Gut Helminth Infection-Induced Immunotolerance and Consequences for Human Papillomavirus Persistence

Abstract

Cervical cancer, a malignancy caused by persistent human papillomavirus (HPV) infection, develops in more than 500,000 women annually. More than 90% of deaths from cervical cancer occur in low- and middle-income countries. A common epidemiological feature of countries with high cervical cancer incidence is a high burden of intestinal helminth infection. The ability of intestinal helminths to trigger immunoregulation, resulting in a "tolerogenic" systemic immune environment, provides fertile soil for the persistence of oncogenic viruses such as HPV. Animal models have shown that intestinal helminth infection permits the persistence of some viruses, however, HPV-specific and human studies are lacking. Large, well-organized trials evaluating the consequences of intestinal helminth infection on the human immune system and HPV persistence may lead to improved strategies for HPV prevention in helminth-endemic regions of the world. Additionally, such studies would offer insight into the specific ways that intestinal helminth infection contributes to immunomodulation, which could identify new therapeutic targets for a range of diseases, from inflammatory disorders to cancer. In this review, we discuss the evidence for helminth-induced systemic and local immune dysregulation, discuss possible mechanisms by which chronic intestinal helminth infection may facilitate HPV persistence, and suggest novel helminth-related interventions that could offer a high leverage (if somewhat unconventional) approach to HPV and cervical cancer control in resource-constrained regions.

Figure 1.

Hypothesized role of the adaptive immune system in control of HPV. The cervical basal endothelium is exposed to human papillomavirus (HPV) via microbreaks in the epithelial layer. (A) In individuals with normal nonpolarized immune systems, resting T cells (blue circular cells) and antigen-presenting cells (APCs; yellow cells) exist in the lower layers of the epithelium. APCs take up and present HPV antigens to Th1 cells (green circular cells), leading to expansion of HPV-specific Th1 cells that contribute to destruction of infected epithelial cells. (B) If an efficient adaptive immune response does not occur (e.g., due to any agent that facilitates a “tolerogenic” immune environment), active HPV infection may establish in the basal epithelial cells. Epithelial cells containing the HPV genome (red cells) migrate toward the epithelial surface. Persistent and/or prolonged high-risk human papillomavirus (hrHPV) infection can lead to cervical dysplasia. Figure created with BioRender.com. IFN-γ = interferon-γ; IL = interleukin; Th1 = T helper type 1; TNF = tumor necrosis factor.

Figure 2.

Outline of key interactions between helminths, the bacterial gut microbiota, and the host immune system. These interactions support the hypothesis that immunomodulatory influences of commensal bacteria and helminths can promote a tolerance phenotype. IL = interleukin; PSA = polysaccharide A; SCFA = short-chain fatty acids; TGF = tumor growth factor; Th1 = type 1 helper T cell; Th2 = type 2 helper T cell; TNF = tumor necrosis factor; Treg = regulatory T cell.