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Abstract
Intestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to protect against pathogens. Here we show that IEC-intrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stopΔIEC) showed higher Salmonella burden in colonic tissues early in the infection that associated with higher luminal and systemic loads of the pathogen at later stages. Higher pathogen burden in stopΔIEC mice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stopΔIEC mice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stopΔIEC mice restored resistance to Salmonella by promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response to Salmonella infection by regulating IL-18 production by IECs.
Highlights
Resistance to an invasive pathogen involves coordination between the early and late phase of the immune response to achieve pathogen clearance without excess collateral damage to the host
Using a model where epithelial cells in the gut cannot respond to vitamin A signals, we find that epithelial vitamin A signaling
We hypothesized that vitamin A signaling in intestinal epithelial cells (IECs) regulates the mucosal immune response to mediate infection susceptibility
Summary
Resistance to an invasive pathogen involves coordination between the early and late phase of the immune response to achieve pathogen clearance without excess collateral damage to the host. The intestinal epithelium is at the forefront of host-microbial interactions and is critical for orchestrating these immune responses during infection. T cells, NK cells as well as neutrophils are recruited to the colon during infection They secrete pro-inflammatory cytokines such as interferon gamma (IFNγ) to promote bacterial clearance and halt systemic spread of the infection [2, 3]. The epithelium itself undergoes cell shedding in the early stages of infection as an innate defense mechanism to clear intracellular pathogens [4, 5]. Mechanisms that orchestrate such diverse functions of intestinal epithelial cells (IECs) during an infection remain poorly studied
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