: There are seven known coronaviruses that infect humans: four mild coronaviruses, including HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, only cause mild respiratory diseases, and three severe coronaviruses, including SARS-CoV, MERS-CoV and SARS-CoV-2, can cause severe respiratory diseases even death of infected patients. Both infection and death caused by SARS-CoV-2 are still rapidly increasing worldwide. In this study, we demonstrate that viral coding proteins of SARS-CoV-2 have distinct features and are most, medium and least conserved with SARS-CoV, MERS-CoV, and the rest four mild coronaviruses (HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1), respectively. Moreover, expression of host responsive genes (HRG), HRG-enriched biological processes, and HRG-enriched KEGG pathways upon infection of SARS-CoV-2 show slightly overlapping with SARS-CoV and MERS-CoV but distinctive to the four mild coronaviruses. Interestingly, enrichment of overactivation of neutrophil by HRGs is only and commonly found in infections of severe SARS-CoV-2, SARS-CoV, and MERS-CoV but not in the other four mild coronaviruses, and the related gene networks show different patterns. Clinical data supports that overactivation of neutrophil for severe patients can be one major factor for the similar clinical symptoms observed in SARS-CoV-2 infection compared to infections of the other two severe coronavirus (SARS-CoV, and MERS-CoV). Taken together, our study provides a mechanistic insight into SARS-CoV-2 epidemic via revealing the conserved and distinct features of SARS-CoV-2, raising the critical role of dysregulation of neutrophil for SARS-CoV-2 infection. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.