Leukocyte-Derived IFN-α/β and Epithelial IFN-λ Constitute a Compartmentalized Mucosal Defense System that Restricts Enteric Virus Infections

Abstract

Epithelial cells are a major port of entry for many viruses, but the molecular networks which protect barrier surfaces against viral infections are incompletely understood. Viral infections induce simultaneous production of type I (IFN-α/β) and type III (IFN-λ) interferons. All nucleated cells are believed to respond to IFN-α/β, whereas IFN-λ responses are largely confined to epithelial cells. We observed that intestinal epithelial cells, unlike hematopoietic cells of this organ, express only very low levels of functional IFN-α/β receptors. Accordingly, after oral infection of IFN-α/β receptor-deficient mice, human reovirus type 3 specifically infected cells in the lamina propria but, strikingly, did not productively replicate in gut epithelial cells. By contrast, reovirus replicated almost exclusively in gut epithelial cells of IFN-λ receptor-deficient mice, suggesting that the gut mucosa is equipped with a compartmentalized IFN system in which epithelial cells mainly respond to IFN-λ that they produce after viral infection, whereas other cells of the gut mostly rely on IFN-α/β for antiviral defense. In suckling mice with IFN-λ receptor deficiency, reovirus replicated in the gut epithelium and additionally infected epithelial cells lining the bile ducts, indicating that infants may use IFN-λ for the control of virus infections in various epithelia-rich tissues. Thus, IFN-λ should be regarded as an autonomous virus defense system of the gut mucosa and other epithelial barriers that may have evolved to avoid unnecessarily frequent triggering of the IFN-α/β system which would induce exacerbated inflammation.

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

“…The predominant type III IFN response and its regulation of ISG induction observed in our studies with HIEs is consistent with previous studies reporting that murine intestinal epithelial cells from poly(I:C)-injected and murine rotavirus-infected mice exhibit equal or greater fold inductions of type III IFN than type I IFN transcripts (17,55,56,58). This contrasts with results using transformed human colonic cell lines that respond to rotavirus infection and poly(I:C) with type I IFN-β at the transcript and protein levels, and type I IFN regulates ISG induction in these cells (16,42,72).…”

“…However, our data demonstrate that IFNL transcripts do not parallel protein levels in epithelial cells during rotavirus infection. Hematopoietic cells can produce IFN-λ protein in response to multiple viruses (57), and a recent study has demonstrated that steady-state IFN-λ in the intestine may actually originate from CD45 + hematopoietic cells rather than epithelial cells in uninfected mice (56). Taken together, the HIE and mouse data suggest that the predominant source of the IFN-λ protein in the small intestine in response to rotavirus infection may be of hematopoietic rather than epithelial origin.…”

“…This result was unexpected because enteric viral replication (rotavirus, reovirus, murine norovirus) is enhanced in mice lacking the type III IFN receptor (54)(55)(56)75), even though it is notable that neutralization of the type III IFN response had a limited effect on reovirus replication (approximately twofold increase in viral transcripts) in a human colonic transformed cell line (70). The basis for the apparent discrepancy may be multifactorial and include differences in how the IFN system was blocked (neutralizing antibodies vs. receptor KOs), development of alternate compensatory pathways in IFN-KO mice, and/or differences in human and mouse type III IFN subtype expression (37,38).…”

“…However, endogenous type III IFN restricts animal rotavirus replication in mice (54,55). The mouse epithelium was thought to produce the type III IFN in vivo, although immune cells can also produce type III IFN (54,56,57). In contrast, murine type I IFN predominantly originates from lamina propria immune cells during rotavirus infection (58).…”

IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18

“…IFN-ls form a heterodimer receptor complex that consists of the unique IL28Ra and IL10Rb (Kotenko et al, 2003;Sheppard et al, 2003). Although both type I and type III interferons induce similar interferon-stimulated genes (ISGs) through the classic JAK-STAT pathway (Marcello et al, 2006;Zhang et al, 2011;Zhou et al, 2007), IFN-l receptors are only expressed in specific organs or tissues, suggesting that IFN-ls have different immune functions in vivo (de Weerd & Nguyen, 2012;Doyle et al, 2006;Mahlakõiv et al, 2015;Mordstein et al, 2010;Sommereyns et al, 2008).…”