The IL-6 response to Chlamydia from primary reproductive epithelial cells is highly variable and may be involved in differential susceptibility to the immunopathological consequences of chlamydial infection

Abstract

BackgroundChlamydia trachomatis infection results in reproductive damage in some women. The process and factors involved in this immunopathology are not well understood. This study aimed to investigate the role of primary human cellular responses to chlamydial stress response proteases and chlamydial infection to further identify the immune processes involved in serious disease sequelae.ResultsLaboratory cell cultures and primary human reproductive epithelial cultures produced IL-6 in response to chlamydial stress response proteases (CtHtrA and CtTsp), UV inactivated Chlamydia, and live Chlamydia. The magnitude of the IL-6 response varied considerably (up to 1000 pg ml-1) across different primary human reproductive cultures. Thus different levels of IL-6 production by reproductive epithelia may be a determinant in disease outcome. Interestingly, co-culture models with either THP-1 cells or autologous primary human PBMC generally resulted in increased levels of IL-6, except in the case of live Chlamydia where the level of IL-6 was decreased compared to the epithelial cell culture only, suggesting this pathway may be able to be modulated by live Chlamydia. PBMC responses to the stress response proteases (CtTsp and CtHtrA) did not significantly vary for the different participant cohorts. Therefore, these proteases may possess conserved innate PAMPs. MAP kinases appeared to be involved in this IL-6 induction from human cells. Finally, we also demonstrated that IL-6 was induced by these proteins and Chlamydia from mouse primary reproductive cell cultures (BALB/C mice) and mouse laboratory cell models.ConclusionsWe have demonstrated that IL-6 may be a key factor for the chlamydial disease outcome in humans, given that primary human reproductive epithelial cell culture showed considerable variation in IL-6 response to Chlamydia or chlamydial proteins, and that the presence of live Chlamydia (but not UV killed) during co-culture resulted in a reduced IL-6 response suggesting this response may be moderated by the presence of the organism.

Human and Pathogen Factors Associated with Chlamydia trachomatis-Related Infertility in Women

“…This study also showed that the PBMC production of IL-13 in response to chlamydial EBs also correlated with a reduced risk of infection (67). Our own research has demonstrated IL-6 production from endometrial and endocervical primary ex vivo cultures from live infections with C. trachomatis (68).…”

Guinea pig genital tract lipidome reveals in vivo and in vitro regulation of phosphatidylcholine 16:0/18:1 and contribution to Chlamydia trachomatis serovar D infectivity

“…We have recently established the regulation of an early event- ICAM-1 via murine microRNA-214 in Ct infected murine genital tract may contribute to late stage upper genital pathology in an IL-17A dependent manner (Arkatkar et al 2015). Additionally, palmitic acid induces TNF-α and IL-6 (Zhou et al 2013), cytokines demonstrated by us and others to contribute significantly to causation of upper genital pathology in Ct infected mice (Murthy et al 2011; Cunningham et al 2013). …”

Chlamydia trachomatis Serovars Drive Differential Production of Proinflammatory Cytokines and Chemokines Depending on the Type of Cell Infected

“…Despite its significant impact on global human health, how and why serovariants infect specific cell types, different tissues, and cause distinct pathology remains largely unknown. The majority of studies evaluating the host innate immune response to C. trachomatis have focused on a single serovar and a single cell-type (Miyairi et al, 2006;Buckner et al, 2013;Cunningham et al, 2013;Giakoumelou et al, 2017). Most studies have used human cervical carcinoma epithelioid (HeLa), human laryngeal carcinoma (Hep2), or murine fibroblast cells to model Chlamydia infection (Rasmussen et al, 1997;Dessus-Babus et al, 2002;Cunningham et al, 2013) while others have focused on epithelial cells of the endocervix (Ibana et al, 2012;Buckner et al, 2013).…”

“…The majority of studies evaluating the host innate immune response to C. trachomatis have focused on a single serovar and a single cell-type (Miyairi et al, 2006;Buckner et al, 2013;Cunningham et al, 2013;Giakoumelou et al, 2017). Most studies have used human cervical carcinoma epithelioid (HeLa), human laryngeal carcinoma (Hep2), or murine fibroblast cells to model Chlamydia infection (Rasmussen et al, 1997;Dessus-Babus et al, 2002;Cunningham et al, 2013) while others have focused on epithelial cells of the endocervix (Ibana et al, 2012;Buckner et al, 2013). While Chlamydia can infect and replicate in a plethora of cell types, recent studies have shown that cells derived from different anatomical sites support different levels of Chlamydia replication and inclusion development (Miyairi et al, 2006;Jolly et al, 2019).…”