Essential Role for Neutrophils in Pathogenesis and Adaptive Immunity in Chlamydia caviae Ocular Infections

Abstract

Trachoma, the world's leading cause of preventable blindness, is produced by chronic ocular infection with Chlamydia trachomatis, an obligate intracellular bacterium. While many studies have focused on immune mechanisms for trachoma during chronic stages of infection, less research has targeted immune mechanisms in primary ocular infections, events that could impact chronic responses. The goal of this study was to investigate the function of neutrophils during primary chlamydial ocular infection by using the guinea pig model of Chlamydia caviae inclusion conjunctivitis. We hypothesized that neutrophils help modulate the adaptive response and promote host tissue damage. To test these hypotheses, guinea pigs with primary C. caviae ocular infections were depleted of neutrophils by using rabbit antineutrophil antiserum, and immune responses and immunopathology were evaluated during the first 7 days of infection. Results showed that neutrophil depletion dramatically decreased ocular pathology, both clinically and histologically. The adaptive response was also altered, with increased C. caviae-specific IgA titers in tears and serum and decreased numbers of CD4 ؉ and CD8 ؉ T cells in infected conjunctivae. Additionally, there were changes in conjunctival chemokines and cytokines, such as increased expression of IgA-promoting interleukin-5 and anti-inflammatory transforming growth factor ␤, along with decreased expression of T cell-recruiting CCL5 (RANTES). This study, the first to investigate the role of neutrophils in primary chlamydial ocular infection, indicates a previously unappreciated role for neutrophils in modulating the adaptive response and suggests a prominent role for neutrophils in chlamydia-associated ocular pathology.

Enhanced Neutrophil Longevity and Recruitment Contribute to the Severity of Oviduct Pathology during Chlamydia muridarum Infection

“…These findings bring into question the ability of anti-Ly6G antibody to successfully eliminate neutrophils in any model that induces robust production of colony-stimulating factors and requires that histological examination of tissues be performed to confirm the absence of cells with neutrophil morphology. In a local conjunctival infection with Chlamydia caviae, administration of antineutrophil antibody resulted in successful depletion of neutrophils in the tissue and significantly reduced levels of pathology (23). These findings support the role of neutrophils in the development of chlamydia-in- duced pathology and the use of antibodies to deplete neutrophils during localized infection.…”

“…These findings support the role of neutrophils in the development of chlamydia-in- duced pathology and the use of antibodies to deplete neutrophils during localized infection. A potential key factor in the success of neutrophil depletion in the C. caviae study was the use of a polyclonal antibody that was specific for an array of proteins expressed by neutrophils, which prevented reduced expression of a single protein from hindering successful depletion, as occurred in our studies (23). Consideration of our data together with multiple prior reports correlating increased neutrophils with enhanced oviduct disease after chlamydial infection supports an important role for these cells and their products in oviduct tissue damage (8,16,38,42).…”

Identifying a Role for Toll-Like Receptor 3 in the Innate Immune Response to Chlamydia muridarum Infection in Murine Oviduct Epithelial Cells

“…However, neutrophils have been implicated in host tissue damage in Chlamydial infections, including guinea pig ocular chlamydial infection models (51). Recent investigations into the role of neutrophil involvement in Chlamydia pathogenesis revealed that neutrophil depletion dramatically decreased ocular pathology both clinically and histologically and that there was an associated alteration in adaptive immunity (26). Our data imply that there is not a significant recruitment of neutrophils elicited by the C. muridarum-infected OE cells; however, the in vivo role of neutrophil involvement in genital tract infections between wild-type and TLR3-deficient mice remains to be investigated.…”

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

“…It is worth noting that TGF-β and IL-10, two of the key IgA-promoting cytokines antagonize rather than stimulate neutrophil functions. Furthermore, other have shown that depletion of neutrophils in guinea pigs with primary C. caviae ocular infections, reduced rather than enhanced the ocular pathology and that this correlated with increased titers of C. caviae-specific IgA in the tears (82). …”