Reciprocal enhancement of SARS-CoV-2 and influenza virus replication in human pluripotent stem cell-derived lung organoids1.

Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (FLUAV) coinfections were associated with severe respiratory failure and more deaths. Here, we developed a model for studying SARS-CoV-2 and FLUAV coinfection using human pluripotent stem cell-induced alveolar type II organoids (hiAT2). hiAT2 organoids were susceptible to infection by both viruses and had features of severe lung damage. A single virus markedly enhanced the susceptibility to other virus infections. SARS-CoV-2 delta variants upregulated α-2-3-linked sialic acid, while FLUAV upregulated angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Moreover, coinfection by SARS-CoV-2 and FLUAV caused hyperactivation of proinflammatory and immune-related signaling pathways and cellular damage compared to a respective single virus in hiAT2 organoids. This study provides insight into molecular mechanisms underlying enhanced infectivity and severity in patients with co-infection of SARS-CoV-2 and FLUAV, which may aid in the development of therapeutics for such co-infection cases.

Insights into pandemic respiratory viruses: manipulation of the antiviral interferon response by SARS-CoV-2 and influenza A virus.

The outbreak of the COVID-19 pandemic one year after the centennial of the 1918 influenza pandemic reaffirms the catastrophic impact respiratory viruses can have on global health and economy. A key feature of SARS-CoV-2 and influenza A viruses (IAV) is their remarkable ability to suppress or dysregulate human immune responses. Here, we summarize the growing knowledge about the interplay of SARS-CoV-2 and antiviral innate immunity, with an emphasis on the regulation of type-I or -III interferon responses that are critically implicated in COVID-19 pathogenesis. Furthermore, we draw parallels to IAV infection and discuss shared innate immune sensing mechanisms and the respective viral countermeasures.

Distinct airway epithelial immune responses after infection with SARS-CoV-2 compared to H1N1.

Children are less likely than adults to suffer severe symptoms when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while influenza A H1N1 severity is comparable across ages except for the very young or elderly. Airway epithelial cells play a vital role in the early defence against viruses via their barrier and immune functions. We investigated viral replication and immune responses in SARS-CoV-2-infected bronchial epithelial cells from healthy paediatric (n = 6; 2.5-5.6 years old) and adult (n = 4; 47-63 years old) subjects and compared cellular responses following infection with SARS-CoV-2 or Influenza A H1N1. While infection with either virus triggered robust transcriptional interferon responses, including induction of type I (IFNB1) and type III (IFNL1) interferons, markedly lower levels of interferons and inflammatory proteins (IL-6, IL-8) were released following SARS-CoV-2 compared to H1N1 infection. Only H1N1 infection caused disruption of the epithelial layer. Interestingly, H1N1 infection resulted in sustained upregulation of SARS-CoV-2 entry factors FURIN and NRP1. We did not find any differences in the epithelial response to SARS-CoV-2 infection between paediatric and adult cells. Overall, SARS-CoV-2 had diminished potential to replicate, affect morphology and evoke immune responses in bronchial epithelial cells compared to H1N1.

Bilateral Avid Axillary Nodes on FDG PET/CT Due to Concurrent Booster COVID-19 Immunization and Seasonal Influenza Vaccination.

ABSTRACT: In an attempt to protect the high-risk demographic and reduce burden on health care systems, concomitant administration of COVID-19 and influenza vaccines has been recommended by health bodies. The ComFluCOV trial indicates this is well tolerated with no reduction in immune response to either vaccine. A 48-year-old woman with right oropharyngeal squamous cell carcinoma underwent postradiotherapy FDG PET/CT, which demonstrated complete metabolic response. Incidental avid bilateral axillary lymphadenopathy of benign configuration was noted and concluded to be reactive in response to recent Pfizer-BioNTech booster and influenza vaccination. This is expected to be seen more frequently over the coming months.

Comparison of Lung-Homing Receptor Expression and Activation Profiles on NK Cell and T Cell Subsets in COVID-19 and Influenza.

