Background Post-vaccination myopericarditis is reported after immunization with COVID-19 mRNA-vaccines. The effect of accidental intravenous injection of this vaccine on the heart is unknown. Methods We compared the clinical manifestations, histopathological changes, tissue mRNA expression and serum levels of cytokine/chemokine in Balb/c mice at different time points after intravenous(IV) or intramuscular(IM) vaccine injection with normal saline(NS) control. Results Though significant weight loss and higher serum cytokine/chemokine levels were found in IM group at 1 to 2 days post-injection(dpi), only IV group developed histopathological changes of myopericarditis as evidenced by cardiomyocyte degeneration, apoptosis and necrosis with adjacent inflammatory cell infiltration and calcific deposits on visceral pericardium, while evidence of coronary artery or other cardiac pathologies was absent. SARS-CoV-2 spike antigen expression by immunostaining was occasionally found in infiltrating immune cells of the heart or injection site, in cardiomyocytes and intracardiac vascular endothelial cells, but not skeletal myocytes. The histological changes of myopericarditis after the first IV-priming dose persisted for 2 weeks and were markedly aggravated by a second IM- or IV-booster dose. Cardiac tissue mRNA expression of IL-1β, IFN-β, IL-6 and TNF-α increased significantly from 1dpi to 2dpi in IV but not IM group, compatible with presence of myopericarditis in IV group. Ballooning degeneration of hepatocytes was consistently found in IV group. All other organs appeared normal. Conclusions This study provided in-vivo evidence that inadvertent intravenous injection of COVID-19 mRNA-vaccines may induce myopericarditis. Brief withdrawal of syringe plunger to exclude blood aspiration may be one possible way to reduce such risk.

The novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) emerged at the end of 2019 and caused the coronavirus disease 19 (COVID‐19) pandemic due to its high transmissibility and early immunosuppression. Previous studies on other betacoronaviruses suggested that betacoronavirus infection is associated with the host autophagy pathway. However, it is unclear whether any components of autophagy or virophagy can be therapeutic targets for COVID‐19 treatment. In this report, we examined the antiviral effect of four well‐characterized small molecule inhibitors that target the key cellular factors involved in key steps of the autophagy pathway. They include small molecules targeting the ULK1/Atg1 complex involved in the induction stage of autophagy (ULK1 inhibitor SBI0206965), the ATG14/Beclin1/VPS34 complex involved in the nucleation step of autophagy (class III PI3‐kinase inhibitor VPS34‐IN1), and a widely‐used autophagy inhibitor that persistently inhibits class I and temporary inhibits class III PI3‐kinase (3‐MA) and a clinically approved autophagy inhibitor that suppresses autophagy by inhibiting lysosomal acidification and prevents the formation of autophagolysosome (HCQ). Surprisingly, not all the tested autophagy inhibitors suppressed SARS‐CoV‐2 infection. We showed that inhibition of class III PI3‐kinase involved in the initiation step of both canonical and noncanonical autophagy potently suppressed SARS‐CoV‐2 at a nano‐molar level. In addition, this specific kinase inhibitor VPS34‐IN1, and its bioavailable analogue VVPS34‐IN1, potently inhibited SARS‐CoV‐2 infection in ex vivo human lung tissues. Taken together, class III PI3‐kinase may be a possible target for COVID‐19 therapeutic development.

Enterovirus A71 (EV-A71) receptors that have been identified to date cannot fully explain the pathogenesis of EV-A71, which is an important global cause of hand, foot, and mouth disease and life-threatening encephalitis. We identified an IFN-γ-inducible EV-A71 cellular entry factor, human tryptophanyl-tRNA synthetase (hWARS), using genome-wide RNAi library screening. The importance of hWARS in mediating virus entry and infectivity was confirmed by virus attachment, in vitro pulldown, antibody/antigen blocking, and CRISPR/Cas9-mediated deletion. Hyperexpression and plasma membrane translocation of hWARS were observed in IFN-γ-treated semipermissive (human neuronal NT2) and cDNA-transfected nonpermissive (mouse fibroblast L929) cells, resulting in their sensitization to EV-A71 infection. Our hWARS-transduced mouse infection model showed pathological changes similar to those seen in patients with severe EV-A71 infection. Expression of hWARS is also required for productive infection by other human enteroviruses, including the clinically important coxsackievirus A16 (CV-A16) and EV-D68. This is the first report to our knowledge on the discovery of an entry factor, hWARS, that can be induced by IFN-γ for EV-A71 infection. Given that we detected high levels of IFN-γ in patients with severe EV-A71 infection, our findings extend the knowledge of the pathogenicity of EV-A71 in relation to entry factor expression upon IFN-γ stimulation and the therapeutic options for treating severe EV-A71-associated complications.

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Infection with human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and tropical spastic paraparesis. Type I interferons (IFNs) are key effectors of the innate antiviral response, and IFN-␣ combined with the nucleoside reverse transcriptase inhibitor zidovudine is considered the standard first-line therapy for ATL. HTLV-1 oncoprotein Tax is known to suppress innate IFN production and response but the underlying mechanisms remain to be fully established. In this study, we report on the suppression of type I IFN production by HTLV-1 Tax Five to 20 million people worldwide are infected with human T-cell leukemia virus type 1 (HTLV-1), among them about 3% might develop adult T-cell leukemia (ATL), and another 1% could suffer from tropical spastic paraparesis. Both diseases are poorly treatable (1, 2). A combination of alpha interferon (IFN-␣) and zidovudine has emerged as the standard first-line therapy for ATL (3, 4). Whereas zidovudine is a nucleoside analog that inhibits reverse transcriptase, IFN-␣ is an antiviral cytokine that serves as a key effector in innate immunity (5). Both IFN-␣ and zidovudine are required in this modality, but how they cooperate to achieve optimal therapeutic effect is not understood. To shed light on this, it will be of importance to elucidate how HTLV-1 perturbs type I IFN production and signaling.Recognition of pathogen-associated molecular patterns by pattern recognition receptors of the host cell triggers innate immune response, including the production of type I IFNs (6, 7). For example, upon recognition of viral nucleic acids, Toll-like and RIG-I-like receptors, as well as other sensors, generate an activation signal that is transmitted through adaptor proteins such as MAVS and STING, resulting in TBK1-dependent phosphorylation of IRF3 and IRF7 transcription factors which translocate into the nucleus to activate IFN promoters (8,9). Increased expression of type I IFNs ultimately leads to the activation of JAK-STAT signaling and the consequent induction of IFN-stimulated genes (ISGs), including those coding for some proinflammatory cytokines (10). Exactly how HTLV-1 infection is sensed by the host cell is poorly understood. The involvement of cytoplasmic RNA sensor RIG-I in the sensing of another retrovirus human immunodeficiency virus type 1 (HIV-1) has been suggested (11). Because optimal function of RIG-I requires PACT, a cellular double-