A Novel Targeted RIG-I Receptor 5'Triphosphate Double Strain RNA-Based Adjuvant Significantly Improves the Immunogenicity of the SARS-CoV-2 Delta-Omicron Chimeric RBD-Dimer Recombinant Protein Vaccine.

The rapid mutation and spread of SARS-CoV-2 variants recently, especially through the emerging variants Omicron BA5, BF7, XBB and BQ1, necessitate the development of universal vaccines to provide broad spectrum protection against variants. For the SARS-CoV-2 universal recombinant protein vaccines, an effective approach is necessary to design broad-spectrum antigens and combine them with novel adjuvants that can induce high immunogenicity. In this study, we designed a novel targeted retinoic acid-inducible gene-I (RIG-I) receptor 5'triphosphate double strain RNA (5'PPP dsRNA)-based vaccine adjuvant (named AT149) and combined it with the SARS-CoV-2 Delta and Omicron chimeric RBD-dimer recombinant protein (D-O RBD) to immunize mice. The results showed that AT149 activated the P65 NF-κB signaling pathway, which subsequently activated the interferon signal pathway by targeting the RIG-I receptor. The D-O RBD + AT149 and D-O RBD + aluminum hydroxide adjuvant (Al) + AT149 groups showed elevated levels of neutralizing antibodies against the authentic Delta variant, and Omicron subvariants, BA1, BA5, and BF7, pseudovirus BQ1.1, and XBB compared with D-O RBD + Al and D-O RBD + Al + CpG7909/Poly (I:C) groups at 14 d after the second immunization, respectively. In addition, D-O RBD + AT149 and D-O RBD + Al + AT149 groups presented higher levels of the T-cell-secreted IFN-γ immune response. Overall, we designed a novel targeted RIG-I receptor 5'PPP dsRNA-based vaccine adjuvant to significantly improve the immunogenicity and broad spectrum of the SARS-CoV-2 recombinant protein vaccine.

Opportunities for Correction of Immunosuppression in Patients with Covid-19

Here, we review thematic publications in available literature sources of the databases PubMed, Scopus, Web of Science, eLibrary, 49 of which were dated of the years 1997-2022. Analysis of such reports is aimed at assessing features of cytokine storm-induced hyperinflammatory reaction with signs of immunosuppression accompanied by pronounced lymphopenia and lowered count of CD4(+)T helpers during severe COVID-19. The prognostic factor for unfavorable prognosis was based on the marker of systemic inflammatory reaction correlating with the disease severity - the soluble IL-2 receptor as well as the neutrophil-to-lymphocyte ratio and the lymphocyte subset imbalance. An immunosuppressive therapy of severe forms of COVID-19, aimed at weakening the inflammatory response, exacerbates immune dysfunction by suppressing the T cell function, mainly due to Th1 lymphocytes involved in recognizing and eliminating intracellular pathogens particularly viruses. Upon that, cell-mediated immunity becomes compromised that relies on cytotoxic T-lymphocytes, natural killer cells and macrophages. Timely and targeted immunocorrection is required to prevent or reduce the immunosuppression that accompanies a severe disease course and leads to serious and prolonged complications, as well as to association of secondary infections. In fight against the cytokine storm, it is important not to miss a time point of developing immunosuppressive condition that transitions into immunoparalysis as follows from recent publications covering the tactics of treating immune-mediated complications of coronavirus infection. The review discusses opportunities for immunosuppressive therapy along with glucocorticosteroids and monoclonal antibodies blocking IL-6 or cognate receptors. Studies using mesenchymal stem cells (MSCs) to reduce systemic inflammatory response at COVID-19 are outlined in the review. The use of antigen-specific Treg and their combinations with antagonists of tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma) as well as low-dose IL-2 in patients with SARS-CoV-2 infection were analyzed. The prognostic perspectives for CAR-T cells and CAR-NK cells technology have been considered as novel therapeutic approaches aimed at "training" effector cells to recognize the surface SARS-CoV-2 virus spike-like (S) protein. The feasibility of a therapeutic approach is also emphasized by comparatively analyzed of efficacy of using IL-7 or IL-15 during lymphopenia in patients with COVID-19. Here, side effects complicating immunocorrection come to the fore. Critical evaluation of corrected immunosuppressive conditions in patients with COVID-19 in the post-COVID-19 period by using low-dose IL-2 therapy revealed its ability to repair cellular immune response. As a result, a low-dose IL-2 therapy is recommended as a cytokine replacement therapy in such patients with COVID-19 during hyper-to-hypo-inflammatory phase transition in immune response.

