Majumdar Shamik, Weaver Joseph D, Pontejo Sergio M, Minai Mahnaz, Lu Xinping, Gao Ji-Liang, Holmes Gibran, Johnson Reed, Zhang Hongwei, Kelsall Brian L, Farber Joshua M, Alves Derron A, Murphy Philip M
Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Infectious Disease Pathogenesis Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
bioRxiv. 2024 Oct 1:2024.09.30.613319. doi: 10.1101/2024.09.30.613319.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, remains endemic worldwide ~5 years since the first documented case. Severe COVID-19 is widely considered to be caused by a dysregulated immune response to SARS-CoV-2 within the respiratory tract. Circulating levels of the chemokine CXCL10 are strongly positively associated with poor outcome; however, its precise role in pathogenesis and its suitability as a therapeutic target have remained undefined. Here, we challenged 4-6 month old C57BL/6 mice genetically deficient in with a mouse-adapted strain of SARS-CoV-2. Infected male, but not female, mice displayed increased mortality compared to wild type controls. Histopathological damage, inflammatory gene induction and virus load in the lungs of male mice 4 days post infection and before death were not broadly influenced by Cxcl10 deficiency. However, accumulation of B cells and both CD4 and CD8 T cells in the lung parenchyma of infected mice was reduced in the absence of Cxcl10. Thus, during acute SARS-CoV-2 infection, Cxcl10 regulates lymphocyte infiltration in the lung and confers protection against mortality. Our preclinical model results do not support targeting CXCL10 therapeutically in severe COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是2019冠状病毒病（COVID-19）大流行的病原体，自首例病例记录以来约5年，它在全球范围内仍然流行。严重的COVID-19被广泛认为是由呼吸道内对SARS-CoV-2的免疫反应失调引起的。趋化因子CXCL10的循环水平与不良预后密切正相关；然而，其在发病机制中的精确作用及其作为治疗靶点的适用性仍不明确。在这里，我们用一种适应小鼠的SARS-CoV-2毒株对4-6月龄基因缺陷的C57BL/6小鼠进行了挑战。与野生型对照相比，感染的雄性而非雌性小鼠死亡率增加。感染后4天且在死亡前，雄性小鼠肺部的组织病理学损伤、炎症基因诱导和病毒载量并未受到Cxcl10缺陷的广泛影响。然而，在没有Cxcl10的情况下，感染小鼠肺实质中B细胞以及CD4和CD8 T细胞的积累减少。因此，在急性SARS-CoV-2感染期间，Cxcl10调节肺内淋巴细胞浸润并提供抗死亡保护。我们的临床前模型结果不支持在严重COVID-19中对CXCL10进行治疗性靶向。
