Viral Trigger Research Articles

COVID-19-associated Cytokine Release Syndrome and Autologous Conditioned Serum: A Hypothesis

Coronavirus disease 2019 (COVID-19) is a rapidly progressing pandemic causing death worldwide, particularly in individuals with comorbidities or in the elderly population. The increased pro-inflammatory cytokines in patients with severe COVID-19 can be considered macrophage activation syndrome or a cytokine storm. It has been reported that an autocrine loop of interleukin (IL) 1 beta (IL-1β) over-secretion leads to a cytokine storm of IL-6, IL-18, ferritin, interferon-gamma, etc. from macrophages. Several features of COVID-19, such as the cytokine profile including pro-inflammatory cytokine levels, subsets of immune cells, serological markers, and clinical symptoms resemble a cytokine storm commonly triggered by viral infections. Although the pathophysiology and management of severe COVID-19 remains uncertain, the use of an easily obtained autologous anti-inflammatory cocktail, termed autologous conditioned serum (ACS), can be hypothesized. ACS consists of a variety of anti-inflammatory cytokines, including mainly IL-1 receptor antagonist (IL-1Ra; as much as 140-fold greater than plasma), and several growth factors. Post-mortem findings of COVID-19 patients reveal that the main pathological events are localized to the alveoli. Therefore, administering ACS via the same pathway as the viral trigger may have a positive impact on treatment. ACS should be discussed for the management of COVID-19 to target and lessen the overactive immune response while still allowing time for the host immune system to clear the virus. To balance the cytokine storm, it could be suggested to administer ACS by the same pathway as the viral trigger, using a nebulizer to directly reach the most intensely affected location: the alveoli.

A Case of Possible SARS-COV-2 Induced Beta-Cell Failure

Background: There are several known viral triggers of ketosis-prone diabetes, including SARS-1 and HHV-81,2. SARS-COV-2 can bind ACE-2 receptors on the beta-cell causing destruction and acute impairment of insulin secretion3. There is accruing evidence to suggest that COVID-19 infection can worsen preexisting diabetes or induce new disease4. Clinical Case: A 40-year-old Hispanic male presented to the ER complaining of fatigue, polyuria, and polydipsia. A screening COVID-19 PCR was positive but he denied URI symptoms. His admission labs were notable for hyperglycemia (434 mg/dL; n 71–99), metabolic acidosis (pH 7.1 [n 7.35–7.45]; HCO3 3 mmoL/L [n 21–32]), increased anion gap (27 mmoL/L; n < 12) and elevated HbA1c (7.9%; n < 5.7%). The patient’s fructosamine was also high (464 umol/L; n 200–285) and discordant from his HbA1c. There was no evidence of pancreatitis, lactic acidosis, renal impairment or hepatic dysfunction. The patient had no known medical problems, did not drink alcohol to excess, and reported good access to nutrition. He had a strong family history of T2DM, but his BMI (23.3 kg/m2) and lipid panel were normal. The DKA was managed in the medical ICU using fluids and IV insulin per protocol. The patient required 180 units of IV insulin/24-hours (2.5 units/kg/day) to maintain blood glucose 180–250 mg/dL. After 48-hours of IV insulin, he was transitioned to subcutaneous insulin and prescribed multiple daily injections at discharge. There were concerns about possible T1DM and/or glucose toxicity leading to further diagnostics. His GAD-65 (<5 [IU]/mL; n 0–5 [IU]/mL) and IA-2 (<5.4 U/mL; n <5.4 U/mL) antibodies were negative but his c-peptide was suppressed (0.64 ng/mL; n 0.8–3.85). The patient was reevaluated at three months post-discharge. His glycemic control and insulin requirements had improved but repeat c-peptide level was undetectable. He was thought to have beta-cell failure and referred to a diabetologist. Conclusion: This is a case of absolute insulin deficiency persisting for at least three months most likely attributable to acute COVID-19 infection.

