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.

尽管基因组多样性有限，严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 在不同患者群体中表现出广泛的临床表现。这些宿主差异背后的机制仍不清楚。在这里，我们检查了 430 名经 PCR 确诊的 SARS-CoV-2 个体和 54 名阴性对照的鼻咽 (NP) 拭子的鸟枪 RNA 测序图谱中宿主反应基因在感染状态、病毒载量、年龄和性别方面的表达情况。 SARS-CoV-2 通过上调OAS1-3和IFIT1-3等抗病毒因子以及 1 型 T 辅助细胞 (Th1) 趋化因子CXCL9/10/11以及核糖体转录减少，诱导强烈的抗病毒反应。蛋白质。人气道上皮 (HAE) 培养物中的 SARS-CoV-2 培养物在感染后 7 天复制了体内抗病毒宿主反应，3 天后没有诱导干扰素刺激的基因。患者匹配的纵向样本（平均经过时间 = 6.3 天）显示干扰素诱导的转录减少、核糖体蛋白转录恢复以及伤口愈合和体液免疫反应的启动。包括ACE2在内的干扰素反应基因的表达随着病毒载量的增加而增加，而在病毒载量较低的患者中，B 细胞特异性蛋白和中性粒细胞趋化因子的转录本则升高。老年人的 Th1 趋化因子CXCL9/10/11及其同源受体CXCR3以及CD8A和颗粒酶 B 的表达减少，表明细胞毒性 T 细胞和自然杀伤 (NK) 细胞的运输和/或功能存在缺陷。 相对于女性，男性的 B 细胞特异性和 NK 细胞特异性转录本减少，核因子 kappa-B (NF-κB) 信号传导抑制剂增加，可能会不适当地抑制抗病毒反应。总的来说，我们的数据表明，宿主对 SARS-CoV-2 的反应取决于病毒载量和感染时间进程，观察到的年龄和性别差异可能会导致疾病严重程度。