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The smallest histone deacetylase (HDAC) and the only class IV HDAC member, HDAC11, is reported to regulate immune activation and tumorigenesis, yet its biochemical function is largely unknown. Here we identify HDAC11 as an efficient lysine defattyacylase that is >10,000-fold more efficient than its deacetylase activity. Through proteomics studies, we hypothesized and later biochemically validated SHMT2 as a defatty-acylation substrate of HDAC11. HDAC11-catalyzed defatty-acylation did not affect the enzymatic activity of SHMT2. Instead, it affects the ability of SHMT2 to regulate type I IFN receptor ubiquitination and cell surface level. Correspondingly, HDAC11 depletion increased type I IFN signaling in both cell culture and mice. This study not only demonstrates that HDAC11 has an activity that is much more efficient than the corresponding deacetylase activity, but also expands the physiological functions of HDAC11 and protein lysine fatty acylation, which opens up opportunities to develop HDAC11-specific inhibitors as therapeutics to modulate immune responses.

Despite significant progress in combating malaria in recent years the burden of severe disease and death due to infections remains a global public health concern. Only a fraction of infected people develops severe clinical syndromes motivating a longstanding search for genetic determinants of malaria severity. Strong genetic effects have been repeatedly ascribed to mutations and allelic variants of proteins expressed in red blood cells but the role of inflammatory response genes in disease pathogenesis has been difficult to discern. We revisited genetic evidence provided by inflammatory response genes that have been repeatedly associated to malaria, namely TNF, NOS2, IFNAR1, HMOX1, TLRs, CD36, and CD40LG. This highlighted specific genetic variants having opposing roles in the development of distinct malaria clinical outcomes and unveiled diverse levels of genetic heterogeneity that shaped the complex association landscape of inflammatory response genes with malaria. However, scrutinizing genetic effects of individual variants corroborates a pathogenesis model where pro-inflammatory genetic variants acting in early infection stages contribute to resolve infection but at later stages confer increased vulnerability to severe organ dysfunction driven by tissue inflammation. Human genetics studies are an invaluable tool to find genes and molecular pathways involved in the inflammatory response to malaria but their precise roles in disease pathogenesis are still unexploited. Genome editing in malaria experimental models and novel genotyping-by-sequencing techniques are promising approaches to delineate the relevance of inflammatory response gene variants in the natural history of infection thereby will offer new rational angles on adjuvant therapeutics for prevention and clinical management of severe malaria.

Yellow fever remains a significant public health concern in endemic regions of South America and Africa, where periodic outbreaks continue to challenge surveillance and control efforts. Despite the widespread use of vaccines and historical YFV strains in experimental settings, there is limited information on the pathogenic behavior of contemporary wild-type isolates in animal models. To address this gap, this study aimed to develop and characterize a murine model infected with a wild-type YFV strain isolated in 2018, from Brazil’s largest sylvatic outbreak in decades. In this study, four-week-old male and female C57BL/6 IFNAR1−/− mice were subcutaneously infected with WT YFV. Mice exhibited a nearly 50% survival rate and developed several clinical signs. Viral loads were assessed in serum and some tissues, collected either upon euthanasia of moribund animals or at the end point. YFV RNA was detected in all sampled tissues and serum. Infectious viral particles were identified in the brains of both sexes and in the testis. No statistically significant differences were observed between males and females in survival, clinical signs, or viral loads. Altogether, this study provides a robust and reproducible murine model for wild-type YFV infection, offering a valuable platform for investigating viral pathogenesis, host responses, and potential therapeutic interventions.

Background Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive. Objectives To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C. Methods Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured. Results We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1 , underlying autosomal recessive IFNAR1 deficiency. Conclusions Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.

Background Interferons (IFNs) play a crucial role in antiviral immunity. Genetic defects in interferon receptors, IFNs, and auto-antibodies against IFNs can lead to the development of life-threatening forms of infectious diseases like a severe form of COVID-19. Case Presentation A 13-year-old boy with a previously reported homozygous loss-of-function mutation in interferon alpha/beta receptor subunit 1 (IFNAR1) (c.674-2A > G) was diagnosed with severe COVID-19. He had cold symptoms and a high-grade fever at the time of admission. He was admitted to the pediatric intensive care unit after showing no response to favipiravir and being hypoxemic. High-resolution computed tomography (HRCT) scanning revealed lung involvement of 70% with extensive areas of consolidation in both lungs. Antibiotics, interferon gamma (IFN-γ), remdesivir, methylprednisolone pulse, and other medications were started in the patient. However, remdesivir and methylprednisolone pulse were discontinued because of their adverse side effects in the patient. His general condition improved, and a few days later was discharged from the hospital. Conclusion We reported a patient with severe COVID-19 who had a mutation in IFNAR1. Our finding suggests that patients with IFNAR1 deficiency are prone to severe forms of COVID-19. Besides, IFN-γ therapy may be a potential drug to treat patients with defects in IFN-α/β signaling pathways which needs further investigations.