Defective Interfering Genomes and the Full-Length Viral Genome Trigger RIG-I After Infection With Vesicular Stomatitis Virus in a Replication Dependent Manner

Replication competent vesicular stomatitis virus (VSV) is the basis of a vaccine against Ebola and VSV strains are developed as oncolytic viruses. Both functions depend on the ability of VSV to induce adequate amounts of interferon-α/β. It is therefore important to understand how VSV triggers interferon responses. VSV activates innate immunity via retinoic acid-inducible gene I (RIG-I), a sensor for viral RNA. Our results show that VSV needs to replicate for a robust interferon response. Analysis of RIG-I-associated RNA identified a copy-back defective-interfering (DI) genome and full-length viral genomes as main trigger of RIG-I. VSV stocks depleted of DI genomes lost most of their interferon-stimulating activity. The remaining full-length genome and leader-N-read-through sequences, however, still triggered RIG-I. Awareness for DI genomes as trigger of innate immune responses will help to standardize DI genome content and to purposefully deplete or use DI genomes as natural adjuvants in VSV-based therapeutics.

Unique Cholangiocyte-Targeted IgM Autoantibodies Correlate With Poor Outcome in Biliary Atresia.

The etiology of biliary atresia (BA) is not known and is likely multifactorial, including a genetic predisposition, a viral or environmental trigger, an aberrant autoimmune response targeting cholangiocytes, and unique susceptibilities of the neonatal bile ducts to injury. Damaged cholangiocytes may express neo self-antigens and elicit autoreactive T-cell-mediated inflammation and B-cell production of autoantibodies. The aim of this study was to discover autoantibodies in BA that correlated with outcomes. An autoantigen microarray encompassing approximately 9,500 autoantigens was used to screen for serum immunoglobulin M (IgM) and immunoglobulin G (IgG) autoantibodies in patients with BA or other liver disease controls. Validation of candidate autoantibodies by enzyme-linked immunosorbent assay on a second cohort of subjects (6-12months following Kasai portoenterostomy) and correlations of autoantibodies with outcomes were performed (serum bilirubin levels and need for liver transplant in first 2years of life). Mean anti-chitinase 3-like 1 (CHI3L1), anti-delta-like ligand (DLL-4), and antisurfactant protein D (SFTPD) IgM autoantibodies in BA were significantly higher compared with controls, and IgM autoantibody levels positively correlated with worse outcomes. Immunofluorescence revealed cholangiocyte-predominant expression of CHI3L1, DLL-4, and SFTPD. The humoral autoantibody response was associated with C3d complement activation and T-cell autoimmunity, based on detection of cholangiocyte-predominant C3d co-staining and peripheral blood autoreactive T cells specific to CHI3L1, DLL-4 and SFTPD, respectively. BA is associated with cholangiocyte-predominant IgM autoantibodies in the first year after Kasai portoenterostomy. Anti-CHI3L1, anti-DLL-4, and anti-SFTPD IgM autoantibody correlations with worse outcomes and the detection of C3d on cholangioctyes and antigen-specific autoreactive T cells suggest that autoimmunity plays a role in the ongoing bile duct injury and progression of disease.

P049 Skeletal muscle involvement in COVID-19 infection: a case report and systematic review

