Department of Microbiology and Immunology, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.
mBio. 2021 Dec 21;12(6):e0275621. doi: 10.1128/mBio.02756-21. Epub 2021 Nov 2.
Outbreaks of emerging viral pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a major medical challenge. There is a pressing need for antivirals that can be rapidly deployed to curb infection and dissemination. We determined the efficacy of interferon lambda-1 (IFN-λ) as a broad-spectrum antiviral agent to inhibit SARS-CoV-2 infection and reduce pathology in a mouse model of disease. IFN-λ significantly limited SARS-CoV-2 production in primary human bronchial epithelial cells in culture. Pretreatment of human lung cells with IFN-λ completely blocked infectious virus production, and treatment with IFN-λ at the time of infection inhibited virus production more than 10-fold. To interrogate the protective effects of IFN-λ in response to SARS-CoV-2 infection, transgenic mice expressing the human angiotensin-converting enzyme 2 (ACE-2) were tested. One dose of IFN-λ administered intranasally was found to reduce animal morbidity and mortality. Our study with SARS-CoV-2 also revealed a sex differential in disease outcome. Male mice had higher mortality, reflecting the more severe symptoms and mortality found in male patients infected with SARS-CoV-2. The results indicate that IFN-λ potentially can treat early stages of SARS-CoV-2 infection and decrease pathology, and this murine model can be used to investigate the sex differential documented in COVID-19. The COVID-19 pandemic has claimed millions of lives worldwide. In this report, we used a preclinical mouse model to investigate the prophylactic and therapeutic value of intranasal IFN-λ for this acute respiratory disease. Specific vaccines have been responsible for curbing the transmission of SARS-CoV-2 in developed nations. However, vaccines require time to generate and keep pace with antigenic variants. There is a need for broad-spectrum prophylactic and therapeutic agents to combat new emerging viral pathogens. Our mouse model suggests IFN-λ has clinical utility, and it reflects the well-documented finding that male COVID-19 patients manifest more severe symptoms and mortality. Understanding this sex bias is critical for considering therapeutic approaches to COVID-19.
新兴病毒病原体（如严重急性呼吸综合征冠状病毒 2（SARS-CoV-2））的爆发是一个重大的医学挑战。迫切需要能够迅速部署以遏制感染和传播的抗病毒药物。我们确定了干扰素 lambda-1（IFN-λ）作为一种广谱抗病毒药物抑制 SARS-CoV-2 感染并减轻疾病小鼠模型中病理学的功效。IFN-λ 显著限制了 SARS-CoV-2 在原代人支气管上皮细胞中的产生。IFN-λ 预处理人肺细胞完全阻断了感染性病毒的产生，而在感染时用 IFN-λ 治疗可使病毒产生抑制 10 倍以上。为了研究 IFN-λ 对 SARS-CoV-2 感染的保护作用，我们对表达人血管紧张素转换酶 2（ACE-2）的转基因小鼠进行了测试。发现鼻腔内给予一剂 IFN-λ 可降低动物发病率和死亡率。我们用 SARS-CoV-2 进行的研究还揭示了疾病结局的性别差异。雄性小鼠死亡率更高，反映了感染 SARS-CoV-2 的男性患者更严重的症状和死亡率。结果表明，IFN-λ 可能能够治疗 SARS-CoV-2 感染的早期阶段并减少病理学，并且该小鼠模型可用于研究 COVID-19 中记录的性别差异。 COVID-19 大流行已在全球范围内夺走了数百万人的生命。在本报告中，我们使用临床前小鼠模型来研究鼻腔内 IFN-λ 对这种急性呼吸道疾病的预防和治疗价值。特定的疫苗已被用于阻止 SARS-CoV-2 在发达国家的传播。然而，疫苗需要时间来产生并跟上抗原变体的步伐。需要广谱的预防和治疗药物来对抗新出现的病毒病原体。我们的小鼠模型表明 IFN-λ 具有临床效用，并且反映了有记录的发现，即男性 COVID-19 患者表现出更严重的症状和死亡率。了解这种性别偏见对于考虑 COVID-19 的治疗方法至关重要。
