Yaqinuddin Ahmed, Kashir Junaid
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Med Hypotheses. 2020 Apr 22;140:109777. doi: 10.1016/j.mehy.2020.109777.
Following the outbreak of a novel coronavirus (SARS-CoV-2), studies suggest that the resultant disease (COVID-19) is more severe in individuals with a weakened immune system. Cytotoxic T-cells (CTLs) and Natural Killer (NK) cells are required to generate an effective immune response against viruses, functional exhaustion of which enables disease progression. Patients with severe COVID-19 present significantly lower lymphocyte, and higher neutrophil, counts in blood. Specifically, CD8 lymphocytes and NK cells were significantly reduced in cases of severe infection compared to patients with mild infection and healthy individuals. The NK group 2 member A (NKG2A) receptor transduces inhibitory signalling, suppressing NK cytokine secretion and cytotoxicity. Overexpression of NKG2A has been observed on CD8 and NK cells of COVID-19 infected patients compared to healthy controls, while NKG2A overexpression also functionally exhausts CD8 cells and NK cells, resulting in a severely compromised innate immune response. Blocking NKG2A on CD8 cells and NK cells in cancers modulated tumor growth, restoring CD8 T and NK cell function. A recently proposed mechanism via which SARS-CoV-2 overrides innate immune response of the host is by over-expressing NKG2A on CD T and NK cells, culminating in functional exhaustion of the immune response against the viral pathogen. Monalizumab is an inhibiting antibody against NKG2A which can restore the function of CD8 + T and NK cells in cancers, successfully ceasing tumor progression with no significant side effects in Phase 2 clinical trials. We hypothesize that patients with severe COVID-19 have a severely compromised innate immune response and could be treated via the use of Monalizumab, interferon α, chloroquine, and other antiviral agents.
新型冠状病毒（SARS-CoV-2）爆发后，研究表明，免疫系统较弱的个体感染该病毒后引发的疾病（COVID-19）更为严重。细胞毒性T细胞（CTL）和自然杀伤（NK）细胞是产生有效抗病毒免疫反应所必需的，它们功能耗竭会导致疾病进展。重症COVID-19患者血液中的淋巴细胞计数显著降低，而中性粒细胞计数升高。具体而言，与轻症感染患者和健康个体相比，重症感染患者的CD8淋巴细胞和NK细胞显著减少。NK细胞亚群2成员A（NKG2A）受体传导抑制性信号，抑制NK细胞因子分泌和细胞毒性。与健康对照相比，在COVID-19感染患者的CD8和NK细胞上观察到NKG2A过表达，而NKG2A过表达也会使CD8细胞和NK细胞在功能上耗竭，导致先天性免疫反应严重受损。在癌症中阻断CD8细胞和NK细胞上的NKG2A可调节肿瘤生长，恢复CD8 T细胞和NK细胞功能。最近提出的一种机制是，SARS-CoV-2通过在CD T细胞和NK细胞上过表达NKG2A来超越宿主的先天性免疫反应，最终导致针对病毒病原体的免疫反应功能耗竭。莫那利珠单抗是一种针对NKG2A的抑制性抗体，可恢复癌症中CD8 + T细胞和NK细胞的功能，在2期临床试验中成功阻止肿瘤进展且无明显副作用。我们假设，重症COVID-19患者的先天性免疫反应严重受损，可通过使用莫那利珠单抗、干扰素α、氯喹和其他抗病毒药物进行治疗。