Background/Aims It is increasingly understood that COVID-19 has a very broad range of multi-system manifestations. Myalgia is a widely publicised feature of SARS-CoV-2 infection, however, more severe muscle injury can occur. There are several case reports of rhabdomyolysis with marked elevation in creatine kinase (CK) and myoglobinuria, leading to acute renal failure, but also reports of myositis characterised by weakness, mildly raised CK and muscle oedema on MRI. We present a systematic literature search to evaluate the clinical characteristics of skeletal muscle involvement. Methods A systematic search for terms related to "SARS-CoV-2" and "myalgia", "myositis", "rhabdomyolysis" or "muscle" was performed across four search engines (Web of Science, Pubmed, Mednar and Medrxiv) on 10/09/2020. Only original research published or translated in English was included. Information relating to skeletal muscle injury in confirmed SARS-CoV-2 infection was summarised. Results The search protocol identified 980 articles of which 200 were appropriate for abstract review. 21 case reports covering 22 patients with rhabdomyolysis were found. Other muscular pathology not defined as rhabdomyolysis by authors, included 1 case of acute myositis leading to compartment syndrome, 2 cases of myositis with classical proximal weakness, elevated creatine kinase and proximal muscle oedema on imaging, and one series of 7 patients with paraspinal myositis on MRI imaging. A histopathological study found evidence of incidental myositis in 2 cases. Critical care myopathy and polyneuropathy are described, along with many other neurological manifestations. While 91 cohort studies were identified, none looked in detail at skeletal muscle involvement. There are 8 meta-analyses which find the prevalence of myalgia between 19-33%. The age of rhabdomyolysis patients appears lower than expected for covid-19 admissions at 46.7 years, but ranged from 16 to 88. Baseline characteristics mirror those at higher risk of severe covid-19: half had either hypertension, type 2 diabetes or obesity and 86.4% were male. Common accompanying symptoms were myalgia (81.8%), fever (68.2%), cough (59.1%), dyspnoea (40.9%). Median peak CK was 22,511IU/L. 68.2% had changes consistent with covid-19 on chest imaging. Intravenous haemofiltration or mechanical ventilation were each required by 4 patients. Short term prognosis showed 18 (81.8%) being discharged, 2 deaths (9.1%) and 2 unknown outcomes. Conclusion Severe skeletal manifestations such rhabdomyolysis occur in covid-19. More research is needed to discover if this is through direct viral invasion of the tissues, or indirectly via systemic cytokine release, hyperlactataemia and hypo-oxygenation. CK should be routinely checked in those critically unwell or with severe myalgia or weakness to identify treatable rhabdomyolysis early. Chronic autoimmune conditions such as the idiopathic inflammatory myopathies may have viral environmental triggers, and one case tested positive for a myositis specific antibody. Whether patients with acute covid-19 related myositis experience ongoing long-term muscle inflammation has not yet been reported. Disclosure J.R. Hannah: None. S. Ali: None. J. Galloway: None. P. Gordon: None.

Altered Spectrum of Lymphoid Neoplasms in a Single-Center Cohort of Common Variable Immunodeficiency with Immune Dysregulation

PurposeCommon variable immune deficiency (CVID) confers an increased risk of lymphoid neoplasms, but reports describing the precise WHO specification of the lymphoma subtypes and their immunological environment are lacking. We therefore classified lymphomas—occurring in a cohort of 21 adult CVID patients during a 17-year period at our center—according to the 2016 WHO classification and characterized the local and systemic immunological contextResultsThe median time between the onset of CVID and lymphoma was 14 years. Patients showed a high prevalence of preceding immune dysregulation: lymphadenopathy (n = 13, 62%), splenomegaly (n = 18, 86%), autoimmune cytopenia (n = 14, 67%), and gastrointestinal involvement (n = 15, 71%). The entities comprised extranodal marginal zone lymphoma (n = 6), diffuse large B cell lymphoma (n = 7), plasmablastic lymphoma (n = 1), classic Hodgkin lymphoma (n = 4, including three cases with germline CTLA4 mutations), T cell large granular lymphocytic leukemia (n = 2), and peripheral T cell lymphoma, not otherwise specified (n = 1), but no follicular lymphoma. An Epstein-Barr virus association was documented in eight of 16 investigated lymphomas. High expression of PDL1 by tumor cells in five and of PDL1 and PD1 by tumor-infiltrating macrophages and T cells in 12 of 12 investigated lymphomas suggested a tolerogenic immunological tumor environment.ConclusionIn summary, a diverse combination of specific factors like genetic background, chronic immune activation, viral trigger, and impaired immune surveillance contributes to the observed spectrum of lymphomas in CVID. In the future, targeted therapies, e.g., PD1/PDL1 inhibitors in CVID associated lymphomas with a tolerogenic environment may improve therapy outcome.

SARS-CoV-2 Infection Induces Psoriatic Arthritis Flares and Enthesis Resident Plasmacytoid Dendritic Cell Type-1 Interferon Inhibition by JAK Antagonism Offer Novel Spondyloarthritis Pathogenesis Insights.

ObjectiveBacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares.MethodsNormal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated.ResultsCD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection).ConclusionEntheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.