Respiratory viral infections with SARS-CoV-2 and influenza viruses commonly induce a strong infiltration of immune cells into the human lung, with potential detrimental effects on the integrity of the lung tissue. Despite comprising the largest fractions of circulating lymphocytes in the lung, rather little is known about how peripheral blood natural killer (NK) cell and T cell subsets are equipped for lung-homing in COVID-19 and influenza. Here, we provide a detailed comparative analysis of NK cells and T cells in patients infected with SARS-CoV-2 or influenza virus, focusing on the protein and gene expression of chemokine receptors known to be involved in recruitment to the lung. For this, we used 28-colour flow cytometry as well as re-analysis of a publicly available single-cell RNA-seq dataset from bronchoalveolar lavage (BAL) fluid. Frequencies of NK cells and T cells expressing CXCR3, CXCR6, and CCR5 were altered in peripheral blood of COVID-19 and influenza patients, in line with increased transcript expression of CXCR3, CXCR6, and CCR5 and their respective ligands in BAL fluid. NK cells and T cells expressing lung-homing receptors displayed stronger phenotypic signs of activation compared to cells lacking lung-homing receptors, and activation was overall stronger in influenza compared to COVID-19. Together, our results indicate a role for CXCR3+, CXCR6+, and/or CCR5+ NK cells and T cells that potentially migrate to the lungs in moderate COVID-19 and influenza patients, identifying common targets for future therapeutic interventions in respiratory viral infections.

COVID-19: Myths and Reality.

COVID-19, a new human respiratory disease that has killed nearly 3 million people in a year since the start of the pandemic, is a global public health challenge. Its infectious agent, SARS-CoV-2, differs from other coronaviruses in a number of structural features that make this virus more pathogenic and transmissible. In this review, we discuss some important characteristics of the main SARS-CoV-2 surface antigen, the spike (S) protein, such as (i) ability of the receptor-binding domain (RBD) to switch between the "standing-up" position (open pre-fusion conformation) for receptor binding and the "lying-down" position (closed pre-fusion conformation) for immune system evasion; (ii) advantage of a high binding affinity of the RBD open conformation to the human angiotensin-converting enzyme 2 (ACE2) receptor for efficient cell entry; and (iii) S protein preliminary activation by the intracellular furin-like proteases for facilitation of the virus spreading across different cell types. We describe interactions between the S protein and cellular receptors, co-receptors, and antagonists, as well as a hypothetical mechanism of the homotrimeric spike structure destabilization that triggers the fusion of the viral envelope with the cell membrane at physiological pH and mediates the viral nucleocapsid entry into the cytoplasm. The transition of the S protein pre-fusion conformation to the post-fusion one on the surface of virions after their treatment with some reagents, such as ß-propiolactone, is essential, especially in relation to the vaccine production. We also compare the COVID-19 pathogenesis with that of severe outbreaks of "avian" influenza caused by the A/H5 and A/H7 highly pathogenic viruses and discuss the structural similarities between the SARS-CoV-2 S protein and hemagglutinins of those highly pathogenic strains. Finally, we touch on the prospective and currently used COVID-19 antiviral and anti-pathogenetic therapeutics, as well as recently approved conventional and innovative COVID-19 vaccines and their molecular and immunological features.

COVID-19: Immunohistochemical Analysis of TGF-ß Signaling Pathways in Pulmonary Fibrosis.

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-ß is intimately involved in the fibrogenic process. When activated, TGF-ß promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 tissue expression) involved in the TGF-ß1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-ß pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-ß inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.