The association among circadian rhythm, circadian genes and chrononutrition, its effect on obesity: a review of current evidence

Circadian rhythms, also known as circadian clocks, are cyclic endogenous biological patterns of an approximately 24-hour cycle which regulate the timing of physiology, metabolism, and behavior. Recent research in the field of circadian science has suggested that the timing of food intake may also play a role in markers of health, in addition to food choice and food quantity. There is emerging evidence suggesting that the timing of dietary intake, so-called chrono-nutrition, may be influenced by an individual<apos;>s chronotype. For example, the evening type has been linked to unhealthy diet, which could indicate a higher possibility of obesity. On the other hand, the continuum of chronotype diversity is largely mediated by genes. The presence of single nucleotide polymorphisms (SNP) of clock genes have been associated with obesity, chronotype, metabolic disturbances, and dietary habits (e.g., breakfast skipping, meal timing, energy/macronutrient intake). In this review, we outline the current knowledge of the interactions between clock genes, chronotype, dietary intake and chrono-nutrition.Additionally, it is emphasized that the COVID-19 pandemichas had a significant impact on the circadian system, dietary choices and meal timing. For this reason, the current review aims to focus on how chronotype/sleep and chrono-nutrition are affected during the COVID-19 pandemic.Copyright © 2022 Informa UK Limited, trading as Taylor & Francis Group.

Alveolar macrophages from people with severe eosinophilic asthma show differential antiviral responses to human rhinovirus 16 and SARS-CoV-2

Background: Rhinovirus is the most common trigger for exacerbations of asthma. Alveolar macrophages (AM) are a major site of RV infection and can also be infected by SARS-CoV-2. The pandemic caused by the SARS-CoV-2 raised concerns that patients with severe asthma (SA) would be at particularly high risk of developing severe disease. To date, evidence for poor outcomes in asthma remains limited suggesting a differential immune response to these two viruses. Method(s): Alveolar macrophages (AM) were isolated from bronchoalveolar lavage samples from patients with SA and infected with RV (n=13), SARS-CoV-2 alpha (B.1.1.7) (n=9) and delta (B.1.627.2)(n=8) variants. Antiviral mediators representing NF-KB-induced interferon-driven mRNAs (IL6 and IL8, RIGI and MDA5, respectively) were measured by qPCR, normalised to GAPDH and compared between infected AM and controls. Result(s): RV infected AM showed significant increases in mRNA expression of RIGI (4.39 fold change +/-4.68, p<0.001 vs control), MDA5 (2.96 fold change +/- 2.93, p=0.002 vs control) and IL6 (1.88 fold change +/- 0.98, p=0.006) compared to AM treated with control media alone, whilst IL8 did not significantly change. However, AM infected with SARS-CoV-2 alpha or delta variants showed no difference in levels of antiviral mediators compared to controls. Longitudinal analysis of AMs infected with SARS-CoV-2 alpha or delta variants showed no antiviral response. Conclusion(s): AM from subjects with severe asthma produce a pattern of anti-viral responses following RV infection that is absent when exposed to SARS-CoV-2 variants currently in circulation.

DEAD-box RNA helicase 21 negatively regulates cytosolic RNA-mediated innate immune signaling.