Allergic rhinitis as a comorbid disease with Covid-19 infection

Allergic rhinitis (AR) is the most common disease (28.3%) among allergic pathology. Coronavirus disease 2019 (Covid-19) is characterized by a variety of clinical conditions ranging from mild symptoms to severe pneumonia and death. Nasal and ocular manifestations are included in the number of possible manifestations of Covid-19, therefore differential diagnosis of AR and coronavirus infection is important. The penetration of the Sars-CoV-2 virus occurs through the nasal and oral mucosa; scientists have paid close attention to the local immunity of these mucous membranes. Respiratory allergies have not been reported as risk factors for SARS- CoV-2 infection. Intranasal corticosteroids have a dose- dependent suppression of the expression of both ACE2 and the transmembrane protease, serine 2. Respiratory allergy (AR, asthma) and controlled exposure to allergens are associated with a significant decrease in ACE2 expression. Patients with Covid-19 infection need to continue intranasal corticosteroid treatment at the recommended dose for AR, as more frequent sneezing after cessation means more spread of SARS-CoV-2 infection. The importance of adhering to inhaled and intranasal corticosteroid therapy, which will achieve optimal control of upper and lower respiratory tract diseases, and may also provide protection against viral triggers, including SARS-CoV-2. Allergic rhinitis is not a contraindication for Covid-19 vaccination.

Understanding and managing anti-MDA 5 dermatomyositis, including potential COVID-19 mimicry.

Anti-Melanoma Differentiation-Associated gene 5 (MDA-5) Dermatomyositis (MDA5, DM) is a recently identified subtype of myositis characteristically associated with Rapidly Progressive Interstitial Lung Disease (RP-ILD) and unique cutaneous features. We reviewed PubMed, SCOPUS and Web of Science databases and selected 87 relevant articles after screening 1485 search results, aiming to gain a better understanding of the pathophysiology, clinical features, diagnosis, and treatment approaches of anti-MDA-5 DM described in the literature. The etiopathogenesis is speculatively linked to an unidentified viral trigger on the background of genetic predisposition culminating in an acquired type I interferonopathy. The clinical phenotype is highly varied in different ethnicities, with new clinical features having been recently described, expanding the spectrum of cases that should raise the suspicion of anti-MDA-5 DM. Unfortunately, the diagnosis is frequently missed despite excessive mortality, calling for wider awareness of suspect symptoms. RP ILD is the major determinant of survival, treatment being largely based on observational studies with recent insights into aggressive combined immunosuppression at the outset.

Endogenously Produced SARS-CoV-2 Specific IgG Antibodies May Have a Limited Impact on Clearing Nasal Shedding of Virus during Primary Infection in Humans.

While SARS-CoV-2 specific neutralizing antibodies have been developed for therapeutic purposes, the specific viral triggers that drive the generation of SARS-CoV-2 specific IgG and IgM antibodies remain only partially characterized. Moreover, it is unknown whether endogenously derived antibodies drive viral clearance that might result in mitigation of clinical severity during natural infection. We developed a series of non-linear mathematical models to investigate whether SARS-CoV-2 viral and antibody kinetics are coupled or governed by separate processes. Patients with severe disease had a higher production rate of IgG but not IgM antibodies. Maximal levels of both isotypes were governed by their production rate rather than different saturation levels between people. Our results suggest that an exponential surge in IgG levels occurs approximately 5–10 days after symptom onset with no requirement for continual antigenic stimulation. SARS-CoV-2 specific IgG antibodies appear to have limited to no effect on viral dynamics but may enhance viral clearance late during primary infection resulting from the binding effect of antibody to virus, rather than neutralization. In conclusion, SARS-CoV-2 specific IgG antibodies may play only a limited role in clearing infection from the nasal passages despite providing long-term immunity against infection following vaccination or prior infection.

Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients.

The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to “clinical” manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.

Our Evolving Understanding of ME/CFS.

