Autophagy, viruses, and intestinal immunity

Abstract

Purpose of review To highlight recent findings that identify an essential role for the cellular degradative pathway of autophagy in governing a balanced response to intestinal pathogens and commensals. Recent findings Following the genetic association of autophagy with inflammatory bowel disease (IBD) susceptibility, increasing evidence indicate that this pathway functions in various epithelial lineages to support the intestinal barrier. New studies are also revealing that autophagy proteins dictate the quality and magnitude of immune responses. Mouse models in particular suggest that autophagy and IBD susceptibility genes regulate inflammatory responses to viruses, a finding that coincides with an increasing appreciation that viruses have intricate interactions with the host and the microbiota beyond the obvious host-pathogen relationship. Summary Autophagy and other immunological or stress response pathways intersect in mucosal immunity to dictate the response to pathogenic and commensal agents. The development of novel treatment strategies as well as prognostic and diagnostic tools for gastrointestinal disorders will be greatly facilitated by a deeper understanding of these interactions at the cell type and microbe-specific manner, which includes less appreciated components of the microbiota such as eukaryotic and prokaryotic viruses.

Key roles of autophagy in regulating T‐cell function

“…Dysfunction of autophagy has been associated with a number of inflammatory diseases (reviewed in ). Different mechanisms have been proposed to account for those associations.…”

Impact of Paneth Cell Autophagy on Inflammatory Bowel Disease

“…Basal autophagy occurs in nearly all kinds of cells to maintain the homeostasis of amino acid pool ( 59 ). Autophagy is generally classified into three types: macroautophagy, microautophagy, and chaperone-mediated autophagy ( 60 , 61 ). During the process of microautophagy, lysosomal/vacuolar membranes invaginate so as to engulf intracellular components via a non-selective degradative mechanism ( 62 ).…”

Links of Autophagy Dysfunction to Inflammatory Bowel Disease Onset

“…Since then, additional genetic studies have uncovered multiple genetic variants in key components of all steps of the autophagic pathway in IBD patients (Figure 1) [14–16]. There is some overlap in these autophagy-related genetic variants in both CD and UC; however, the majority of the identified variants are more strongly associated with ileal CD.…”

“…Recent studies demonstrated that additional IBD risk genes, NOD2 and leucine rich repeat kinase 2 (LRRK2), play roles in Paneth cell lysozyme packaging and secretion as well, suggesting that this autophagic response is regulated by multiple IBD risk genes [31]. A link more direct link to human IBD was identified through studies of transgenic mice with reduced Atg16L1 expression that demonstrated a requirement for an additional environmental insult for the development of altered Paneth cell morphology and CD-like ileitis [14]. These findings suggest that dysfunctional autophagy in Paneth cells may contribute to IBD onset through induction of intestinal dysbiosis that sensitizes these individuals to environmental triggers of IBD.…”

“…SQSTM1/p62 is an adaptor protein that targets cargo to the forming autophagosome, and disease-associated variants also result in AIEC intracellular survival and viable bacteria within the cytoplasm of epithelial cells [37]. Finally, a polymorphism in the coding region for leucine-rich repeat kinase 2 (LRRK2) , which is important for autophagosomal maturation, is also linked to defective xenophagy [14]. These findings highlight how multiple steps in the autophagy pathway are impaired by disease-associated variants and pathway dysfunction enhances intracellular bacterial survival in IBD.…”