Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the second messenger cGAMP, and the adaptor molecule STING. Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62‐deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens. In the absence of p62, STING failed to traffic to autophagy‐associated vesicles. Thus, DNA sensing induces the cGAS‐STING pathway to activate TBK1, which phosphorylates IRF3 to induce IFN expression, but also phosphorylates p62 to stimulate STING degradation and attenuation of the response. Synopsis Stimulation of the cGAS‐STING pathway by cytosolic DNA leads to STING ubiquitination and degradation. The downstream cGAS‐STING kinase TBK1 also phosphorylates the selective autophagy receptor p62, which in turn directs STING for degradation by autophagy. Abrogation of autophagy severely impaired DNA‐stimulated STING degradation. p62 is essential for DNA‐stimulated STING degradation. Cells lacking p62 have elevated interferon responses to cytoplasmic DNA and DNA pathogens. TBK1 phosphorylates p62, which promoted STING degradation and regulation of the pathway.

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro—a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

In recent years, there has been an increasing interest in immunomodulatory therapy as a means to treat various conditions, including infectious diseases. For instance, Toll-like receptor (TLR) agonists have been evaluated for treatment of genital herpes. However, although the TLR7 agonist imiquimod was shown to have antiviral activity in individual patients, no significant effects were observed in clinical trials, and the compound also exhibited significant side effects, including local inflammation. Cytosolic DNA is detected by the enzyme cyclic GMP-AMP (2’3’-cGAMP) synthase (cGAS) to stimulate antiviral pathways, mainly through induction of type I interferon (IFN)s. cGAS is activated upon DNA binding to produce the cyclic dinucleotide (CDN) 2’3’-cGAMP, which in turn binds and activates the adaptor protein Stimulator of interferon genes (STING), thus triggering type I IFN expression. In contrast to TLRs, STING is expressed broadly, including in epithelial cells. Here we report that natural and non-natural STING agonists strongly induce type I IFNs in human cells and in mice in vivo, without stimulating significant inflammatory gene expression. Systemic treatment with 2’3’-cGAMP reduced genital herpes simplex virus (HSV) 2 replication and improved the clinical outcome of infection. More importantly, local application of CDNs at the genital epithelial surface gave rise to local IFN activity, but only limited systemic responses, and this treatment conferred total protection against disease in both immunocompetent and immunocompromised mice. In direct comparison between CDNs and TLR agonists, only CDNs acted directly on epithelial cells, hence allowing a more rapid and IFN-focused immune response in the vaginal epithelium. Thus, specific activation of the STING pathway in the vagina evokes induction of the IFN system but limited inflammatory responses to allow control of HSV2 infections in vivo. Herpes simplex virus (HSV)-2 is the leading cause of genital ulcers, and HSV-2 infection has also been reported to amplify HIV-transmission. So far, all attempts at making an effective anti-HSV2 vaccine have failed. In recent years, there has been an increasing interest in immunomodulatory therapy as a means to treat infections. Although the TLR7 agonist imiquimod has been shown to have antiviral activity in individual patients, no significant effects were observed in clinical trials, and the compound also exhibited significant side effects including local inflammation. Type I interferon (IFN)s are key players in antiviral defense, and it is now known that the DNA sensor cyclic GMP-AMP synthase produces the cyclic di-nucleotide (CDN) 2’3’-cyclic GMP-AMP (cGAMP), which activates the adaptor protein STING to induce IFN expression. In this work we show that natural and non-natural CDNs activate strong type I IFN responses in vivo without stimulating significant expression of genes driven by the transcription factor NF-κB, which induces inflammation. Application of CDNs at epithelial surfaces gave rise to local IFN activity, but only limited systemic responses. Importantly, all tested treatment regimens, strongly reduced replication of HSV-2 in a model for genital herpes, and significantly reduced development of disease. Finally, when comparing to TLR agonists, CDNs showed the best profile with strong IFN response specifically in the epithelial cells and limited induction of inflammation.

Herpesvirus infections can lead to a number of severe clinical manifestations, particularly when involving the central nervous system (CNS), causing encephalitis and meningitis. However, understanding of the host factors conferring increased susceptibility to these diseases and their complications remains incomplete. Previous studies have uncovered defects in the innate Toll-like receptor 3 pathway and production of type I interferon (IFN-I) in children and adults that predispose them to herpes simplex encephalitis. More recently, there is accumulating evidence for an important role of IFN-independent cell-autonomous intrinsic mechanisms, including small nucleolar RNAs, RNA lariat metabolism, and autophagy, in restricting herpesvirus replication and conferring protection against CNS infection. The present review first describes clinical manifestations of HSV infection with a focus on neurological complications and then summarizes the host–pathogen interactions and innate immune pathways responsible for sensing herpesviruses and triggering antiviral responses and immunity. Next, we review the current landscape of inborn errors of immunity and the underlying genetic defects and disturbances of cellular immune pathways that confer increased susceptibility to HSV infection in CNS. Ultimately, we discuss some of the present outstanding unanswered questions relating to inborn errors of immunity and HSV CNS infection together with some perspectives and future directions for research in the pathogenesis of these severe diseases in humans.

Long COVID (LC) is an emerging global health concern. The underlying mechanism and pathophysiology remain unclear. Presence of neutralizing autoantibodies against type 1 interferons (IFN) has been established as a predictor of critical COVID‐19. We hypothesized that persistent autoimmune activity with autoantibodies against type 1 IFN may contribute to symptoms in patients with LC. Plasma samples and clinical information were obtained from a Danish LC cohort consisting of adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Information on symptoms and quality of life was derived from an LC‐specific questionnaire and the EQ‐5D‐5L questionnaire. Detection of type 1 IFN autoantibodies in plasma were performed by ELISA. Samples collected between June, 2020, and September, 2021, from 279 patients were analyzed and compared to a control group of 94 individuals with prior mild SARS‐CoV‐2 infection who did not develop LC symptoms. In total, five LC patients (1.8%) and 3 (3.2%) of the controls had detectable circulating type 1 IFN autoantibodies. Collectively, prevalence of autoantibodies against type 1 IFN subtypes in our LC cohort were primarily driven by men and did not exceed the prevalence in controls. Thus, in our cohort, anti‐type I IFN autoantibodies are unlikely to drive LC symptoms.