DEAD-box RNA helicase 21 (DDX21), also known as RHII/Gu, is an ATP-dependent RNA helicase. In addition to playing a vital role in regulating cellular RNA splicing, transcription, and translation, accumulated evidence has suggested that DDX21 is also involved in the regulation of innate immunity. However, whether DDX21 induces or antagonizes type I interferon (IFN-I) production has not been clear and most studies have been performed through ectopic overexpression or RNA interference-mediated knockdown. In this study, we generated DDX21 knockout cell lines and found that knockout of DDX21 enhanced Sendai virus (SeV)-induced IFN-ß production and IFN-stimulated gene (ISG) expression, suggesting that DDX21 is a negative regulator of IFN-ß. Mechanistically, DDX21 competes with retinoic acid-inducible gene I (RIG-I) for binding to double-stranded RNA (dsRNA), thereby attenuating RIG-I-mediated IFN-ß production. We also identified that the 217-784 amino acid region of DDX21 is essential for binding dsRNA and associated with its ability to antagonize IFN production. Taken together, our results clearly demonstrated that DDX21 negatively regulates IFN-ß production and functions to maintain immune homeostasis.

Dexamethasone, but Not Vitamin D or A, Dampens the Inflammatory Neutrophil Response to Protect At-risk COVID-19 Patients.

Dexamethasone (DEX) was the first drug shown to save lives of critically ill coronavirus disease 2019 (COVID-19) patients suffering from respiratory distress. A hyperactivated state of neutrophils was found in COVID-19 patients compared to non-COVID pneumonia cases. Given the beneficial effects of DEX in COVID-19 patients, we investigated the effects of DEX and of other immunomodulatory drugs vitamin D3 (VD3) and retinoic acid (RA) on neutrophil function. DEX, but not VD3 or RA, significantly inhibited all tested aspects of neutrophil function, e.g., degranulation, intracellular ROS production, CXCL8 release and NETosis. Interestingly, RA displayed the opposite effect by significantly increasing both CXCL8 and NET release by neutrophils. Taken together, these data suggest that the lower COVID-19 mortality in DEX-treated patients may in part be due to the dampening effect of DEX on the inflammatory neutrophil response, which could prevent neutrophil plugs with NETS in the lungs and other inflamed organs of patients.

Development of Inhalable ATRA-Loaded PLGA Nanoparticles as Host-Directed Immunotherapy against Tuberculosis.

Developing new effective treatment strategies to overcome the rise in multi-drug resistant tuberculosis cases (MDR-TB) represents a global challenge. A host-directed therapy (HDT), acting on the host immune response rather than Mtb directly, could address these resistance issues. We developed an HDT for targeted TB treatment, using All Trans Retinoic Acid (ATRA)-loaded nanoparticles (NPs) that are suitable for nebulization. Efficacy studies conducted on THP-1 differentiated cells infected with the H37Ra avirulent Mycobacterium tuberculosis (Mtb) strain, have shown a dose-dependent reduction in H37Ra growth as determined by the BACT/ALERT® system. Confocal microscopy images showed efficient and extensive cellular delivery of ATRA-PLGA NPs into THP-1-derived macrophages. A commercially available vibrating mesh nebulizer was used to generate nanoparticle-loaded droplets with a mass median aerodynamic diameter of 2.13 µm as measured by cascade impaction, and a volumetric median diameter of 4.09 µm as measured by laser diffraction. In an adult breathing simulation experiment, 65.1% of the ATRA PLGA-NP dose was inhaled. This targeted inhaled HDT could offer a new adjunctive TB treatment option that could enhance current dosage regimens leading to better patient prognosis and a decreasing incidence of MDR-TB.

PET imaging of innate immunity activation In Vivo with redox-tuned 4-[ 18F]fluoro-1-naphthol

