Adaptive immunity to retroelements promotes barrier integrity.

Maintenance of tissue integrity is a requirement of host survival. This mandate is of prime importance at barrier sites that are constitutively exposed to the environment. Here, we show that exposure of the skin to non-inflammatory xenobiotics promotes tissue repair; more specifically, mild detergent exposure promotes the reactivation of defined retroelements leading to the induction of retroelement-specific CD8+ T cells. These T cell responses are Langerhans cell dependent and establish tissue residency within the skin. Upon injury, retroelement-specific CD8+ T cells significantly accelerate wound repair via IL-17A. Collectively, this work demonstrates that tonic environmental exposures and associated adaptive responses to retroelements can be coopted to preemptively set the tissue for maximal resilience to injury.

Gutcha: The microbiota drives tumor-induced mortality.

Tumors can cause wasting and mortality, but the connection between these outcomes is unclear. In this issue of Immunity, Chen and colleagues find the outcomes are separable as the tumor-altered gut microbiota activates renal immunity and alters metabolism, leading to mortality independently of wasting.

Orally acquired cyclic dinucleotides drive dSTING-dependent antiviral immunity in enterocytes.

Enteric pathogens overcome barrier immunity within the intestinal environment that includes the endogenous flora. The microbiota produces diverse ligands, and the full spectrum of microbial products that are sensed by the epithelium and prime protective immunity is unknown. Using Drosophila, we find that the gut presents a high barrier to infection, which is partially due to signals from the microbiota, as loss of the microbiota enhances oral viral infection. We report cyclic dinucleotide (CDN) feeding is sufficient to protect microbiota-deficient flies from enhanced oral infection, suggesting that bacterial-derived CDNs induce immunity. Mechanistically, we find CDN protection is dSTING- and dTBK1-dependent, leading to NF-kB-dependent gene expression. Furthermore, we identify the apical nucleoside transporter, CNT2, as required for oral CDN protection. Altogether, our studies define a role for bacterial products in priming immune defenses in the gut.

Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2.

There is an urgent need for antivirals to treat the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To identify new candidates, we screen a repurposing library of ∼3,000 drugs. Screening in Vero cells finds few antivirals, while screening in human Huh7.5 cells validates 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we find that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we find nine drugs are antiviral in respiratory cells, seven of which have been used in humans, and three are US Food and Drug Administration (FDA) approved, including cyclosporine. We find that the antiviral activity of cyclosporine is targeting Cyclophilin rather than calcineurin, revealing essential host targets that have the potential for rapid clinical implementation.

Using Diverse Model Systems to Define Intestinal Epithelial Defenses to Enteric Viral Infections.

The intestine is an essential physical and immunological barrier comprised of a monolayer of diverse and specialized epithelial cells that perform functions ranging from nutrient absorption to pathogen sensing and intestinal homeostasis. The intestinal barrier prevents translocation of intestinal microbes into internal compartments. The microbiota is comprised of a complex community largely populated by diverse bacterial species that provide metabolites, nutrients, and immune stimuli that promote intestinal and organismal health. Although commensal organisms promote health, enteric pathogens, including a diverse plethora of enteric viruses, cause acute and chronic diseases. The barrier epithelium plays fundamental roles in immune defenses against enteric viral infections by integrating diverse signals, including those from the microbiota, to prevent disease. Importantly, many model systems have contributed to our understanding of this complex interface. This review will focus on the antiviral mechanisms at play within the intestinal epithelium and how these responses are shaped by the microbiota.

Sirtuin Inhibitors Are Broadly Antiviral against Arboviruses.

Arthropod-borne viruses are diverse pathogens and are often associated with human disease. These viruses span multiple genera, including flaviviruses, alphaviruses, and bunyaviruses. In a high-throughput drug screen, we found that tenovin-1 was antiviral against the flaviviruses Zika virus and dengue virus. Tenovin-1 is a sirtuin inhibitor, and here we found that inhibition of sirtuins, but not inhibition of the related histone deacetylases, is potently antiviral against diverse arboviruses. Sirtuin inhibitors block infection of arboviruses in multiple human cell types. We found that sirtuin inhibitors arrest infection downstream of entry but that they do so at an early step, preventing the accumulation of viral RNA and protein. However, sirtuin inhibitors had no impact on the replication of flaviviral replicons, suggesting a defect in the establishment of replication. Consistent with this, we found that sirtuin inhibitors impacted double-stranded RNA (dsRNA) accumulation during flaviviral infection. Since these viruses infect vector insects, we also tested whether sirtuin inhibitors impacted infection of adult flies and found that these inhibitors blocked infection; therefore, they target highly conserved facets of replication. Taken together, these results suggest that sirtuin inhibitors represent a new class of potent host-targeting antivirals.IMPORTANCE Arthropod-borne viruses are diverse pathogens and are associated with human disease. Through high-throughput drug screening, we found that sirtuin inhibitors are potently antiviral against diverse arboviruses, including flaviviruses such as West Nile virus, bunyaviruses such as Rift Valley fever virus, and alphaviruses such as chikungunya virus. Sirtuin inhibitors block infection of these viruses in multiple human cell types. Moreover, we found that sirtuin inhibitors arrest infection downstream of entry but that they do so at an early step, preventing the accumulation of viral RNA and protein. Since these viruses infect vector insects, we also tested whether sirtuin inhibitors impacted infection of adult flies and found that these inhibitors blocked infection; therefore, they target highly conserved facets of replication. Taken together, these results suggest that sirtuin inhibitors represent a new class of potent host-targeting antivirals.