ABSTRACT
Severe coronavirus disease 2019 (COVID-19) has been associated with certain preexisting health conditions and can cause respiratory failure along with other multi-organ injuries. However, the mechanism of these relationships is unclear, and prognostic biomarkers for the disease and its systemic complications are lacking. This study aims to examine the plasma protein profile of COVID-19 patients and evaluate overlapping protein modules with biomarkers of common comorbidities. Blood samples were collected from COVID-19 cases (n=307) and negative controls (n=78) among patients with acute respiratory distress. Proteins were measured by proximity extension assay utilizing next-generation sequencing technology. Its associations to COVID-19 disease characteristics were compared to that of preexisting conditions and established biomarkers for myocardial infarction (MI), stroke, hypertension, diabetes, smoking, and chronic kidney disease. Several proteins were differentially expressed in COVID-19, including multiple pro-inflammatory cytokines such as IFN-{gamma}, CXCL10, and CCL7/MCP-3. Elevated IL-6 was associated with increased severity, while baseline IL1RL1/ST2 levels were associated with a worse prognosis. Network analysis identified several protein modules associated with COVID-19 disease characteristics overlapping with processes of preexisting hypertension and impaired kidney function. BNP and NTpro-BNP, markers for MI and stroke, increased with disease progression and were positively associated with severity. MMP12 was similarly elevated and has been previously linked to smoking and inflammation in emphysema, along with increased cardiovascular disease risk. In conclusion, this study provides an overview of the systemic effects of COVID-19 and candidate biomarkers for clinical assessment of disease progression and the risk of systemic complications.
ABSTRACT
Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection, induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung, and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, while PKR activation is evident in iAT2 and iCM. In SARS-CoV-2 infected Calu-3 and A549ACE2 lung-derived cell lines, IFN induction remains relatively weak; however activation of OAS-RNase L and PKR is observed. This is in contrast to MERS-CoV, which effectively inhibits IFN signaling as well as OAS-RNase L and PKR pathways, but similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, both OAS-RNase L and PKR are activated in MAVS knockout A549ACE2 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in RNASEL knockout A549ACE2 cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host-virus interactions may contribute to the unique pathogenesis of SARS-CoV-2. SignificanceSARS-CoV-2 emergence in late 2019 led to the COVID-19 pandemic that has had devastating effects on human health and the economy. Early innate immune responses are essential for protection against virus invasion. While inadequate innate immune responses are associated with severe COVID-19 diseases, understanding of the interaction of SARS-CoV-2 with host antiviral pathways is minimal. We have characterized the innate immune response to SARS-CoV-2 infections in relevant respiratory tract derived cells and cardiomyocytes and found that SARS-CoV-2 activates two antiviral pathways, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and protein kinase R (PKR), while inducing minimal levels of interferon. This in contrast to MERS-CoV which inhibits all three pathways. Activation of these pathways may contribute to the distinctive pathogenesis of SARS-CoV-2.