ABSTRACT
Two years into the SARS-CoV-2 pandemic, the post-acute sequelae of infection are compounding the global health crisis. Often debilitating, these sequelae are clinically heterogeneous and of unknown molecular etiology. Here, a transcriptome-wide investigation of this new condition was performed in a large cohort of acutely infected patients followed clinically into the post-acute period. Gene expression signatures of post-acute sequelae were already present in whole blood during the acute phase of infection, with both innate and adaptive immune cells involved. Plasma cells stood out as driving at least two distinct clusters of sequelae, one largely dependent on circulating antibodies against the SARS-CoV-2 spike protein and the other antibody-independent. Altogether, multiple etiologies of post-acute sequelae were found concomitant with SARS-CoV-2 infection, directly linking the emergence of these sequelae with the host response to the virus.
Subject(s)
COVID-19 , InfectionsABSTRACT
In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between brain tropism, neuroinflammation and host immune response has not been well characterized. We analyzed 68,557 single-nucleus transcriptomes from three brain regions (dorsolateral prefrontal cortex, medulla oblongata and choroid plexus) and identified an increased proportion of stromal cells and monocytes in the choroid plexus of COVID-19 patients. Differential gene expression, pseudo-temporal trajectory and gene regulatory network analyses revealed microglial transcriptome perturbations, mediating a range of biological processes, including cellular activation, mobility and phagocytosis. Quantification of viral spike S1 protein and SARS-CoV-2 transcripts did not support the notion of brain tropism. Overall, our findings suggest extensive neuroinflammation in patients with acute COVID-19.
Subject(s)
Coronavirus Infections , COVID-19 , Brain Diseases , Papilloma, Choroid PlexusABSTRACT
Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in golden Syrian hamster (GSH) causes lungs pathology and resembles to human corona virus disease (Covid-19). Extra-pulmonary pathologies and immunological parameters of SARS-CoV-2 infection remained undefined in GSH. Using in silico modelling, we identified the similarities between human and hamster angiotensin-converting enzyme-2 (ACE-2), neuropilin-1 (NRP-1) that bind to receptor-binding domain (RBD) and S1 fragment of spike protein of SARS-CoV-2. SARS-CoV-2 infection led to lung pathologies, and cardiovascular complications (CVC) marked by interstitial coronary fibrosis and acute inflammatory response. Serum lipidomic and metabolomic profile of SARS-CoV-2-infected GSH revealed changes in serum triglycerides (TG) and low-density lipoprotein (LDL), and alterations in metabolites that correlated with Covid19. Together, we propose GSH as an animal model to study SARS-CoV-2 infection and its therapy associated with pulmonary and extra-pulmonary pathologies.
Subject(s)
Coronavirus Infections , Cardiovascular Diseases , Severe Acute Respiratory Syndrome , Coronary Disease , Virus Diseases , COVID-19ABSTRACT
A main clinical parameter of Covid-19 pathophysiology is hypoxia. Here we show that hypoxia decreases the attachment of the receptor binding domain (RBD) and the S1 subunit (S1) of the spike protein to epithelial cells. In Vero E6 cells, hypoxia reduces the protein levels of ACE2, which might in part explain the observed reduction of the infection rate. However, hypoxia also inhibits the binding of the spike to human lung epithelial cells lacking ACE2 expression, indicating that hypoxia modulates the expression of additional binding partners of SARS-CoV-2. We show that hypoxia also decreases the total cell surface levels of heparan sulfate, a known attachment receptor of SARS-CoV-2, by reducing the expression of syndecan-1 and syndecan3, the main proteoglycans containing heparan sulfate. Our study indicates that hypoxia acts to prevent SARS-CoV-2 infection, suggesting that the hypoxia signaling pathway might offer therapeutic opportunities for the treatment of Covid-19.
Subject(s)
Infections , COVID-19 , HypoxiaABSTRACT
Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition. By projecting the MIS-C signature onto a co-expression network, we identified disease gene modules and found genes downregulated in MIS-C clustered in a module enriched for the transcriptional signatures of exhausted CD8+ T-cells and CD56dimCD57+ NK cells. Bayesian network analyses revealed nine key regulators of this module, including TBX21, a central coordinator of exhausted CD8+ T-cell differentiation. Together, these findings suggest dysregulated cytotoxic lymphocyte response to SARS-Cov-2 infection in MIS-C.