High redox potential reactive oxygen and nitrogen species (ROS/RNS), such as O2 free radicals, superoxide, and hypochlorous acid, generated by activities of the NADPH oxidase-2 (NOX2)/myeloperoxidase (MPO) axis and related enzymes, are key effector molecules of innate immunity in physiological and diseased inflammatory states. Other lower energy species (H2O2, NO) provide adjuvant signaling functions. NOX2- and MPO-derived high energy radicals are known to oxidize naphthol species, wherein the naphthol products bind to proximate proteins and activated myeloid cells. Herein, we present 4-[18F]fluoro-1-naphthol ([18F]4FN), a novel redox-tuned radiopharmaceutical that selectively detects by positron emission tomography (PET) high energy radicals produced by activated innate immunity. The products of human MPO plus H2O2 , but not H2O2 alone, rapidly and completely oxidized [18F]4FN. All-trans-retinoic acid-differentiated HL-60 'neutrophil-like' human cells activated with phorbol-12-myristate-13-acetate (PMA) retained [ 18F]4FN 5-fold over unstimulated cells. 4-ABAH, an MPO-specific inhibitor, or DPI, a broad oxidase inhibitor, blocked cellular retention by >95%. [18F]4FN PET/CT imaging readily discriminated foci of inflammation in vivo in three distinct murine models of acute inflammation: endotoxin-induced whole-body toxic shock, PMA-induced mild contact dermatitis of the ear, and lipopolysaccharide (LPS)-induced ankle arthritis. Mechanistically, in mice in vivo, 4-ABAH reduced inflammationinduced [18F]4FN retention, and Cybb-/- (Nox2-/-) gene-deletion strongly and significantly abrogated PMA-induced [18F]4FN retention. Thus, [18F]4FN shows promise as a robust redox-tuned reporter for imaging activation states of innate immunity by PET/CT, is ready for translation. [18F]4FN PET imaging may find application in a variety of inflammatory states associated with cancer therapy, immunotherapy-related adverse events, as well as other diseases, including arthritis, hepatitis, atherosclerosis, COVID-19, as well as up-staging and monitoring multi-organ inflammation.

A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the global pandemic and life-threatening coronavirus disease 2019 (COVID-19). Although vaccines and therapeutic antibodies are available, their efficacy is continuously undermined by rapidly emerging SARS-CoV-2 variants. Here, we found that all-trans retinoic acid (ATRA), a vitamin A (retinol) derivative, showed potent antiviral activity against all SARS-CoV-2 variants in both human cell lines and human organoids of the lower respiratory tract. Mechanistically, ATRA directly binds in a deep hydrophobic pocket of the receptor binding domain (RBD) located on the top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation. In summary, our results reveal the pharmacological biotargets and structural mechanism of ATRA and other retinoids in SARS-CoV-2 infection and suggest that ATRA and its derivatives could be potential hit compounds against a broad spectrum of coronaviruses. IMPORTANCE Retinoids, a group of compounds including vitamin A and its active metabolite all-trans retinoic acid (ATRA), regulate serial physiological activity in multiple organ systems, such as cell growth, differentiation, and apoptosis. The ATRA analogues reported to date include more than 4,000 natural and synthetic molecules that are structurally and/or functionally related to ATRA. Here, we found that ATRA showed potent antiviral activity against all SARS-CoV-2 variants by directly binding in a deep hydrophobic pocket of the receptor binding domain (RBD) located on top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation, suggesting the pharmacological feasibility of using ATRA or its derivatives as a remedy for and prevention of COVID-19 disease.

