The impact of hypoxia on B cells in COVID-19.

Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This presentation resembles the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. Detailed B cell phenotyping was undertaken by flow-cytometry on longitudinal samples from patients with COVID-19 across a range of severities (NIHR Cambridge BioResource). The impact of hypoxia on the transcriptome was assessed by single-cell and whole blood RNA sequencing analysis. The direct effect of hypoxia on B cells was determined through immunisation studies in genetically modified and hypoxia-exposed mice. We demonstrate the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes also observed in B cell VHL-deficient mice. These findings were associated with hypoxia-related transcriptional changes in COVID-19 patient B cells, and similar B cell abnormalities were seen in mice kept in hypoxic conditions. Hypoxia may contribute to the pronounced and persistent B cell pathology observed in acute COVID-19 pneumonia. Assessment of the impact of early oxygen therapy on these immune defects should be considered, as their correction could contribute to improved outcomes. Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR, Wellcome Trust

新冠病毒（COVID - 19）的早期显著特征包括严重的（通常临床上无症状的）缺氧以及B细胞显著减少，后者在抵御新冠病毒（SARS - CoV - 2）中具有重要作用。这种表现类似于B细胞中缺氧诱导因子（VHL）缺陷型小鼠的表型，在这种小鼠中缺氧诱导因子具有组成性活性，这表明缺氧可能导致新冠病毒感染中B细胞异常。 通过流式细胞术对来自不同严重程度的新冠病毒感染患者的纵向样本（英国国家健康研究所剑桥生物资源库）进行了详细的B细胞表型分析。通过单细胞和全血RNA测序分析评估了缺氧对转录组的影响。通过对转基因和缺氧暴露小鼠的免疫研究确定了缺氧对B细胞的直接影响。 我们证实了在中度/重度新冠病毒感染中B细胞亚群早期和持续性缺陷的广泛程度，包括边缘区样、记忆和过渡型B细胞减少，这些变化在B细胞VHL缺陷型小鼠中也能观察到。这些发现与新冠病毒感染患者B细胞中与缺氧相关的转录变化有关，并且在缺氧条件下饲养的小鼠中也观察到了类似的B细胞异常。 缺氧可能导致在急性新冠病毒肺炎中观察到的显著且持续的B细胞病理改变。应考虑评估早期氧疗对这些免疫缺陷的影响，因为纠正这些缺陷可能有助于改善治疗结果。 伊夫林信托、阿登布鲁克慈善信托、英国研究与创新署/英国国家健康研究所、维康信托