Purpose A causal role of type-I interferons (IFN-I) in autoinflammatory type-I interferonopathies such as SAVI (STING–associated vasculopathy with onset in infancy) and CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) is suggested by elevated expression of IFN-I stimulated genes (ISGs). Hitherto, the lack of specific inhibitors of IFN-I signaling has prevented the verification of a causal role for IFN-I in these conditions. Commonly used inhibitors of the JAK/STAT pathway exert broad effects on multiple signaling pathways leading to more general immunosuppression beyond IFN-I signaling. Methods Here we show in four patients with SAVI and one patient with CANDLE syndrome that blockade of the IFNAR1 receptor (Anifrolumab) exerts an additive effect over JAK-inhibitor alone. In two patients with SAVI, monotherapy with Anifrolumab is sufficient to retain a suppressed IFN-I signature and clinical improvement. Results Anifrolumab normalizes IFN-I signature genes and relieves symptoms beyond what is typically achieved by a JAK-inhibitor (Baricitinib) alone in patients with type-I interferonopathies. In two patients Anifrolumab was used successfully as monotherapy. Addition of Anifrolumab enabled steroid tapering and cessation with reduced overall immunosuppression and lower risks of opportunistic infections and improved metabolic states and growth which is highly beneficial in these young patients. Conclusion These results verify a causal role of IFN-I signaling in type-I Interferonopathies SAVI and CANDLE and suggests Anifrolumab as an important new treatment option in autoinflammatory diseases with elevated IFN-I induced gene expression. Genia Kretzschmar, Laura Piñero Páez, and Ziyang Tan are shared-first authors. Sara Alehashemi, AnnaCarin Horne, and Petter Brodin are co-senior author.

Influenza virus infections particularly when followed by bacterial superinfections (BSI) result in significant morbidities and mortalities especially during influenza pandemics. Type I interferons (IFNs) regulate both anti-influenza immunity and host susceptibility to subsequent BSIs. These type I IFNs consisting of, among others, 14 IFN-α's and a single IFN-β, are recognized by and signal through the heterodimeric type I IFN receptor (IFNAR) comprised of IFNAR1 and IFNAR2. However, the individual receptor subunits can bind IFN-β or IFN-α's independently of each other and induce distinct signaling. The role of type I IFN signaling in regulating host susceptibility to both viral infections and BSI has been only examined with respect to IFNAR1 deficiency. Here, we demonstrate that despite some redundancies, IFNAR1 and IFNAR2 have distinct roles in regulating both anti-influenza A virus (IAV) immunity and in shaping host susceptibility to subsequent BSI caused by . We found IFNAR2 to be critical for anti-viral immunity. In contrast to mice, IAV-infected mice displayed both increased and accelerated morbidity and mortality compared to WT mice. Furthermore, unlike IFNAR1, IFNAR2 was sufficient to generate protection from lethal IAV infection when stimulated with IFN-β. With regards to BSI, unlike what we found previously in mice, mice were not susceptible to BSI induced on day 3 post-IAV, even though absence of IFNAR2 resulted in increased viral burden and an increased inflammatory environment. The mice similar to what we previously found in mice were less susceptible than WT mice to BSI induced on day 7 post-IAV, indicating that signaling through a complete receptor increases BSI susceptibility late during clinical IAV infection. Thus, our results support a role for IFNAR2 in induction of anti-IAV immune responses that are involved in altering host susceptibility to BSI and are essential for decreasing the morbidity and mortality associated with IAV infection. These results begin to elucidate some of the mechanisms involved in how the individual IFNAR subunits shape the anti-viral immune response. Moreover, our results highlight the importance of examining the contributions of entire receptors, as individual subunits can induce distinct outcomes as shown here.

