Abstract
Despite limited genomic diversity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across infection status, viral load, age, and sex among shotgun RNA sequencing profiles of nasopharyngeal (NP) swabs from 430 individuals with PCR-confirmed SARS-CoV-2 and 54 negative controls. SARS-CoV-2 induced a strong antiviral response with up-regulation of antiviral factors such as OAS1-3 and IFIT1-3 and T helper type 1 (Th1) chemokines CXCL9/10/11, as well as a reduction in transcription of ribosomal proteins. SARS-CoV-2 culture in human airway epithelial (HAE) cultures replicated the in vivo antiviral host response 7 days post infection, with no induction of interferon-stimulated genes after 3 days. Patient-matched longitudinal specimens (mean elapsed time = 6.3 days) demonstrated reduction in interferon-induced transcription, recovery of transcription of ribosomal proteins, and initiation of wound healing and humoral immune responses. Expression of interferon-responsive genes, including ACE2, increased as a function of viral load, while transcripts for B cell–specific proteins and neutrophil chemokines were elevated in patients with lower viral load. Older individuals had reduced expression of the Th1 chemokines CXCL9/10/11 and their cognate receptor CXCR3, as well as CD8A and granzyme B, suggesting deficiencies in trafficking and/or function of cytotoxic T cells and natural killer (NK) cells. Relative to females, males had reduced B cell–specific and NK cell–specific transcripts and an increase in inhibitors of nuclear factor kappa-B (NF-κB) signaling, possibly inappropriately throttling antiviral responses. Collectively, our data demonstrate that host responses to SARS-CoV-2 are dependent on viral load and infection time course, with observed differences due to age and sex that may contribute to disease severity.
Highlights
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 from Wuhan, China, has rapidly spread throughout the world, causing more than 6 million cases and 400,000 deaths globally as of June 2020
We found only 2 genes altered as a result of the interaction between age and SARS-CoV-2 infection: a 30-fold reduction in production of CXCL11 (Fig 5B), an interferon-induced chemokine for natural killer (NK) and CD8+ T cells, and a 17-fold reduction in polycomb group factor 6 (PCGF6) (S2A Fig), a polycomb repressor complex protein known to play a role in repression of dendritic cell activation [31]
Infection of BALB/c mice with SARS-CoV did not result in detectable interferon beta (IFNβ) until 24 hours, at which point viral titers had nearly reached a peak; lung damage resulting from the subsequent massive infiltration of inflammatory macrophages could be abrogated by pre-treatment with type I interferons [11]
Summary
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 from Wuhan, China, has rapidly spread throughout the world, causing more than 6 million cases and 400,000 deaths globally as of June 2020. Coronavirus disease 2019 (COVID-19) morbidity and mortality has been overwhelmingly concentrated in elderly individuals and those with preexisting comorbidities [1]. Males are known to be generally more susceptible to infectious disease than females [4], and severe acute respiratory syndrome coronavirus (SARS-CoV)-infected male mice had increased infiltration of inflammatory macrophages into their lungs, leading to a deleterious inflammatory response [5]. The mechanisms behind increased mortality among older adults and males with COVID-19 remain speculative
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