Host Chemokine and Cytokine Response in the Endocervix within the First Developmental Cycle of Chlamydia muridarum

Abstract

The initial host response in a primary chlamydial infection is the onset of acute inflammation. However, we still know very little about the early temporal events in the induction of the acute inflammatory response and how these events relate to the initial chlamydial developmental cycle in an actual genital infection. Because it was critical to initiate a synchronous infection in the endocervix in the first 24 h to evaluate the sequential expression of the host response, we developed the surgical methodology of depositing Chlamydia muridarum directly on the endocervix. Cervical tissue was collected at 3, 12, and 24 h after inoculation and the expression array of chemokines, cytokines, and receptors was assessed to characterize the response during the initial developmental cycle. Polymorphonuclear leukocyte (PMN) infiltration was first observed at 12 h after inoculation, and a few PMNs could be seen in the epithelium at 24 h. Electron microscopic analysis at 24 h showed that virtually all inclusions were at the same stage of development, indicating a synchronous infection. Several chemokine and cytokine genes were expressed as early as 3 h after infection, but by 12 h, 41 genes were expressed. Thus, activation of the host response occurs both with the introduction of elementary bodies into the host and early replication of reticulate bodies. No significant response was observed when UV-inactivated organisms were inoculated into the cervix at any time interval. This model provides an ideal opportunity to investigate the mechanisms by which the early inflammatory response is induced in vivo.

Chlamydial Intracellular Survival Strategies

“…As early as 3 h postinfection, genes encoding chemokines (CCL20, CCL3, and CCL24) that recruit immature dendritic cells (DCs) are up-regulated, as well as those encoding for TNF-a and C3 (alternative complement). Therefore, early responses prime the site of infection for immature DC infiltration, which is an important step of the adaptive response (Rank et al 2010). By 12 h postinfection, expression of chemokines that are chemotactic for natural killer (NK) cells (CXCL9-11, CCL2-4, CCL7, CCL8, and CCL12) is significantly induced, which is in agreement with the observed recruitment of NK cells to the site of infection (Tseng and Rank 1998;Rank et al 2010).…”

“…Chlamydia blocks degradation of the NF-kB retention factor IkBa and nuclear translocation Kaukoranta-Tolvanen et al 1996;Rasmussen et al 1997;Dessus-Babus et al 2000;Geng et al 2000;Netea et al 2004;Rothfuchs et al 2004;Rank et al 2010.…”

“…Therefore, early responses prime the site of infection for immature DC infiltration, which is an important step of the adaptive response (Rank et al 2010). By 12 h postinfection, expression of chemokines that are chemotactic for natural killer (NK) cells (CXCL9-11, CCL2-4, CCL7, CCL8, and CCL12) is significantly induced, which is in agreement with the observed recruitment of NK cells to the site of infection (Tseng and Rank 1998;Rank et al 2010). Not surprisingly, the proinflammatory cytokines IL1a, IL-1b, IL-1F6, and IL-1F8 are also expressed as are PMN-recruiting chemokines (CXCL1, CXCL5, and CXCL15) (Rank et al 2010).…”

Human Conjunctival Transcriptome Analysis Reveals the Prominence of Innate Defense inChlamydia trachomatisInfection

“…With the exception of two recent studies (43,64), each has described the in vitro response in experimentally infected cell lines or cells isolated from tissue. Numerous genes and pathways have been implicated as being important in the innate response to infection.…”

“…Gene expression profiling studies have used a variety of array platforms to study the host response to chlamydial infection (2,18,32,43,44,47,64,66,70,86,89,93). With the exception of two recent studies (43,64), each has described the in vitro response in experimentally infected cell lines or cells isolated from tissue.…”