Metabolomic diferences between COVID-19 and H1N1 influenza induced ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by lung inflammation and pulmonary edema. Coronavirus disease 2019 (COVID-19) is associated with ARDS in the more severe cases. This study aimed to compare the specificity of the metabolic alterations induced by COVID-19 or Influenza A pneumonia (IAP) in ARDS. METHODS: Eighteen patients with ARDS due to COVID-19 and twenty patients with ARDS due to IAP, admitted to the intensive care unit. ARDS was defined as in the American-European Consensus Conference. As compared with patients with COVID-19, patients with IAP were younger and received more often noradrenaline to maintain a mean arterial pressure > 65 mm Hg. Serum samples were analyzed by Nuclear Magnetic Resonance Spectroscopy. Multivariate Statistical Analyses were used to identify metabolic differences between groups. Metabolic pathway analysis was performed to identify the most relevant pathways involved in ARDS development. RESULTS: ARDS due to COVID-19 or to IAP induces a different regulation of amino acids metabolism, lipid metabolism, glycolysis, and anaplerotic metabolism. COVID-19 causes a significant energy supply deficit that induces supplementary energy-generating pathways. In contrast, IAP patients suffer more marked inflammatory and oxidative stress responses. The classificatory model discriminated against the cause of pneumonia with a success rate of 100%. CONCLUSIONS: Our findings support the concept that ARDS is associated with a characteristic metabolomic profile that may discriminate patients with ARDS of different etiologies, being a potential biomarker for the diagnosis, prognosis, and management of this condition.

Nasopharyngeal metabolomics and machine learning approach for the diagnosis of influenza.

BACKGROUND: Respiratory virus infections are significant causes of morbidity and mortality, and may induce host metabolite alterations by infecting respiratory epithelial cells. We investigated the use of liquid chromatography quadrupole time-of-flight mass spectrometry (LC/Q-TOF) combined with machine learning for the diagnosis of influenza infection. METHODS: We analyzed nasopharyngeal swab samples by LC/Q-TOF to identify distinct metabolic signatures for diagnosis of acute illness. Machine learning models were performed for classification, followed by Shapley additive explanation (SHAP) analysis to analyze feature importance and for biomarker discovery. FINDINGS: A total of 236 samples were tested in the discovery phase by LC/Q-TOF, including 118 positive samples (40 influenza A 2009 H1N1, 39 influenza H3 and 39 influenza B) as well as 118 age and sex-matched negative controls with acute respiratory illness. Analysis showed an area under the receiver operating characteristic curve (AUC) of 1.00 (95% confidence interval [95% CI] 0.99, 1.00), sensitivity of 1.00 (95% CI 0.86, 1.00) and specificity of 0.96 (95% CI 0.81, 0.99). The metabolite most strongly associated with differential classification was pyroglutamic acid. Independent validation of a biomarker signature based on the top 20 differentiating ion features was performed in a prospective cohort of 96 symptomatic individuals including 48 positive samples (24 influenza A 2009 H1N1, 5 influenza H3 and 19 influenza B) and 48 negative samples. Testing performed using a clinically-applicable targeted approach, liquid chromatography triple quadrupole mass spectrometry, showed an AUC of 1.00 (95% CI 0.998, 1.00), sensitivity of 0.94 (95% CI 0.83, 0.98), and specificity of 1.00 (95% CI 0.93, 1.00). Limitations include lack of sample suitability assessment, and need to validate these findings in additional patient populations. INTERPRETATION: This metabolomic approach has potential for diagnostic applications in infectious diseases testing, including other respiratory viruses, and may eventually be adapted for point-of-care testing. FUNDING: None.

Adipocyte inflammation and pathogenesis of viral pneumonias: an overlooked contribution.

Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to viral respiratory pneumonias associated with H1N1 influenza and SARS-CoV-2 pandemics. Given the global obesity prevalence, a better understanding of the mechanisms behind obese susceptibility to infection is imperative. Altered immune cell metabolism and function are often perceived as a key causative factor of dysregulated inflammation. However, the contribution of adipocytes, the dominantly altered cell type in obesity with broad inflammatory properties, to infectious disease pathogenesis remains largely ignored. Thus, skewing of adipocyte-intrinsic cellular metabolism may lead to the development of pathogenic inflammatory adipocytes, which shape the overall immune responses by contributing to either premature immunosenescence, delayed hyperinflammation, or cytokine storm in infections. In this review, we discuss the underappreciated contribution of adipocyte cellular metabolism and adipocyte-produced mediators on immune system modulation and how such interplay may modify disease susceptibility and pathogenesis of influenza and SARS-CoV-2 infections in obese individuals.

Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins.