Microbial Dysbiosis and Epithelial Dysfunction in Vitamin A-Deficient Lungs

Once believed to be sterile, recent studies now show microbes inhabiting healthy lungs that are dysregulated in patients with chronic obstructive pulmonary disease (COPD), asthma, tuberculosis (TB), and SARS-CoV-2 infection. Other studies have shown an increase in pulmonary disease and recurrent respiratory infections in malnourished patients. According to the World Health Organization, vitamin A deficiency (VAD) is now a major public health issue in low-income communities and many developing countries. While VAD has been shown to alter gene expression and tissue morphology in humans and mice, research suggests the lung microbiome plays an intimate role in the metabolic regulation, pathogen inhibition, and inflammatory responses in the lung. Whether dysbiosis is a cause or consequence of chronic respiratory conditions, or whether retinoic acid (RA) - the bioactive metabolite of Vitamin A - is essential for lung microbiome homeostasis, remains unknown. Therefore, we hypothesize that dietary VAD leads to epithelial remodeling which promotes microbial dysbiosis;the dysbiosis then perpetuates epithelial remodeling via host-microbe interactions. Our preliminary results show anatomical/pathological changes to the epithelium in VAD adult mouse lungs compared to controls (VAS). Using our Nkx2- 1creERT2/dnRAR Rosa26 tdTomato transgenic mouse model that selectively induces VAD in the adult lung epithelium following tamoxifen injections, our data supports the hypothesis that host epithelial aberration associated with dietary VAD is induced locally in the lung and not via distal or systemic mechanisms. Our data also indicates the onset of dysbiosis in adult mouse lungs as early as three weeks post-diet modulation as observed through changes in microbial composition in VAD mice compared to controls. Finally, our bulk RNAseq analysis of host and microbial gene signatures has uncovered mechanisms associated with microbial metabolic functions, ciliopathy, host cellular polarity, and immune response to infection, that are dysregulated in the absence of vitamin A. Further, we have also identified altered transcriptional activity of microbes that are traditionally symbiotic or pathobiotic under normal homeostasis. This work indicates the presence of specific host-microbe interactions that are essential for lung homeostasis and protection against lung infection and disease that are dysregulated or lost in the absence of dietary vitamin A.

NEUROPILIN-1 MEDIATES SARS-CoV-2 INFECTION of ASTROCYTES PROMOTING NEURON DYSFUNCTION

Background: SARS-CoV-2 primarily infects the lung but may also damage other organs including the brain, heart, kidney, and intestine. Central nervous system (CNS) disorders include loss of smell and taste, headache, delirium, acute psychosis, seizures, and stroke. Pathological loss of gray matter occurs in SARS-CoV-2 infection but it is unclear whether this is due to direct viral infection, indirect effects associated with systemic inflammation, or both. Methods: We used iPSC-derived brain organoids and primary human astrocytes from cerebral cortex to study direct SARS-CoV-2 infection, as confirmed by Spike and Nucleocapsid immunostaining and RT-qPCR. siRNAs, blocking antibodies, and small molecule inhibitors were used to assess SARS-CoV-2 receptor candidates. Bulk RNA-seq, DNA methylation seq, and Nanostring GeoMx digital spatial profiling were utilized to identify virus-induced changes in host gene expression. Results: Astrocytes were robustly infected by SARS-CoV-2 in brain organoids while neurons and neuroprogenitor cells supported only low-level infection. Based on siRNA knockdowns, Neuropilin-1, not ACE2, functioned as the primary receptor for SARS-CoV-2 in astrocytes. The endolysosomal two-pore channel protein, TPC, also facilitated infection likely through its regulatory effects on endocytosis. Other alternative receptors, including the AXL tyrosine kinase, CD147, and dipeptidyl protease 4 (DPP4), did not function as SARS-CoV-2 receptors in astrocytes. SARS-CoV-2 infection dynamically induced type I, II, and III interferons, and genes involved in Toll-like receptor signaling, MDA5 and RIG-I sensing of double-stranded RNA, and production of inflammatory cytokines. Genes activating apoptosis were also increased. Down-regulated genes included those involved in water, ion and lipid transport, synaptic transmission, and formation of cell junctions. Epigenetic analyses revealed transcriptional changes related to DNA methylation states, particularly decreased DNA methylation in interferon-related genes. Long-term viral infection of brain organoids resulted in progressive neuronal degeneration and death. Conclusion: Our findings support a model where SARS-CoV-2 infection of astrocytes produces a panoply of changes in the expression of genes regulating innate immune signaling and inflammatory responses. Deregulation of these genes in astrocytes produces a microenvironment within the CNS that ultimately disrupts normal neuron function, promoting neuronal cell death and CNS deficits.

