When Bacteria and Viruses Collide: A Tale of Chlamydia trachomatis and Sexually Transmitted Viruses

Abstract

The global incidence of sexually transmitted infections (STIs) remains high, with the World Health Organization (WHO) estimating that over 1 million people acquire STIs daily. STIs can lead to infertility, pregnancy complications, and cancers. Co-infections with multiple pathogens are prevalent among individuals with an STI and can lead to heightened infectivity and more severe clinical manifestations. Chlamydia trachomatis (CT) is the most reported bacterial STI worldwide in both men and women, and several studies have demonstrated co-infection of CT with viral and other bacterial STIs. CT is a gram-negative bacterium with a unique biphasic developmental cycle including infectious extracellular elementary bodies (EBs) and metabolically active intracellular reticulate bodies (RBs). The intracellular form of this organism, RBs, has evolved mechanisms to persist for long periods within host epithelial cells in a viable but non-cultivable state. The co-infections of CT with the most frequently reported sexually transmitted viruses: human immunodeficiency virus (HIV), human papillomavirus (HPV), and herpes simplex virus (HSV) have been investigated through in vitro and in vivo studies. These research studies have made significant strides in unraveling the intricate interactions between CT, these viral STIs, and their eukaryotic host. In this review, we present an overview of the epidemiology of these co-infections, while specifically delineating the underlying mechanisms by which CT influences the transmission and infection dynamics of HIV and HSV. Furthermore, we explore the intricate relationship between CT and HPV infection, with a particular emphasis on the heightened risk of cervical cancer. By consolidating the current body of knowledge, we provide valuable insights into the complex dynamics and implications of co-infection involving CT and sexually transmitted viruses.

Keywords: Chlamydia trachomatis; co-infection; herpes simplex virus; human immunodeficiency virus; human papillomavirus; sexually transmitted infection.

Figure 1

Interplay of Chlamydia trachomatis and host immune responses, and its impact on human immunodeficiency virus infection in the endocervix. The columnar epithelium of the endocervix in women is a primary site of infection for Chlamydia trachomatis (CT) and a permissive site for human immunodeficiency virus (HIV) entry. Infection of CT in the columnar epithelial cells of the cervix induces pro-inflammatory responses that can lead to an influx of macrophages and neutrophils and the formation of lymphoid follicles in the submucosa. These lymphoid follicles contain B cells and T cells. CT infection in endocervical epithelial cells could facilitate HIV infection by (i) decreasing epithelial integrity and transepithelial resistance and enhancing paracellular permeability by providing direct contact with underlying infiltrating immune cells, (ii) providing additional targets for the virus by recruiting immune cells such as CD4+ T cells and macrophages to the site of infection, (iii) increasing cell surface expression of HIV-1 alternative primary receptor, galactosylceramide, and co-receptors, CXCR4 and CCR5 on CT-infected epithelial cells, (iv) secretion of cytokines/unidentified factors that may be acting directly upon CD4+ cells to facilitate HIV entry and/or replication. Created with BioRender.com.

Figure 2

Interplay of Chlamydia trachomatis and host immune responses, and its impact on human papillomavirus infection in ectocervix and oncogenic transformation. Chlamydia trachomatis (CT) infection may increase susceptibility to human papillomavirus (HPV) infection through different strategies. (i) In the endocervix, infection of immature endocervical cells with CT leads to epithelial transformation (metaplasia). Metaplastic tissues are preferred by HPV for infection. (ii) In the ectocervix, CT infection in the squamous epithelium may lead to the release of reactive oxygen species (ROS), inflammatory cytokines, and molecules with degradative characteristics. ROS induces cellular DNA breaks that facilitate the integration of viral DNA. (iii) Chronic inflammation resulting from CT infection induces inflammatory responses that impair the epithelial integrity of the ectocervix and facilitates entry of HPV, therefore functioning as an entryway for the virions to the basal epithelium layer. (iv) Inflammatory cytokines released from CT-infected epithelial cells may influence HPV cell entry, replication, and enhance viral persistence. Created with BioRender.com.