Waddlia chondrophila induces systemic infection, organ pathology, and elicits Th1-associated humoral immunity in a murine model of genital infection

Abstract

Waddlia chondrophila is a known bovine abortigenic Chlamydia-related bacterium that has been associated with adverse pregnancy outcomes in human. However, there is a lack of knowledge regarding how W. chondrophila infection spreads, its ability to elicit an immune response and induce pathology. A murine model of genital infection was developed to investigate the pathogenicity and immune response associated with a W. chondrophila infection. Genital inoculation of the bacterial agent resulted in a dose-dependent infection that spread to lumbar lymph nodes and successively to spleen and liver. Bacterial-induced pathology peaked on day 14, characterized by leukocyte infiltration (uterine horn, liver, and spleen), necrosis (liver) and extramedullary hematopoiesis (spleen). Immunohistochemistry demonstrated the presence of a large number of W. chondrophila in the spleen on day 14. Robust IgG titers were detected by day 14 and remained high until day 52. IgG isotypes consisted of high IgG2a, moderate IgG3 and no detectable IgG1, indicating a Th1-associated immune response. This study provides the first evidence that W. chondrophila genital infection is capable of inducing a systemic infection that spreads to major organs, induces uterus, spleen, and liver pathology and elicits a Th1-skewed humoral response. This new animal model will help our understanding of the mechanisms related to intracellular bacteria-induced miscarriages, the most frequent complication of pregnancy that affects one in four women.

Culture‐independent genomics of a novel chlamydial pathogen of fish provides new insight into host‐specific adaptations utilized by these intracellular bacteria

“…Molecular and sero-epidemiological surveys have detected CRBs in association with respiratory disease in humans (Kahane et al, 1998;Friedman et al, 1999) and livestock (Wheelhouse et al, 2013) and reproductive disease in both humans and animals (Borel et al, 2007;Baud et al, 2011;Barkallah et al, 2014). Further, murine respiratory disease models have recently been established for Waddlia chondrophila (Pilloux et al, 2016) and Parachlamydia acanthamoebae (Casson et al, 2008), as has a bovine model of P. acanthamoebae respiratory disease (Lohr et al, 2014) and a murine model of W. chondrophila genital infection (Vasilevsky et al, 2015), confirming Koch's postulates for these causative agents of disease. Questions nevertheless remain about whether these organisms are truly pathogens of their varied host species.…”

What is the true clinical relevance of Simkania negevensis and other emerging Chlamydiales members?

“…Similar to S. negevensis, W. chondrophila is an emerging Chlamydia -related bacterium. Several studies have implicated it in genital infections [31] , [32] . Indeed, both serologic evidence and molecular detection of W. chondrophila have been associated with miscarriages [1] , [2] , while high antibody titres were correlated with tubal infertility [33] .…”

Impact of Waddlia chondrophila infection on pregnancy in the mouse

“…Infection by the intrauterine route was performed as previously described [8]. Infections were performed in three separate experiments, for a total of 22 mice per group ( W. chondrophila and mock controls).…”

“…Two weeks after the introduction of the infection, two females were placed in a cage housing a male mouse. This was chosen according to our previous experiments, which demonstrated a maximum immune response and organ pathology at 2 weeks post-infection [8]. Vaginal plug assessments were completed on a daily basis and once observed, female mice were housed in separate cages to avoid cross-contamination.…”

“…Although the study did not confirm the role of W. chondrophila as an abortive agent, one animal showed pathogen-associated lesions in the placenta, suggesting a tropism towards reproductive organs. To study the role of W. chondrophila in miscarriages, we have previously developed a genital mouse-model of infection [8]. Intrauterine infection by W. chondrophila was able to induce a systemic infection and organ pathology, while eliciting a T helper type 1-associated humoral immunity, typical of Chlamydia -like bacteria.…”