Plasmacytoid dendritic cells in the intestine preferentially produce interferon lambda at homeostasis contributing to tonic localized innate immune responses.

Unlabelled: The healthy intestine maintains homeostasis in part via immune responses to microbiota, which includes basal production of interferon cytokines. Previous work showed that Type III Interferon (IFN-λ) stimulates localized pockets of interferon-stimulated genes (ISGs) in the adult mouse intestinal epithelium at homeostasis that provide preemptive protection from viral pathogens. Here, we demonstrate that a major source of homeostatic IFN-λ production in the intestine is a population of epithelium-associated plasmacytoid dendritic cells (pDC).

Homeostatic antiviral protection of the neonatal gut epithelium by interferon lambda.

Cell-intrinsic antiviral gene expression by intestinal epithelial cells (IECs) limits infection by enteric viral pathogens. Here, we find that neonatal IECs express antiviral genes at homeostasis that depend on interferon lambda (IFN-λ) and are required for early control of mouse rotavirus (mRV) infection. Neonatal homeostatic IFN-λ responses are independent of microbiota and pervasively distributed among IECs, distinguishing them from the homeostatic responses of adult mice.

Interferon regulatory factor 6 (IRF6) determines intestinal epithelial cell development and immunity.

Intestinal epithelial cell (IEC) responses to interferon (IFN) favor antiviral defense with minimal cytotoxicity, but IEC-specific factors that regulate these responses remain poorly understood. Interferon regulatory factors (IRFs) are a family of nine related transcription factors, and IRF6 is preferentially expressed by epithelial cells, but its roles in IEC immunity are unknown. In this study, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screens found that Irf6 deficiency enhanced IFN-stimulated antiviral responses in transformed mouse IECs but not macrophages.

Transcriptional and Cytotoxic Responses of Human Intestinal Organoids to IFN Types I, II, and III.

The three types of IFN have roles in antimicrobial immunity and inflammation that must be properly balanced to maintain tissue homeostasis. For example, IFNs are elevated in the context of inflammatory bowel disease and may synergize with inflammatory cytokines such as TNF-α to promote tissue damage. Prior studies suggest that in mouse intestinal epithelial cells (IECs), type III IFNs are preferentially produced during viral infections and are less cytotoxic than type I IFN.

Salmonella enterica Serovar Typhimurium Induces NAIP/NLRC4- and NLRP3/ASC-Independent, Caspase-4-Dependent Inflammasome Activation in Human Intestinal Epithelial Cells.

Salmonella enterica serovar Typhimurium is a Gram-negative pathogen that causes diseases ranging from gastroenteritis to systemic infection and sepsis. Salmonella uses type III secretion systems (T3SS) to inject effectors into host cells. While these effectors are necessary for bacterial invasion and intracellular survival, intracellular delivery of T3SS products also enables detection of translocated Salmonella ligands by cytosolic immune sensors.

Homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium.

Interferon-lambda (IFN-λ) protects intestinal epithelial cells (IECs) from enteric viruses by inducing expression of antiviral IFN-stimulated genes (ISGs). Here, we find that bacterial microbiota stimulate a homeostatic ISG signature in the intestine of specific pathogen-free mice. This homeostatic ISG expression is restricted to IECs, depends on IEC-intrinsic expression of IFN-λ receptor (), and is associated with IFN-λ production by leukocytes.

Interferon Lambda in the Pathogenesis of Inflammatory Bowel Diseases.

Interferon λ (IFN-λ) is critical for host viral defense at mucosal surfaces and stimulates immunomodulatory signals, acting on epithelial cells and few other cell types due to restricted IFN-λ receptor expression. Epithelial cells of the intestine play a critical role in the pathogenesis of Inflammatory Bowel Disease (IBD), and the related type II interferons (IFN-γ) have been extensively studied in the context of IBD. However, a role for IFN-λ in IBD onset and progression remains unclear.

Innate immune sensing by epithelial barriers.

Epithelial cells in barrier tissues perform a critical immune function by detecting, restricting, and often directly eliminating extrinsic pathogens. Membrane-bound and cytosolic pattern recognition receptors in epithelial cells bind to diverse ligands, detecting pathogen components and behaviors and stimulating cell-autonomous immunity. In addition to directly acting as first-responders to pathogens, epithelial cells detect commensal-derived and diet-derived products to promote homeostasis.

Identification of SARS-CoV-2 RNA in healthcare heating, ventilation, and air conditioning units.

Evidence continues to grow supporting the aerosol transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the potential role of heating, ventilation, and air conditioning (HVAC) systems in airborne viral transmission, this study sought to determine the viral presence, if any, on air handling units in a healthcare setting where coronavirus disease 2019 (COVID-19) patients were being treated. The presence of SARS-CoV-2 RNA was detected in approximately 25% of samples taken from ten different locations in multiple air handlers.

A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity.

Affordable and effective antiviral therapies are needed worldwide, especially against agents such as dengue virus that are endemic in underserved regions. Many antiviral compounds have been studied in cultured cells but are unsuitable for clinical applications due to pharmacokinetic profiles, side effects, or inconsistent efficacy across dengue serotypes. Such tool compounds can, however, aid in identifying clinically useful treatments.

Selective Interferon Responses of Intestinal Epithelial Cells Minimize Tumor Necrosis Factor Alpha Cytotoxicity.

Interferon (IFN) family cytokines stimulate genes (interferon-stimulated genes [ISGs]) that are integral to antiviral host defense. Type I IFNs act systemically, whereas type III IFNs act preferentially at epithelial barriers. Among barrier cells, intestinal epithelial cells (IECs) are particularly dependent on type III IFN for the control and clearance of virus infection, but the physiological basis of this selective IFN response is not well understood.

Targeting intramolecular proteinase NS2B/3 cleavages for -dominant inhibition of dengue virus.

Many positive-strand RNA viruses translate their genomes as single polyproteins that are processed by host and viral proteinases to generate all viral protein products. Among these is dengue virus, which encodes the serine proteinase NS2B/3 responsible for seven different cleavages in the polyprotein. NS2B/3 has been the subject of many directed screens to find chemical inhibitors, of which the compound ARDP0006 is among the most effective at inhibiting viral growth.