Blunting immunopathology without abolishing host defense is the foundation for safe and effective modulation of infectious and autoimmune diseases. Sphingosine 1-phosphate receptor 1 (S1PR1) agonists are effective in treating infectious and multiple autoimmune pathologies; however, mechanisms underlying their clinical efficacy are yet to be fully elucidated. Here, we uncover an unexpected mechanism of convergence between S1PR1 and interferon alpha receptor 1 (IFNAR1) signaling pathways. Activation of S1PR1 signaling by pharmacological tools or endogenous ligand sphingosine-1 phosphate (S1P) inhibits type 1 IFN responses that exacerbate numerous pathogenic conditions. Mechanistically, S1PR1 selectively suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells (pDCs), a specialized DC subset, for robust type I IFN release. S1PR1 agonist suppression is pertussis toxin-resistant, but inhibited by an S1PR1 C-terminal–derived transactivating transcriptional activator (Tat)-fusion peptide that blocks receptor internalization. S1PR1 agonist treatment accelerates turnover of IFNAR1, suppresses signal transducer and activator of transcription 1 (STAT1) phosphorylation, and down-modulates total STAT1 levels, thereby inactivating the autoamplification loop. Inhibition of S1P-S1PR1 signaling in vivo using the selective antagonist Ex26 significantly elevates IFN-α production in response to CpG-A. Thus, multiple lines of evidence demonstrate that S1PR1 signaling sets the sensitivity of pDC amplification of IFN responses, thereby blunting pathogenic immune responses. These data illustrate a lipid G-protein coupled receptor (GPCR)-IFNAR1 regulatory loop that balances effective and detrimental immune responses and elevated endogenous S1PR1 signaling. This mechanism will likely be advantageous in individuals subject to a range of inflammatory conditions.

BACKGROUND Hepatitis B virus (HBV) remains difficult to eradicate due to the persistence of covalently closed circular DNA (cccDNA). Matrix metalloproteinase-9 (MMP-9) enhances HBV replication, but the effects of its inhibition remain unexplored. This study aimed to investigate the effects of MMP-9 inhibitors on HBV replication markers. METHODS Primary hepatocyte cultures were obtained from the livers of 6 Tupaia javanica. Cultures were infected with HBV from human sera and divided into control and intervention groups. The intervention group received MMP-9 inhibitors at 1, 3, and 7 nM. The control group received phosphate-buffered saline. Levels of hepatitis B surface antigen (HBsAg), HBV DNA, cccDNA, MMP-9, interferon alpha and beta receptor subunit 1 (IFNAR1), and interferon beta (IFN-β) were measured in both groups before and 72 hours post-intervention. RESULTS MMP-9 inhibitor administration at 1, 3, and 7 nM consistently reduced HBsAg, HBV DNA, cccDNA, and MMP-9 levels, though not statistically significant. Median HBV DNA levels at 1, 3, and 7 nM were 7.05, 5.29, and 5.98 ×103 copies/ml, respectively. Mean cccDNA levels at 1, 3, and 7 nM were 14.15, 11.04, and 13.94 ×103 copies/ml, respectively. The 3 nM dose increased IFNAR1 levels, while the 7 nM dose increased IFN-β, but neither change was significant. Among the tested doses, 3 nM showed the most favorable effects despite the lack of significance. CONCLUSIONS MMP-9 inhibitor suppressed HBsAg, HBV DNA, cccDNA, and MMP-9 while increasing IFNAR1 and IFN-β in vitro.

Akabane virus (AKAV) is a Simbu serogroup virus that can cause congenital abnormalities in ruminants. In 2010, an AKAV-7 strain exhibiting different characteristics and belonging to a distinctive genogroup compared to previous AKAVs was isolated in South Korea. Although this novel pathogenic AKAV-7 has been discovered, in vivo studies on AKAV-7 are currently insufficient due to limitations of using large animals and suckling mice. Therefore, the development of a novel small animal model for AKAV studies is necessary. Type I interferon receptor knock out (IFNAR1 KO) mice are widely employed as an infection model for Bunyavirales viruses. Here, we evaluated the suitability of IFNAR1 KO mice as a small animal model for AKAV infection. IFNAR1 KO mice inoculated with AKAV-7 strain by intraperitoneal (IP) and subcutaneous (SC) routes showed 100% mortality with high viral loads in organs and histopathological changes in the spleen and liver. These findings suggest that IFNAR1 KO mouse is susceptible to AKAV-7 infection and suitable for use as a uniformly lethal mouse model of AKAV-7. Furthermore, IFNAR1 KO mice vaccinated with the AKAV vaccine showed full protection against AKAV-7 challenge, suggesting that IFNAR1 KO mice might be useful as an animal model for AKAV vaccine studies.