th2-biased and suppressed immune response, while A/J had a strong, Th1-biased immune response. Of all transcripts of immune C57BL/6 on LL diet on day 3, only the T cell-specific CD3d transcript was highly significantly (p < 0.0001) reduced by more than four-fold. These results strongly suggest that it is a suppressed early Th1 immune and inflammatory response that primes immune C57BL/6 mice for later severe Th1 inflammatory disease.