RESUMO
The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics.
Assuntos
Monofosfato de Adenosina , Adenosina , Alanina , Antivirais , COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/química , Humanos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/química , COVID-19/imunologia , COVID-19/virologia , Animais , Agentes de Imunomodulação/farmacologia , Agentes de Imunomodulação/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Pandemias , Tratamento Farmacológico da COVID-19 , Chlorocebus aethiops , Replicação Viral/efeitos dos fármacos , Células Vero , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Receptor A2A de Adenosina/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologiaRESUMO
Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-binding TLRs is unknown. Here we show that human RBCs express the RNA sensor TLR7. TLR7 is present on the red cell membrane and is associated with the RBC membrane protein Band 3. In patients with SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in the RBC membrane are increased when compared with healthy controls. In vitro, RBCs bind synthetic ssRNA and RNA from ssRNA viruses. Thus, RBCs may serve as a previously unrecognized sink for exogenous RNA, expanding the repertoire of non-gas exchanging functions performed by RBCs.
Assuntos
COVID-19 , Eritrócitos , SARS-CoV-2 , Receptor 7 Toll-Like , Humanos , Receptor 7 Toll-Like/metabolismo , Receptor 7 Toll-Like/genética , Eritrócitos/metabolismo , COVID-19/virologia , COVID-19/metabolismo , SARS-CoV-2/metabolismo , Sepse/metabolismo , Sepse/sangue , Sepse/genética , Membrana Eritrocítica/metabolismo , Masculino , RNA/metabolismo , RNA/genética , FemininoRESUMO
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mitochondrial oxidative phosphorylation (OXPHOS) and elevates mitochondrial reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1α), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of mitochondrial DNA (mtDNA) and activation of innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these viral effects, we challenged mice expressing human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2 and intervened using transgenic and pharmacological mitochondrially targeted catalytic antioxidants. Transgenic expression of mitochondrially targeted catalase (mCAT) or systemic treatment with EUK8 decreased weight loss, clinical severity, and circulating levels of mtDNA; as well as reduced lung levels of HIF-1α, viral proteins, and inflammatory cytokines. RNA-sequencing of infected lungs revealed that mCAT and Eukarion 8 (EUK8) up-regulated OXPHOS gene expression and down-regulated HIF-1α and its target genes as well as innate immune gene expression. These data demonstrate that SARS-CoV-2 pathology can be mitigated by catalytically reducing mROS, potentially providing a unique host-directed pharmacological therapy for COVID-19 which is not subject to viral mutational resistance.
Assuntos
Antioxidantes , COVID-19 , Camundongos Transgênicos , Mitocôndrias , Fosforilação Oxidativa , SARS-CoV-2 , Animais , Camundongos , COVID-19/virologia , COVID-19/metabolismo , COVID-19/imunologia , COVID-19/patologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Humanos , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Pulmão/virologia , Pulmão/patologia , Pulmão/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Catalase/metabolismo , Catalase/genética , Tratamento Farmacológico da COVID-19 , Modelos Animais de Doenças , Imunidade InataRESUMO
Rift Valley fever virus (RVFV) is an encephalitic bunyavirus that can infect neurons in the brain. There are no approved therapeutics that can protect from RVFV encephalitis. Innate immunity, the first line of defense against infection, canonically antagonizes viruses through interferon signaling. We found that interferons did not efficiently protect primary cortical neurons from RVFV, unlike other cell types. To identify alternative neuronal antiviral pathways, we screened innate immune ligands and discovered that the TLR2 ligand Pam3CSK4 inhibited RVFV infection, and other bunyaviruses. Mechanistically, we found that Pam3CSK4 blocks viral fusion, independent of TLR2. In a mouse model of RVFV encephalitis, Pam3CSK4 treatment protected animals from infection and mortality. Overall, Pam3CSK4 is a bunyavirus fusion inhibitor active in primary neurons and the brain, representing a new approach toward the development of treatments for encephalitic bunyavirus infections.
Assuntos
Lipopeptídeos , Neurônios , Febre do Vale de Rift , Vírus da Febre do Vale do Rift , Animais , Vírus da Febre do Vale do Rift/efeitos dos fármacos , Camundongos , Lipopeptídeos/farmacologia , Febre do Vale de Rift/virologia , Febre do Vale de Rift/prevenção & controle , Neurônios/metabolismo , Neurônios/virologia , Camundongos Endogâmicos C57BL , Humanos , Imunidade Inata/efeitos dos fármacos , Encefalite Viral/virologia , Encefalite Viral/imunologia , Encefalite Viral/prevenção & controle , Encefalite Viral/tratamento farmacológico , Antivirais/farmacologiaRESUMO
Inappropriate type I interferon (IFN) signaling during embryo implantation and placentation is linked to poor pregnancy outcomes. Here, we evaluated the consequence of elevated type I IFN exposure on implantation using a biomimetic model of human implantation in an organ-on-a-chip device. We found that type I IFN reduced extravillous trophoblast (EVT) invasion capacity. Analyzing single-cell transcriptomes, we uncovered that IFN truncated endovascular EVT emergence in the implantation-on-a-chip device by stunting EVT epithelial-to-mesenchymal transition. Disruptions to the epithelial-to-mesenchymal transition is associated with the pathogenesis of preeclampsia, a life-threatening hypertensive disorder of pregnancy. Strikingly, unwarranted IFN stimulation induced genes associated with increased preeclampsia risk and a preeclamptic gene-like signature in EVTs. These dysregulated EVT phenotypes ultimately reduced EVT-mediated endothelial cell vascular remodeling in the implantation-on-a-chip device. Overall, our work indicates IFN signaling can alter EVT epithelial-to-mesenchymal transition progression which results in diminished EVT-mediated spiral artery remodeling and a preeclampsia gene signature upon sustained stimulation. Our work implicates unwarranted type I IFN as a maternal disturbance that can result in abnormal EVT function that could trigger preeclampsia.