RESTRICTED INFECTION of MACROPHAGES by SARS-CoV-2 INDUCES PROINFLAMMATORY RESPONSES

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with immune hyperactivation and high levels of proinflammatory cytokines. Extensive lung infiltration by CD169+ inflammatory monocytes and presence of activated CD169+ alveolar macrophages suggest monocyte/macrophages are key drivers of severe morbidity and mortality. In this study, we determined whether CD169 mediated ACE2-independent SARS-CoV-2 entry and restricted viral genome replication in macrophages triggers pro-inflammatory cytokine expression. Methods: Monocyte-derived macrophages (MDMs) and PMA-differentiated THP-1 macrophages engineered to constitutively express CD169, ACE2, or CD169 and ACE2 were infected with USA-WA1/2020/SARS-CoV-2 isolate with or without Remdesivir pre-treatment. To identify mechanism of innate immune activation, nucleic acid sensing pathways were selectively depleted in CD169+ macrophages. Extent of viral genomic (gRNA) and sub-genomic (sgRNA) expression and induction of pro-inflammatory cytokines was determined by qRT-PCR and single molecule RNA FISH analysis. Viral protein expression and infectious virus particle production was determined by immunofluorescence analysis and TCID50. Results: While productive virus infection (viral protein expression and infectious virus particle release) was only observed in ACE2+ macrophages, SARS-CoV-2 N or S expression and infectious virus production was not observed in CD169+ macrophages. Co-expression of ACE2 and CD169 significantly enhanced infectious virus production and spread. Interestingly, smFISH and RT-qPCR analysis revealed CD169+ cells express cytosolic negative-strand gRNA and positive strand sgRNA. Importantly, CD169-mediated SARS-CoV-2 infection of macrophages and expression of viral mRNAs led to induction of pro-inflammatory cytokines, IL-6, TNFα, and IL-1β, despite lack of viral protein expression in CD169+ macrophages. Pre-treatment with Remdesivir blocked de novo expression of viral mRNAs and induction of inflammatory cytokines in CD169-dependent infection of macrophages. Furthermore, knockdown of cytosolic RLRs (RIG-I and MDA-5) or MAVS significantly attenuated inflammatory cytokine expression in CD169+ macrophages, confirming that nucleic acid sensing of restricted cytosolic viral mRNA expression in macrophages triggers innate immune activation. Conclusion: These results suggest that restricted SARS-CoV-2 infection of CD169+ macrophages contributes to COVID-19-associated hyperinflammatory cytokine response.

Retinol Depletion in COVID-19.

Background and aims: COVID-19 has been a devastating pandemic. There are indications that vitamin A is depleted during infections. Vitamin A is important in development and immune homeostasis. It has been used successfully in measles, RSV and AIDS infections. In this study, we aimed to measure the serum retinol levels in severe COVID-19 patients to assess the importance of vitamin A in the COVID-19 pathogenesis. Methods: The serum retinol level was measured in two groups of patients: the COVID-19 group, which consisted of 27 severe COVID-19 patients hospitalized in the intensive care unit with respiratory failure, and the control group, which consisted of 23 patients without COVID-19 symptoms. Results: The mean serum retinol levels were 0.37 mg/L in the COVID-19 group and 0.52 mg/L in the control group. The difference between the serum retinol levels in the two groups was statistically significant. There was no significant difference in retinol levels between different ages and genders within the COVID-19 group. Comorbidity did not affect serum retinol levels. Conclusion: The serum retinol level was significantly lower in patients with severe COVID-19, and this difference was independent of age or underlying comorbidity. Our data show that retinol and retinoic acid signaling might be important in immunopathogenesis of COVID-19.

Significantly Reduced Retinol Binding Protein 4 (RBP4) Levels in Critically Ill COVID-19 Patients.

