How blood group A might be a risk and blood group O be protected from coronavirus (COVID-19) infections (how the virus invades the human body via ABO(H) blood group carbohydrates).

When according to the numbers of Wikipedia (although they are disputed) in countries like Chile, Ecuador, Colombia, Simbabwe and Mexico 59 to 85 percent of the people have blood group O and these countries officially publish extremely low COVID-19 cases and death rates per 1 million inhabitants, this may not alone result from insufficient investigations but might suggest a lower susceptibility of blood group O to the disease. The molecular biology of a virus infection pathogenesis determines the genetic target and the human phenotype-determining enzymes decide about the difference between infection and disease. In the case that <i>O</i>-glycosylation plays a key role in the pathogenesis of coronavirus infections, as was discussed already 14 years ago in a SARS-CoV virus infection and is currently again predicted for SARS-CoV-2 or COVID-19, this would involve the formation of hybrid, serologically A-like, <i>O</i>-GalNAcα1-Ser/Thr-R, Tn (“T nouvelle”) antigenic structures. Although the ACE2 (angiotensin-converting-enzyme 2) protein is defined as the primary SARS-CoV receptor, it is the history of the amino acid serine, suggesting the actual or additional binding via an intermediate hybrid <i>O</i>-glycan: the protease-mobilized, virus-encoded serine molecule gets access to the host's N-acetyl-D-galactosamine (GalNAc) metabolism and the resulting intermediate, hybrid A-like/Tn structure performs the adhesion of the virus to host cells primarily independent of the ABO blood group, while the phenotype-determining sugars become the final glycosidic target. Individuals with blood group A cannot respond with either acquired or innate antibodies to the synthesis of A-like hybrid structures due to clonal selection and phenotypic accommodation of plasma proteins but perform a further (blood group-A-specific) hybrid binding. A first statistical study suggests that people with blood group A have a significantly higher risk for acquiring COVID-19, whereas people with blood group O have a significantly lower risk for the infection compared with non-O blood groups (Zhao, J. <i>et al., </i>2020). While these findings await confirmations, blood group O individuals, lacking the blood group-A-determining enzyme, may develop the least molecular contact with the virus and maintain the anti-A/Tn cross-reactive, complement-dependent isoagglutinin activity, which is exerted by the polyreactive, nonimmune immunoglobulin M (IgM), representing the humoral spearhead of innate immunity and a first line of defense.<b>Reference</b>: Zhao, J. <i>et al.</i> Relationship between the ABO Blood Group and the COVID-19 Susceptibility. <i>medRxiv</i> (2020) doi:10.1101/2020.03.11.20031096.<br>

尽管维基百科（Wikipedia）的数据存在争议，但智利、厄瓜多尔、哥伦比亚、津巴布韦及墨西哥等国的相关数据显示，其国内O型血人群占比达59%至85%，且这些国家官方公布的每百万居民新冠（COVID-19）确诊病例与死亡率均处于极低水平。这一现象或许并非仅因调查不足，也可能提示O型血人群对该疾病的易感性更低。

病毒感染发病机制的分子生物学特性决定了其遗传靶标，而决定人类表型的酶则决定了感染与发病之间的差异。早在14年前就有针对严重急性呼吸综合征冠状病毒（SARS-CoV）感染的相关讨论，如今针对严重急性呼吸综合征冠状病毒2型（SARS-CoV-2，即新冠病毒）或COVID-19的相关研究也再次提出，若O-糖基化（O-glycosylation）在冠状病毒感染的发病机制中发挥关键作用，那么将会形成杂合的、血清学上类似A型的O-GalNAcα1-Ser/Thr-R及T新（T nouvelle，即Tn）抗原结构。

尽管血管紧张素转换酶2（ACE2, angiotensin-converting-enzyme 2）蛋白被认定为SARS-CoV的主要受体，但丝氨酸氨基酸的相关特性表明，病毒或可通过中间杂合O-聚糖实现实际结合或额外结合：经蛋白酶激活的病毒编码丝氨酸分子可进入宿主的N-乙酰-D-半乳糖胺（GalNAc）代谢通路，由此生成的中间杂合类A/Tn结构可独立于ABO血型系统介导病毒黏附宿主细胞，而决定表型的糖类则成为最终的糖苷作用靶标。

由于克隆选择与血浆蛋白的表型适配，A型血个体无法通过获得性或先天性抗体对类A杂合结构的合成产生应答，但会产生额外的A型血特异性杂合结合。一项早期统计学研究表明，A型血人群感染COVID-19的风险显著更高，而O型血人群的感染风险则显著低于非O型血人群（Zhao, J. 等, 2020）。

尽管上述发现尚待验证，但缺乏A型血决定性酶的O型血个体，与病毒的分子接触最少，且可维持抗A/Tn交叉反应性、依赖补体的同种凝集素活性——该活性由多反应性非免疫免疫球蛋白M（IgM）介导，而IgM是先天性免疫的体液先锋与第一道防线。

**参考文献**：Zhao, J. 等. ABO血型与COVID-19易感性的相关性. medRxiv (2020) doi:10.1101/2020.03.11.20031096.