Mucosal immune responses following intestinal nematode infection

Abstract

In most natural environments, the large majority of mammals harbour parasitic helminths that often live as adults within the intestine for prolonged periods (1-2 years). Although these organisms have been eradicated to a large extent within westernized human populations, those living within rural areas of developing countries continue to suffer from high infection rates. Indeed, recent estimates indicate that approximately 2.5 billion people worldwide, mainly children, currently suffer from infection with intestinal helminths (also known as geohelminths and soil-transmitted helminths) . Paradoxically, the eradication of helminths is thought to contribute to the increased incidence of autoimmune diseases and allergy observed in developed countries. In this review, we will summarize our current understanding of host-helminth interactions at the mucosal surface that result in parasite expulsion or permit the establishment of chronic infections with luminal dwelling adult worms. We will also provide insight into the adaptive immune mechanisms that provide immune protection against re-infection with helminth larvae, a process that is likely to be key to the future development of successful vaccination strategies. Lastly, the contribution of helminths to immune modulation and particularly to the treatment of allergy and inflammatory bowel disease will be discussed.

Keywords: geohelminth; immune-expulsion; intestinal helminth; mucosal immunity; nematode; type 2 immunity.

Figure 1

Mechanisms of expulsion of intestinal worms. Although the initial interaction between helminths and the host are poorly defined, infection results in the production of epithelial cell-derived cytokines such as thymic stromal lymphopoietin (TSLP), IL-33 and IL-25. Resistance to some helminth infections is independent of TSLP. Induction of TSLP regulates dendritic cell (DC) production of IL-12 and promotes basophilia (Baso), both leading to priming of type CD4⁺ T-cell responses (Th2). IL-33 is normally a nuclear protein that is released upon cellular damage. IL-33 is a potent activator of type 2 innate lymphoid cells (ILCs) that occurs early after helminth infection. IL-25 is induced in response to the microbiota and is increased following helminth infection. IL-25 induces a multipotent progenitor cell (MPP) that can give rise to other innate cell lineages. The result of these pathways is to promote a T_H2 cell response and high levels of IL-4 and IL-13. These cytokines promote worm expulsion by inducing physiological changes in the intestinal epithelium. Some expulsion mechanisms include goblet cell hyperplasia and mucus secretion, increased proliferation and turnover and smooth muscle contractility and peristalsis. In addition, although they are not critical for resistance, other factors such as cells (neutrophils, macrophages and Th17 cells), cytokines (IL-22) and the microbiota are dynamically regulated during infection and most likely play a regulatory role in the development of protective immunity to helminth infection.