ISG15 is a ubiquitin-like modifier that also functions extracellularly, signaling through the LFA-1 integrin to promote interferon (IFN)-γ release from natural killer (NK) and T cells. The signals that lead to the production of extracellular ISG15 and the relationship between its two core functions remain unclear. We show that both epithelial cells and lymphocytes can secrete ISG15, which then signals in either an autocrine or paracrine manner to LFA-1-expressing cells. Microbial pathogens and Toll-like receptor (TLR) agonists result in both IFN-ß-dependent and -independent secretion of ISG15, and residues required for ISG15 secretion are mapped. Intracellular ISGylation inhibits secretion, and viral effector proteins, influenza B NS1, and viral de-ISGylases, including SARS-CoV-2 PLpro, have opposing effects on secretion of ISG15. These results establish extracellular ISG15 as a cytokine-like protein that bridges early innate and IFN-γ-dependent immune responses, and indicate that pathogens have evolved to differentially inhibit the intracellular and extracellular functions of ISG15.

The risk of pancreatic adenocarcinoma following SARS-CoV family infection.

COVID 19 disease has become a global catastrophe over the past year that has claimed the lives of over two million people around the world. Despite the introduction of vaccines against the disease, there is still a long way to completely eradicate it. There are concerns about the complications following infection with SARS-CoV-2. This research aimed to evaluate the possible correlation between infection with SARS-CoV viruses and cancer in an in-silico study model. To do this, the relevent dataset was selected from GEO database. Identification of differentially expressed genes among defined groups including SARS-CoV, SARS-dORF6, SARS-BatSRBD, and H1N1 were screened where the |Log FC| ≥ 1and p < 0.05 were considered statistically significant. Later, the pathway enrichment analysis and gene ontology (GO) were used by Enrichr and Shiny GO databases. Evaluation with STRING online was applied to predict the functional interactions of proteins, followed by Cytoscape analysis to identify the master genes. Finally, analysis with GEPIA2 server was carried out to reveal the possible correlation between candidate genes and cancer development. The results showed that the main molecular function of up- and down-regulated genes was "double-stranded RNA binding" and actin-binding, respectively. STRING and Cytoscape analysis presented four genes, PTEN, CREB1, CASP3, and SMAD3 as the key genes involved in cancer development. According to TCGA database results, these four genes were up-regulated notably in pancreatic adenocarcinoma. Our findings suggest that pancreatic adenocarcinoma is the most probably malignancy happening after infection with SARS-CoV family.

Dysregulation of the mevalonate pathway during SARS-CoV-2 infection: An in silico study.

SARS-CoV-2 triggers a dysregulated innate immune system activation. As the mevalonate pathway (MVP) prevents the activation of inflammasomes and cytokine release and regulates endosomal transport, compromised signaling could be associated with the pathobiology of COVID-19. Prior transcriptomic studies of host cells in response to SARS-CoV-2 infection have not reported to date the effects of SARS-CoV-2 on the MVP. In this study, we accessed public data sets to report in silico investigations into gene expression. In addition, we proposed candidate genes that are thought to have a direct association with the pathogenesis of COVID-19, and which may be dependent on signals derived from the MVP. Our results revealed dysregulation of genes involved in the MVP. These results were not found when investigating the gene expression data from host cells infected with H3N2 influenza virus, H1N1 influenza virus, or respiratory syncytial virus. Our manually curated gene set showed significant gene expression variability in A549 cells infected with SARS-CoV-2, as per Blanco-Melo et al. data set (GSE147507). In light of the present findings, SARS-CoV-2 could hijack the MVP, leading to hyperinflammatory responses. Prompt reconstitution of this pathway with available agents should be considered in future studies.

TRIM37 negatively regulates inflammatory responses induced by virus infection via controlling TRAF6 ubiquitination.