The SARS-CoV-2 virus is the causative agent of the COVID-19 pandemic. The disease causes respiratory failure in some individuals accompanied by marked hyperinflammation. Vitamin A (syn. retinol) can exist in the body in the storage form as retinyl ester, or in the transcriptionally active form as retinoic acid. The main function of retinol binding protein 4 (RBP4), synthesized in the liver, is to transport hydrophobic vitamin A to various tissues. Vitamin A has an important role in the innate and acquired immune system. In particular, it is involved in the repair of lung tissue after infections. In viral respiratory diseases such as influenza pneumonia, vitamin A supplementation has been shown to reduce mortality in animal models. In critically ill COVID-19 patients, a significant decrease in plasma vitamin A levels and an association with increased mortality have been observed. However, there is no evidence on RBP4 in relation to COVID-19. This prospective, multicenter, observational, cross-sectional study examined RBP4 (enzyme-linked immunosorbent assay) and vitamin A plasma levels (high-performance liquid chromatography) in COVID-19 patients, including 59 hospitalized patients. Of these, 19 developed critical illness (ARDS/ECMO), 20 developed severe illness (oxygenation disorder), and 20 developed moderate illness (no oxygenation disorder). Twenty age-matched convalescent patients following SARS-CoV-2 infection, were used as a control group. Reduced RBP4 plasma levels significantly correlated with impaired liver function and elevated inflammatory markers (CRP, lymphocytopenia). RBP4 levels were decreased in hospitalized patients with critical illness compared to nonpatients (p < 0.01). In comparison, significantly lower vitamin A levels were detected in hospitalized patients regardless of disease severity. Overall, we conclude that RBP4 plasma levels are significantly reduced in critically ill COVID-19 patients during acute inflammation, and vitamin A levels are significantly reduced in patients with moderate/severe/critical illness during the acute phase of illness.

SARS-Cov2 acute and post-active infection in the context of autoimmune and chronic inflammatory diseases.

The clinical and immunological spectrum of acute and post-active COVID-19 syndrome overlaps with criteria used to characterize autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Indeed, following SARS-Cov2 infection, the innate immune response is altered with an initial delayed production of interferon type I (IFN-I), while the NF-kappa B and inflammasome pathways are activated. In lung and digestive tissues, an alternative and extrafollicular immune response against SARS-Cov2 takes place with, consequently, an altered humoral and memory T cell response leading to breakdown of tolerance with the emergence of autoantibodies. However, the risk of developing severe COVID-19 among SLE and RA patients did not exceed the general population except in those having pre-existing neutralizing autoantibodies against IFN-I. Treatment discontinuation rather than COVID-19 infection or vaccination increases the risk of developing flares. Last but not least, a limited number of case reports of individuals having developed SLE or RA following COVID-19 infection/vaccination have been reported. Altogether, the SARS-Cov2 pandemic represents an unique opportunity to investigate the dangerous interplay between the immune response against infectious agents and autoimmunity, and to better understand the triggering role of infection as a risk factor in autoimmune and chronic inflammatory disease development.

Vancomycin Induced Maturation Arrest with Reactive Promyelocyte Proliferation: A Diagnosticand Therapeutic Challenge

Introduction: Drug induced leucopenia complicates any clinicalsituation especially when it's associated with COVID-19 infection.Here we report a case of vancomycin induced myeloid maturationarrest in a patient with COVID-19 infection where his conditionreverted to normal after stopping the drug.Aims &Objectives: It highlights the adverse effects of Vancomycinleading to promyelocyte proliferation posing a diagnostic challenge todifferentiate it from neoplastic promyelocyte proliferation.Materials &Methods: Case report: A 47 year old male presentedwith fever, dry cough and difficulty in breathing for 12 days. He wasCOVID-19 positive with CT lung showing bilateral pneumonic consolidations for which Vancomycin was started. Hemogram showedhemoglobin-6.8 gm/dl, total leucocyte count-3200/cumm with a differential count revealing: Neutrophil-28% (with left shift and featuresof dyspoiesis), Lymphocyte-66%, Monocyte-4%, Eosinophil-2%(Fig. 1a), and platelets-90,000/cumm. Bone marrow aspiration(BMA) and biopsy was advised. BMA was hypercellular for age withmarked promyelocyte proliferation &maturation arrest with strongMPO positivity (1b, c d). Bone marrow biopsy also reflected similarfindings (Fig-1e). FISH for PML-RARA translocation turned out to benegative, differentiating it from Acute promyeloytic Leukemia(Fig. 1f). A diagnosis of drug induced leucopenia with reactivepromyelocyte proliferation was made. Considering worsening of thesehematological findings, Vancomycin was stopped and patient'shematological findings improved drastically with stabilization ofhematological parameters.Result: Discussion: Drug induced leukopenia occurs in a dosedependent or dose-independent (idiosyncratic) reaction. Vancomycindependent antibodies against neutrophils lead to an autoimmunereaction directly affecting progenitor cell growth especially of myeloid cell lineage leading to maturation arrest. Secondly cytotoxicT-cell mediated response also has damaging effects on hematopoieticcells. Infections like COVID-19 can also lead to suppression ofnormal myeloid maturation due to release of interleukins.Conclusions: Myeloid maturation arrest with marked promyelocyteproliferation poses a diagnostic dilemma especially in patients presenting with cytopenia as they are confused with Acute promyelocytic Leukemia. This case highlights the importance of detailed knowledgerelated to drug induced myeloid maturation arrest which is reversibleafter stoppage of the offending drug.