The potential benefits of the scientific insights gleaned from years of treating ME/CFS for the emerging symptoms of COVID-19, and in particular Longhaul- or Longhauler-COVID-19 are discussed in this opinion article. Longhaul COVID-19 is the current name being given to the long-term sequelae (symptoms lasting beyond 6 weeks) of SARS-CoV-2 infection. Multiple case definitions for ME/CFS exist, but post-exertional malaise (PEM) is currently emerging as the ‘hallmark’ symptom. The inability to identify a unique trigger of ME/CFS, as well as the inability to identify a specific, diagnostic laboratory test, led many physicians to conclude that the illness was psychosomatic or non-existent. However, recent research in the US and the UK, championed by patient organizations and their use of the internet and social media, suggest underlying pathophysiologies, e.g., oxidative stress and mitochondrial dysfunction. The similarity and overlap of ME/CFS and Longhaul COVID-19 symptoms suggest to us similar pathological processes. We put forward a unifying hypothesis that explains the precipitating events such as viral triggers and other documented exposures: For their overlap in symptoms, ME/CFS and Longhaul COVID-19 should be described as Post Active Phase of Infection Syndromes (PAPIS). We further propose that the underlying biochemical pathways and pathophysiological processes of similar symptoms are similar regardless of the initiating trigger. Exploration of the biochemical pathways and pathophysiological processes should yield effective therapies for these conditions and others that may exhibit these symptoms. ME/CFS patients have suffered far too long. Longhaul COVD-19 patients should not be subject to a similar fate. We caution that failure to meet the now combined challenges of ME/CFS and Longhaul COVID-19 will impose serious socioeconomic as well as clinical consequences for patients, the families of patients, and society as a whole.

Foot-and-Mouth Disease Virus Evades Innate Immune Response by 3C-Targeting of MDA5.

Foot-and-mouth disease (FMD) is a highly contagious disease caused by FMD virus (FMDV) in cloven-hoofed animals. Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are representative receptors in the cytoplasm for the detection of viral RNA and trigger antiviral responses, leading to the production of type I interferon. Although MDA5 is a crucial receptor for sensing picornavirus RNA, the interplay between MDA5 and FMDV is relatively unknown compared to the interplay between RIG-I and FMDV. Here, we observed that the FMDV infection inhibits MDA5 protein expression. Of the non-structural proteins, the Lb and 3C proteinases (Lbpro and 3Cpro) were identified to be primarily responsible for this inhibition. However, the inhibition by 3Cpro was independent of proteasome, lysosome and caspase-dependent pathway and was by 3C protease activity. A direct interaction between 3Cpro and MDA5 protein was observed. In conclusion, this is the first report that 3Cpro inhibits MDA5 protein expression as a mechanism to evade the innate immune response during FMDV infection. These results elucidate the pathogenesis of FMDV and provide fundamental insights for the development of a novel vaccine or therapeutic agent.

Signatures of host-pathogen evolutionary conflict reveal MISTR-A conserved MItochondrial STress Response network.

Host–pathogen conflicts leave genetic signatures in genes that are critical for host defense functions. Using these “molecular scars” as a guide to discover gene functions, we discovered a vertebrate-specific MItochondrial STress Response (MISTR) circuit. MISTR proteins are associated with electron transport chain (ETC) factors and activated by stress signals such as interferon gamma (IFNγ) and hypoxia. Upon stress, ultraconserved microRNAs (miRNAs) down-regulate MISTR1(NDUFA4) followed by replacement with paralogs MItochondrial STress Response AntiViral (MISTRAV) and/or MItochondrial STress Response Hypoxia (MISTRH). While cells lacking MISTR1(NDUFA4) are more sensitive to chemical and viral apoptotic triggers, cells lacking MISTRAV or expressing the squirrelpox virus-encoded vMISTRAV exhibit resistance to the same insults. Rapid evolution signatures across primate genomes for MISTR1(NDUFA4) and MISTRAV indicate recent and ongoing conflicts with pathogens. MISTR homologs are also found in plants, yeasts, a fish virus, and an algal virus indicating ancient origins and suggesting diverse means of altering mitochondrial function under stress. The discovery of MISTR circuitry highlights the use of evolution-guided studies to reveal fundamental biological processes.

