高致病性冠状病毒感染导致宿主免疫应答异常

近二十多年，全球范围内先后爆发了由严重急性呼吸综合征冠状病毒（severe acute respiratory syndrome coronavirus，SARS-CoV）、中东呼吸综合征冠状病毒（middle east respiratory syndrome coronavirus，MERS-CoV）和严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus 2，SARS-CoV-2）3种高致病性冠状病毒导致的疫情。这3种高致病性冠状病毒感染通常伴随着免疫系统功能失调，临床表现有淋巴细胞减少症、细胞因子风暴、急性呼吸系统窘迫综合征，甚至多器官衰竭而导致死亡。揭示高致病性冠状病毒在免疫应答中的作用机制，对于预防与控制冠状病毒感染具有重要意义。本文总结了SARS-CoV、MRES-CoV和SARS-CoV-2的进入机制和受体特征、固有免疫应答和适应性免疫应答失调方面的研究进展，强调了高致病性冠状病毒与宿主免疫应答之间的复杂相互作用，以期为防治冠状病毒感染提供参考。

The Highly Pathogenic Coronavirus Infection Disturbs The Host Immune Response

In the past two decades, there have been outbreaks caused by 3 types of highly pathogenic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MRES-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These highly pathogenic coronavirus infections are usually accompanied by immune system dysfunction, with clinical manifestations such as lymphopenia, cytokine storm, acute respiratory distress syndrome and even death due to multiple organ failure. Revealing the effects of highly pathogenic coronaviruses on immune responses and the underlying mechanisms is of great significance for preventing and controlling coronaviruses infection. The cell receptors of these 3 highly pathogenic coronaviruses are different, which determines the differences in the types of cells they infect. This review firstly introduces the entry mechanisms of coronavirus and receptor characteristics as well as infected cells of SARS-CoV, MRES-CoV and SARS-CoV-2. Unlike other coronaviruses, SARS-CoV, MRES-CoV, and SARS-CoV-2 are able to infect immune cells, including innate immune cells, T and B lymphocytes, which lays the foundation for highly pathogenic coronaviruses to interfere with the host immune responses. Secondly, we summarize the mechanisms by which highly pathogenic coronaviruses impair the innate immune responses. Researches demonstrate that highly pathogenic coronaviruses can effectively evade innate immune recognition through cap and methylation modification as well as the formation of double-membrane vesicle (DMV). And, highly pathogenic coronaviruses can directly interfere with the pattern recognition receptor (PRR) signaling pathway, affecting the secretion of type I interferon, blocking interferon signaling and inhibiting the formation of stress particles. Notably, these highly pathogenic coronavirus can damage innate immune cells, inducing the secretion of cytokines and chemokines by macrophages, and the formation of neutrophil extracellular traps (NET) by neutrophils, which leads to cytokine storm and subsequent PANoptosis. In addition, the functions of dendritic cells and NK cells are also damaged by highly pathogenic coronavirus infection. Thirdly, we summarize the mechanisms by which highly pathogenic coronaviruses affect the adaptive immune response. Studies show highly pathogenic coronaviruses cause dysregulation of adaptive immune responses by disrupting T and B cell immune responses. Coronavirus infection can decrease the number of lymphocytes through a variety of ways. T cells in patients with highly pathogenic coronavirus infection are in an over-activated or exhausted state, and the specific T cell response and inflammation state will maintain for a long time. The continuous evolution of highly pathogenic coronaviruses often leads to the failure of neutralizing antibodies. Additionally, non-neutralizing antibodies can cause antibody-dependent enhancement (ADE) effects that triggers tissue damage. The duration of memory B cell-mediated response induced by different highly pathogenic coronaviruses is different, but the formation of germinal centers is often affected. Studies have highlighted the complex interaction between highly pathogenic coronaviruses and host immune responses. Finally, we discuss the adverse effects and treatment strategies of coronavirus disease 2019 (COVID-19) in order to provide reference for the prevention and treatment of coronavirus infection.