Treatment of acute promyelocytic leukemia (APL) in a symptomatic patient with Coronavirus disease 19 (COVID-19) pneumonia

Introduction: In December 2019, a new variant of a coronavirus led to a pandemic outbreak. Patients with haematological malignancies are at high risk for a severe progression of COVID-19 with high mortality rates. Case report: 54-year-old patient was tested positive for COVID-19 upon admission. The CT scan showed bilateral ground-glass pulmonary opacities. He received dexamethasone and remdesivir. Due to severe thrombocytopenia and detection of blasts in peripheral blood a bone marrow biopsy was done. Cytological and molecular results confirmed the diagnosis intermediate risk APL. We started a therapy with arsenic trioxide and all-trans retinoic acid (ATO/ATRA). The white blood cells (WBC) increased and the respiratory situation worsened. The patient developed a thrombophlebitis. Bleeding complications appeared as an epistaxis, which required an intervention. 28 days after starting the induction, the bone marrow biopsy showed < 5% blasts. A complete peripheral remission was documented on day 50. Discussion: A major concern in treating APL is the differentiation syndrome, which can ultimately result in pulmonary failure. This patient presented with severely impaired lung function due to simultaneous COVID-19 pneumonitis. Therapy of APL had to consider both clinical conditions. Key decisions were (beyond antiviral therapy and supportive measures) a consequent dosing of glucocorticoids and early cytoreductive therapy using hydroxyurea (HU). The pulmonary function was critical during days 7-15 after start of APL therapy, consistent with differentiation syndrome being the main cause of worsening, and clinically met by stop of ATO/ATRA. Another concern was coagulation dysfunction, given the high risk of thromboembolic complications associated with COVID-19, the severe thrombocytopenia and plasmatic coagulation disorder caused by APL. In this case - besides supportive platelet transfusions - we treated by low dose heparin only when a thrombophlebitis occurred. Overall in this patient presenting with COVID-19 and simultaneously APL, the most challenging problem was overcoming pulmonary worsening in the initial phase of APL therapy.

All hands on deck: SARS-CoV-2 proteins that block early anti-viral interferon responses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is responsible for the current pandemic coronavirus disease of 2019 (COVID-19). Like other pathogens, SARS-CoV-2 infection can elicit production of the type I and III interferon (IFN) cytokines by the innate immune response. A rapid and robust type I and III IFN response can curb viral replication and improve clinical outcomes of SARS-CoV-2 infection. To effectively replicate in the host, SARS-CoV-2 has evolved mechanisms for evasion of this innate immune response, which could also modulate COVID-19 pathogenesis. In this review, we discuss studies that have reported the identification and characterization of SARS-CoV-2 proteins that inhibit type I IFNs. We focus especially on the mechanisms of nsp1 and ORF6, which are the two most potent and best studied SARS-CoV-2 type I IFN inhibitors. We also discuss naturally occurring mutations in these SARS-CoV-2 IFN antagonists and the impact of these mutations in vitro and on clinical presentation. As SARS-CoV-2 continues to spread and evolve, researchers will have the opportunity to study natural mutations in IFN antagonists and assess their role in disease. Additional studies that look more closely at previously identified antagonists and newly arising mutants may inform future therapeutic interventions for COVID-19.