Virus-induced cytokine storm has been a devastating actuality in clinic. The abnormal production of type I interferon (IFN-1) and upregulation of multiple cytokines induced strong inflammation and thus lead to shock and organ failure. As an E3 ubiquitin ligase, tripartite motif-containing 37 (TRIM37) regulates the ubiquitination of multiple proteins including TRAFs. RNA sequencing was performed to investigated the alteration of transcriptional profile of H1N1-infected patients. qRT-PCR assay was performed to investigate the RNA levels of certain genes. The group of immune cells was examined by the Flow cytometry analysis. H&E staining was applied to evaluate lung inflammation of WT and TRIM37-KO mice. ELISA assay was performed to demonstrate the alteration of multiple cytokines. The protein levels in NF-kB signaling was estimated by western blotting and immunoprecipitation assays were applied to demonstrate the direct interaction between TRIM37 and TRAF-6. The RNA level of TRIM37 decreased in CD11b+ cells of Flu-infected patients. Knockout of TRIM37 inhibited the immune responses of H1N1-infected mice. TRIM37 deficiency reduced the levels of virous proinflammatory cytokines in bone marrow derived macrophages (BMDMs). Mechanically, TRIM37 promoted the K63-linked ubiquitination of TRAF6. TRIM37 negatively regulated inflammatory responses induced by virus infection via promoting TRAF6 ubiquitination at K63.

Elderberry for prevention and treatment of viral respiratory illnesses: a systematic review.

BACKGROUND: Elderberry has traditionally been used to prevent and treat respiratory problems. During the COVID-19 pandemic, there has been interest in elderberry supplements to treat or prevent illness, but also concern that elderberry might overstimulate the immune system and increase the risk of 'cytokine storm'. We aimed to determine benefits and harms of elderberry for the prevention and treatment of viral respiratory infections, and to assess the relationship between elderberry supplements and negative health impacts associated with overproduction of pro-inflammatory cytokines. METHODS: We conducted a systematic review and searched six databases, four research registers, and two preprint sites for studies. Two reviewers independently assessed studies for inclusion, extracted data from studies, assessed risk of bias using Cochrane tools, and evaluated certainty of estimates using GRADE. Outcomes included new illnesses and the severity and duration of illness. RESULTS: We screened 1187 records and included five randomized trials on elderberry for the treatment or prevention of viral respiratory illness. We did not find any studies linking elderberry to clinical inflammatory outcomes. However, we found three studies measuring production of cytokines ex vivo after ingestion of elderberry. Elderberry may not reduce the risk of developing the common cold; it may reduce the duration and severity of colds, but the evidence is uncertain. Elderberry may reduce the duration of influenza but the evidence is uncertain. Compared to oseltamivir, an elderberry-containing product may be associated with a lower risk of influenza complications and adverse events. We did not find evidence on elderberry and clinical outcomes related to inflammation. However, we found evidence that elderberry has some effect on inflammatory markers, although this effect may decline with ongoing supplementation. One small study compared elderberry to diclofenac (a nonsteroidal anti-inflammatory drug) and provided some evidence that elderberry is as effective or less effective than diclofenac in cytokine reduction over time. CONCLUSIONS: Elderberry may be a safe option for treating viral respiratory illness, and there is no evidence that it overstimulates the immune system. However, the evidence on both benefits and harms is uncertain and information from recent and ongoing studies is necessary to make firm conclusions.

