Mechanisms of sexually transmitted infection-induced inflammation in women: implications for HIV risk

Abstract

Introduction: Globally, sexually transmitted infections (STI) affect >300 million people annually, and are a major cause of sexual and reproductive health complications in women. In this commentary, we describe how STIs interact with the immune and non-immune cells, both within and below the cervicovaginal mucosal barrier, to cause inflammation, which in turn has been associated with increased HIV acquisition risk.

Discussion: STIs have a major impact on the female genital mucosa, which is an important biological and physical barrier that forms the first line of defence against invading microorganisms such as HIV. Pattern recognition of STI pathogens, by receptors expressed either on the cell surface or inside the cell, typically triggers inflammation at the mucosal barrier. The types of mucosal responses vary by STI, and can be asymptomatic or culminate in the formation of discharge, ulcers and/or warts. While the aim of this response is to clear the invading microbes, in many cases these responses are either evaded or cause pathology that impairs barrier integrity and increases HIV access to target cells in the sub-mucosa. In addition, innate responses to STIs can result in an increased number of immune cells, including those that are the primary targets of HIV, and may contribute to the association between STIs and increased susceptibility to HIV acquisition. Many of these cells are mediators of adaptive immunity, including tissue-resident cells that may also display innate-like functions. Bacterial vaginosis (BV) is another common cause of inflammation, and evidence for multiple interactions between BV, STIs and HIV suggest that susceptibility to these conditions should be considered in concert.

Conclusions: STIs and other microbes can induce inflammation in the genital tract, perturbing the normal robust function of the mucosal barrier against HIV. While the impact of STIs on the mucosal immune system and HIV acquisition is often under-appreciated, understanding their interactions of the infections with the immune responses play an important role in improving treatment and reducing the risk of HIV acquisition. The frequent sub-clinical inflammation associated with STIs underscores the need for better STI diagnostics to reverse the immunological consequences of infection.

Keywords: HIV; adaptive immune responses; bacterial vaginosis; immunology; inflammation; mucosal immune responses; sexually transmitted infections; women.

Figure 1

Mucosal innate immune responses to STIs in the female genital tract that could potentiate HIV transmission risk. Depicted are several of the modes through which STIs might increase the risk of HIV acquisition. Infection with STIs results to physical abrasion, ulcer formation and increase of pro‐inflammatory cytokines resulting in inflammation. Inflammation increases the availability of HIV target cells in the sub‐mucosa. During N. gonorrhoeae infection, TLR2 and 4 detect lipooligosaccharide and induce a NF‐KB driven immune response resulting to production of cytokines. Infection with C. trachomatis results in death of some cells which in turn produce elementary bodies. C. trachomatis infection is detected by inflammasomes resulting to production of IL‐1b and IL‐8 through the NLR3 pathway. TLR9 detects the CpG island in Genomic material of the HPV virus inducing an immune response through the MYD88 pathway. TLR3 detects the viral nucleic acid to induce an immune response through the IRF and IR7 pathways.