HANTAVIRUS CARDIOMYOPATHY IN A PATIENT WITH NEWLY DIAGNOSED SYSTEMIC LUPUS ERYTHEMATOSUS

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Hantavirus infection, traditionally associated with Hantavirus Pulmonary Syndrome in critically ill adults, has been described in less severe illness with resultant cardiopulmonary consequences, particularly in strains endemic to Texas. Characterized by pulmonary infiltrates and azotemia, cardiomyopathy is a feared complication of acute disease. Systemic Lupus Erythematosus (SLE), a pathology of diffuse inflammation, may serve as a predisposition to the development of viral sequelae. CASE PRESENTATION: A 37-year-old healthy female with occupational lumber exposure presented with one week of persistent, positional and pleuritic pain and dyspnea following self-limited upper respiratory symptoms.She was afebrile and hypertensive (140/100) with tachycardia (102) and ambulatory pulse oximetry 88%. Auscultation was limited due to pain with inspiration but exam yielded no murmurs or rubs. Electrocardiogram revealed no PR or ST segment changes and CT angiogram demonstrated bilateral ground glass opacities and reactive lymphadenopathy without pulmonary embolism.Laboratory analysis returned significant for creatinine 1.28, albumin 2.7, troponin <.03, negative HIV and respiratory virus panel and normal complements. Urine studies had subnephrotic range proteinuria without casts. Serologic studies reported ANA >1:2560, elevated RNP, Rheumatoid Factor, Smith and SS-A antibodies and positive IgM testing for hantavirus. Echocardiogram verified an ejection fraction of 25-30% without pericardial effusion. Coronary and pulmonary artery catheterization were negative for ischemic heart disease or pulmonary hypertension. DISCUSSION: She was treated with colchicine, prednisone and furosemide with improvement. Given the presence of specific antibodies, negative cardiac catheterization, characteristic echocardiographic findings and clear viral trigger, the patient was clinically diagnosed with hantavirus cardiomyopathy in the setting of newly diagnosed SLE serving as a predisposition to a worsening inflammatory cascade. Due to high pretest probability and invasive nature of the procedure, endomyocardial biopsy was deferred. Ejection fraction recovered after three months following therapy with carvedilol and lisinopril. Hantavirus has been described as a precipitant of functional, often reversible, cardiomyopathy without myocardial structure disruption. Given the rapid return of cardiac function following guideline directed medical optimization, we posit a significant viral contribution. CONCLUSIONS: This case contributes to the body of literature identifying hantavirus as a cause of functional cardiomyopathy. In the setting of co-morbid SLE, it lends to the importance of considering infectious etiologies in tandem with underlying inflammatory physiology. We believe the incidence of hantavirus to be underreported and must be considered in a patient with pulmonary infiltrates, renal involvement and cardiomyopathy. Reference #1: Knust B, Rollin PE. Twenty-year summary of surveillance for human hantavirus infections, United States. Emerg Infect Dis. 2013;19(12):1934–1937 Reference #2: Fabiano P. Saggioro, Marcos A. Rossi, Maria Irma S. Duarte, Carmen Cinira S. Martin, Venâncio A. F. Alves, Marcos L. Moreli, Luis Tadeu M. Figueiredo, Jorge E. Moreira, Alessandra A. Borges, Luciano Neder, Hantavirus Infection Induces a Typical Myocarditis That May Be Responsible for Myocardial Depression and Shock in Hantavirus Pulmonary Syndrome, The Journal of Infectious Diseases, Volume 195, Issue 10, 15 May 2007, Pages 1541–1549, https://doi.org/10.1086/513874 Reference #3: Machado, A. M., De Figueiredo, G. G., Sabino dos Santos Jr, G., & Figueiredo, L. T. M. (2009). Laboratory diagnosis of human hantavirus infection: novel insights and future potential. Future Virology, 4(4), 383-389. DISCLOSURES: No relevant relationships by Molly Horstman, source=Web Response No relevant relationships by Christopher Nemeh, source=Web Response No relevant relationships by Thiennga Vo, source=Web Response

Ubiquitination of TLR3 by TRIM3 signals its ESCRT-mediated trafficking to the endolysosomes for innate antiviral response