Lung Epithelial Cell Transcriptional Regulation as a Factor in COVID-19-associated Coagulopathies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global pandemic. In addition to the acute pulmonary symptoms of coronavirus disease (COVID-19) (the disease associated with SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients. Currently, the molecular pathogenesis underlying COVID-19-associated coagulopathies are unknown. Identifying the molecular basis of how SARS-CoV-2 drives coagulation is essential to mitigating short- and long-term thrombotic risks of sick and recovered patients with COVID-19. We aimed to perform coagulation-focused transcriptome analysis of in vitro infected primary respiratory epithelial cells, patient-derived bronchial alveolar lavage cells, and circulating immune cells during SARS-CoV-2 infection. Our objective was to identify transcription-mediated signaling networks driving coagulopathies associated with COVID-19. We analyzed recently published experimentally and clinically derived bulk or single-cell RNA sequencing datasets of SARS-CoV-2 infection to identify changes in transcriptional regulation of blood coagulation. We also confirmed that the transcriptional expression of a key coagulation regulator was recapitulated at the protein level. We specifically focused our analysis on lung tissue-expressed genes regulating the extrinsic coagulation cascade and the plasminogen activation system. Analyzing transcriptomic data of in vitro infected normal human bronchial epithelial cells and patient-derived bronchial alveolar lavage samples revealed that SARS-CoV-2 infection induces the extrinsic blood coagulation cascade and suppresses the plasminogen activation system. We also performed in vitro SARS-CoV-2 infection experiments on primary human lung epithelial cells to confirm that transcriptional upregulation of tissue factor, the extrinsic coagulation cascade master regulator, manifested at the protein level. Furthermore, infection of normal human bronchial epithelial cells with influenza A virus did not drive key regulators of blood coagulation in a similar manner as SARS-CoV-2. In addition, peripheral blood mononuclear cells did not differentially express genes regulating the extrinsic coagulation cascade or plasminogen activation system during SARS-CoV-2 infection, suggesting that they are not directly inducing coagulopathy through these pathways. The hyperactivation of the extrinsic blood coagulation cascade and the suppression of the plasminogen activation system in SARS-CoV-2-infected epithelial cells may drive diverse coagulopathies in the lung and distal organ systems. Understanding how hosts drive such transcriptional changes with SARS-CoV-2 infection may enable the design of host-directed therapeutic strategies to treat COVID-19 and other coronaviruses inducing hypercoagulation.

Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia.

Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury after viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and SARS coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell prorepair function after lung injury remains unknown. Here, we showed that aging results in a cell-autonomous impairment of reparative Treg cell function after experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provided insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Strategies to restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.

Quercetin as a Natural Therapeutic Candidate for the Treatment of Influenza Virus.

The medical burden caused by respiratory manifestations of influenza virus (IV) outbreak as an infectious respiratory disease is so great that governments in both developed and developing countries have allocated significant national budget toward the development of strategies for prevention, control, and treatment of this infection, which is seemingly common and treatable, but can be deadly. Frequent mutations in its genome structure often result in resistance to standard medications. Thus, new generations of treatments are critical to combat this ever-evolving infection. Plant materials and active compounds have been tested for many years, including, more recently, active compounds like flavonoids. Quercetin is a compound belonging to the flavonols class and has shown therapeutic effects against influenza virus. The focus of this review includes viral pathogenesis as well as the application of quercetin and its derivatives as a complementary therapy in controlling influenza and its related symptoms based on the targets. We also touch on the potential of this class of compounds for treatment of SARS-COV-2, the cause of new pandemic.

Interleukin-38 ameliorates poly(I:C) induced lung inflammation: therapeutic implications in respiratory viral infections.

Interleukin-38 has recently been shown to have anti-inflammatory properties in lung inflammatory diseases. However, the effects of IL-38 in viral pneumonia remains unknown. In the present study, we demonstrate that circulating IL-38 concentrations together with IL-36α increased significantly in influenza and COVID-19 patients, and the level of IL-38 and IL-36α correlated negatively and positively with disease severity and inflammation, respectively. In the co-cultured human respiratory epithelial cells with macrophages to mimic lung microenvironment in vitro, IL-38 was able to alleviate inflammatory responses by inhibiting poly(I:C)-induced overproduction of pro-inflammatory cytokines and chemokines through intracellular STAT1, STAT3, p38 MAPK, ERK1/2, MEK, and NF-κB signaling pathways. Intriguingly, transcriptomic profiling revealed that IL-38 targeted genes were associated with the host innate immune response to virus. We also found that IL-38 counteracts the biological processes induced by IL-36α in the co-culture. Furthermore, the administration of recombinant IL-38 could mitigate poly I:C-induced lung injury, with reduced early accumulation of neutrophils and macrophages in bronchoalveolar lavage fluid, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier. Taken together, our study indicates that IL-38 plays a crucial role in protection from exaggerated pulmonary inflammation during poly(I:C)-induced pneumonia, thereby providing the basis of a novel therapeutic target for respiratory viral infections.