Intestinal immune responses to commensal and pathogenic protozoa

Abstract

The physical barrier of the intestine and associated mucosal immunity maintains a delicate homeostatic balance between the host and the external environment by regulating immune responses to commensals, as well as functioning as the first line of defense against pathogenic microorganisms. Understanding the orchestration and characteristics of the intestinal mucosal immune response during commensal or pathological conditions may provide novel insights into the mechanisms underlying microbe-induced immunological tolerance, protection, and/or pathogenesis. Over the last decade, our knowledge about the interface between the host intestinal mucosa and the gut microbiome has been dominated by studies focused on bacterial communities, helminth parasites, and intestinal viruses. In contrast, specifically how commensal and pathogenic protozoa regulate intestinal immunity is less well studied. In this review, we provide an overview of mucosal immune responses induced by intestinal protozoa, with a major focus on the role of different cell types and immune mediators triggered by commensal (Blastocystis spp. and Tritrichomonas spp.) and pathogenic (Toxoplasma gondii, Giardia intestinalis, Cryptosporidium parvum) protozoa. We will discuss how these various protozoa modulate innate and adaptive immune responses induced in experimental models of infection that benefit or harm the host.

Keywords: Cryptosporidium; Giardia; Toxoplasma; blastocystis; commensal; intestinal immunity; protozoa.

Figure 1

Overview of the intestinal mucosal immunity during homeostasis, commensal protozoa colonization, and pathogenic protozoa infection. (A) The homeostasis of a healthy intestine is maintained by several biochemical and cellular components that form a physical barrier, including a mucus layer that isolates the lumen from the epithelium and underlying the mucus. There is a group of specialized epithelial cells composed of enterocytes, goblet cells, and Paneth cells that secrete antimicrobial peptides (AMPs), tuft cells that constitutively express IL-25, and intraepithelial lymphocytes (IELs) that regulate epithelial growth through the secretion of TGF-β1. Underneath the epithelium is the lamina propria (LP), and the main cells involved in homeostasis are macrophages and dendritic cells (DCs) responsible for tolerance and T-cell activation. Innate lymphoid cell 3 (ILC3) is the main source of granulocyte–macrophage colony-stimulating factor (GM-CSF), while T regulatory cells (Tregs) are key to maintaining intestinal balance and tolerance through the secretion of IL-10 and TGF-β. (B) The commensal protozoa colonization is represented by two protists, Tritrichomonas ssp. and Blastocystis spp. In the small intestine, Tritrichomonas spp. secrete succinate molecules that bind in tuft cells SUCNR1 receptors, inducing these cells to release IL-25 resulting in ILC2 activation and IL-13 secretion, leading to Th2 response and goblet cells hyperplasia. Meanwhile, in the large intestine, Tritrichomonas spp. induce Th1 and Th17 immune responses by eliciting IL-1β, IL-18, and IL-17 cytokine release. Blastocystis colonization induces goblet cell hyperplasia, which leads to neutral mucin production and stimulates Th1/Th17 immune response, with IL-17 and IL-23 cytokine signatures. (C) The intestinal mucosal immunity to pathogenic protozoa infection is represented by three parasites: Toxoplasma gondii, Giardia intestinalis, and Cryptosporidium parvum. T. gondii infection is characterized by a strong Th1 immunity, tissue damage, and immunopathology. The immune response to this protozoan is characterized by high levels of IL-33- and IL-18-producing epithelial cells, as well as IL-12 production by DCs. All these three cytokines act together to induce CD4⁺ T cells producing IFN-γ. The infection is also characterized by Treg collapse and a loss of Paneth cells due to the high levels of IFN-γ. G. intestinalis infection is characterized by a Th17 immunity, elicited by IL-6-producing DCs and IL-17-producing CD4⁺ T cells. In addition, G. intestinalis increases intestinal epithelial permeability and microbial translocation, as well as enhances IgA, AMPs, nitric oxide (NO) levels, and mucin secretion. C. parvum infection is characterized by a Th1 immune response, which is associated with secretion of AMPs and IL-18 by epithelial cells, IL-12 by DCs, and IFN-γ production by both innate lymphoid cells 1 (ILC1) and CD4⁺ T cells. Created with BioRender.com.