Trafficking of toll-like receptor 3 (TLR3) from the endoplasmic reticulum (ER) to endolysosomes and its subsequent proteolytic cleavage are required for it to sense viral double-stranded RNA (dsRNA) and trigger antiviral response, yet the underlying mechanisms remain enigmatic. We show that the E3 ubiquitin ligase TRIM3 is mainly located in the Golgi apparatus and transported to the early endosomes upon stimulation with the dsRNA analog poly(I:C). TRIM3 mediates K63-linked polyubiquitination of TLR3 at K831, which is enhanced following poly(I:C) stimulation. The polyubiquitinated TLR3 is recognized and sorted by the ESCRT (endosomal sorting complex required for transport) complexes to endolysosomes. Deficiency of TRIM3 impairs TLR3 trafficking from the Golgi apparatus to endosomes and its subsequent activation. Trim3-/- cells and mice express lower levels of antiviral genes and show lower levels of inflammatory response following poly(I:C) but not lipopolysaccharide (LPS) stimulation. These findings suggest that TRIM3-mediated polyubiquitination of TLR3 represents a feedback-positive regulatory mechanism for TLR3-mediated innate immune and inflammatory responses.

The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients.

The article describes the rationale for inhibition of the renin-angiotensin system (RAS) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent positive feedback-loop mechanisms. Based purely on experimental studies in which RAS pathway inhibitors were administered in vivo to humans/rodents, a reasonable hypothesis of using inhibitors that block both ACE and ACE2 zinc metalloproteases and their downstream pathways in COVID-19 patients will be proposed. In particular, metal (zinc) chelators and renin inhibitors may work alone or in combination to inhibit the positive feedback loops (initially triggered by SARS-CoV-2 and subsequently sustained by hypoxia independently on viral trigger) as both arms of renin-angiotensin system are upregulated, leading to critical, advanced and untreatable stages of the disease.

Identification of the PANoptosome: A Molecular Platform Triggering Pyroptosis, Apoptosis, and Necroptosis (PANoptosis).

Programmed cell death plays crucial roles in organismal development and host defense. Recent studies have highlighted mechanistic overlaps and extensive, multifaceted crosstalk between pyroptosis, apoptosis, and necroptosis, three programmed cell death pathways traditionally considered autonomous. The growing body of evidence, in conjunction with the identification of molecules controlling the concomitant activation of all three pathways by pathological triggers, has led to the development of the concept of PANoptosis. During PANoptosis, inflammatory cell death occurs through the collective activation of pyroptosis, apoptosis, and necroptosis, which can circumvent pathogen-mediated inhibition of individual death pathways. Many of the molecular details of this emerging pathway are unclear. Here, we describe the activation of PANoptosis by bacterial and viral triggers and report protein interactions that reveal the formation of a PANoptosome complex. Infection of macrophages with influenza A virus, vesicular stomatitis virus, Listeria monocytogenes, or Salmonella enterica serovar Typhimurium resulted in robust cell death and the hallmarks of PANoptosis activation. Combined deletion of the PANoptotic components caspase-1 (CASP1), CASP11, receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and CASP8 largely protected macrophages from cell death induced by these pathogens, while deletion of individual components provided reduced or no protection. Further, molecules from the pyroptotic, apoptotic, and necroptotic cell death pathways interacted to form a single molecular complex that we have termed the PANoptosome. Overall, our study identifies pathogens capable of activating PANoptosis and the formation of a PANoptosome complex.

B and T Cells Driving Multiple Sclerosis: Identity, Mechanisms and Potential Triggers.

Historically, multiple sclerosis (MS) has been viewed as being primarily driven by T cells. However, the effective use of anti-CD20 treatment now also reveals an important role for B cells in MS patients. The results from this treatment put forward T-cell activation rather than antibody production by B cells as a driving force behind MS. The main question of how their interaction provokes both B and T cells to infiltrate the CNS and cause local pathology remains to be answered. In this review, we highlight key pathogenic events involving B and T cells that most likely contribute to the pathogenesis of MS. These include (1) peripheral escape of B cells from T cell-mediated control, (2) interaction of pathogenic B and T cells in secondary lymph nodes, and (3) reactivation of B and T cells accumulating in the CNS. We will focus on the functional programs of CNS-infiltrating lymphocyte subsets in MS patients and discuss how these are defined by mechanisms such as antigen presentation, co-stimulation and cytokine production in the periphery. Furthermore, the potential impact of genetic variants and viral triggers on candidate subsets will be debated in the context of MS.

100 years of influenza research seen through the lens of Covid-19.

100 years of influenza research seen through the lens of Covid-19.