Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
In the present study, we focus on defining the host response to SARS-CoV-2 and other human respiratory viruses in cell lines, primary cell cultures, ferrets, and COVID-19 patients. In general, our data show that the overall transcriptional footprint of SARS-CoV-2 infection was distinct in comparison with other highly pathogenic coronaviruses and common respiratory viruses such as IAV, HPIV3, and RSV. It is noteworthy that, despite a reduced IFN-I and -III response to SARS-CoV-2, we observed a consistent chemokine signature. One exception to this observation is the response to high-MOI infection in A549-ACE2 and Calu-3 cells, where replication was robust and an IFN-I and -III signature could be observed. In both of these examples, cells were infected at a rate to theoretically deliver two functional virions per cell in addition to any defective interfering particles within the virus stock that were not accounted for by plaque assays. Under these conditions, the threshold for PAMP may be achieved prior to the ability of the virus to evade detection through production of a viral antagonist. Alternatively, addition of multiple genomes to a single cell may disrupt the stoichiometry of viral components, which, in turn, may itself generate PAMPs that would not form otherwise. These ideas are supported by the fact that, at a low-MOI infection in A549-ACE2 cells, high levels of replication could also be achieved, but in the absence of IFN-I and -III induction. Taken together, these data suggest that, at low MOIs, the virus is not a strong inducer of the IFN-I and -III system, as opposed to conditions where the MOI is high. These dynamics are also likely to contribute to development of COVID-19 during the course of infection (Wolfel et al., 2020).
A recurrent observation in each of our systems is a robust production of cytokines and their subsequent transcriptional response. According to our longitudinal in vivo data, this response starts as early as 3 days after infection and continues beyond clearance of the virus. A recent study analyzing severe versus mild cases of COVID-19 showed that peripherally derived macrophages predominated in the lungs of severe cases (Liao et al., 2020). Consistent with this, we found, in all of our systems, significant induction of monocyte-associated chemokines such as CCL2 and CCL8. In addition, our data suggest that neutrophils could also contribute to the disease observed in COVID-19 patients, as demonstrated by CXCL2 and CXCL8 induction. This is consistent with data showing elevated circulating neutrophil levels among COVID-19 patients (Chen et al., 2020, Qin et al., 2020), which may have prognostic value for identifying individuals at risk for developing severe disease. It is also noteworthy that two of the cytokines uniquely elevated in response to SARS-CoV-2 are IL-6 and IL1RA, suggesting that there might be a parallel between COVID-19 and cytokine release syndrome (CRS), a complication commonly seen following CAR T-cell treatment (Giavridis et al., 2018). Should this be true, drugs such as tocilizumab and anakinra may prove to be beneficial for treatment of COVID-19 (Norelli et al., 2018). Future studies will be needed to address this formally.
Like SARS-CoV-2, the clinical manifestation of SARS-CoV-1 has been proposed to stem from a dysregulated immune response in patients and delayed expression of IFN-I (Channappanavar et al., 2016, Law et al., 2005, Menachery et al., 2014). Based on animal models, SARS-CoV-1 has been found to induce a robust cytokine response that generally shows a delay in IFN-I, culminating in improper recruitment of inflammatory monocyte-macrophage populations (Channappanavar et al., 2016). This dynamic seems to be in line with what we observed with SARS-CoV-2 because low levels of IFN-I and -III are likely produced in response to infection. Given the moderate viral replication levels observed in vivo, one explanation for the low IFN expression could be that a small subset of cells is refractory to the antagonistic mechanism of SARS-CoV-2, producing sufficient amounts of IFN-I and/or IFN-III to guide immune cell activation and ISG induction.
What makes SARS-CoV-2 distinct from other viruses used in this study is the propensity to selectively induce morbidity and mortality in older populations (Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020). The physiological basis for this morbidity is believed to be selective death of type II pneumocytes, which results in loss of air exchange and fluid leakage into the lungs (Qian et al., 2013, Xu et al., 2020). Although it remains to be determined whether the inappropriate inflammatory response to SARS-CoV-2 is responsible for the abnormally high lethality in older populations, it does explain why the virus is generally asymptomatic in young people with healthy and robust immune systems (Lu et al., 2020). Given the results here, it is tempting to speculate that an already restricted immune response in the aging population prevents successful inhibition of viral spread at early stages of infection, further exacerbating the morbidity and mortality observed for this age group (Jing et al., 2009, Montecino-Rodriguez et al., 2013).
Taken together, the data presented here suggest that the response to SARS-CoV-2 is imbalanced with regard to controlling virus replication versus activation of the adaptive immune response. Given this dynamic, treatments for COVID-19 have less to do with the IFN response and more to do with controlling inflammation. Because our data suggest that numerous chemokines and ILs are elevated in COVID-19 patients, future efforts should focus on U.S. Food and Drug Administration (FDA)-approved drugs that can be rapidly deployed and have immunomodulating properties.
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