Graphical abstract Highlights • The SARS-CoV-2 virus binds to human ACE2 much weaker at 40 °C than 37 °C. • The infection efficiency of SARS-CoV-2 is much weaker at high febrile temperature. • The temperature dependence of viral infection co-evolves with inflammatory response. The SARS-CoV-2 virus and its homolog SARS-CoV penetrate human cells by binding of viral spike protein and human angiotensin converting enzyme II (ACE2). SARS-CoV causes high fever in almost all patients, while SARS-CoV-2 does not. Moreover, analysis of the clinical data revealed that the higher body temperature is a protective factor in COVID-19 patients, making us to hypothesize a temperature-dependent binding affinity of SARS-CoV-2 to human ACE2 receptor. In this study, our molecular dynamics simulation and protein surface plasmon resonance cohesively proved the SARS-CoV-2-ACE2 binding was less affinitive and stable under 40 °C (~18 nM) than the optimum temperature 37 °C (6.2 nM), while SARS-CoV-ACE2 binding was not (6.4 nM vs. 8.5 nM), which evidenced the temperature-dependent affinity and explained that higher temperature is related to better clinical outcome. The decreased infection at higher temperature was also validated by pseudovirus entry assay using Vero and Caco-2 cells. We also demonstrated the structural basis of the distinct temperature-dependence of the two coronaviruses. Furthermore, the meta-analysis revealed a milder inflammatory response happened in the early stage of COVID-19, which explained the low fever tendency of COVID-19 and indicated the co-evolution of the viral protein structure and the inflammatory response. The temperature dependence of the binding affinity also indicated that higher body temperature at early stages might be beneficial to the COVID-19 patients.
【저자키워드】 COVID-19, SARS-CoV-2, Spike protein, affinity, structural basis, Temperature dependence, 【초록키워드】 Meta-analysis, viral infection, ACE2, Coronaviruses, SARS-CoV, Infection, SARS-CoV-2 virus, binding affinity, Molecular dynamics simulation, Clinical outcome, human ACE2, Protein, Fever, temperature, early stage, patients, body temperature, COVID-19 patients, binding, Caco-2 cells, pseudovirus entry, Inflammatory response, Analysis, Vero, Efficiency, viral spike protein, Viral protein, Abstract, Clinical data, protective factor, human ACE2 receptor, febrile, homolog, human cell, bind, indicated, less, explained, demonstrated, cause, evidenced, the binding affinity, enzyme II, penetrate, 【제목키워드】 Clinical outcome, human ACE2, COVID-19 progression, determine, the SARS-CoV-2,