Zhejiang University: Heat treatment as a novel strategy to fight against SARS-CoV-2

The real-time cumulative number of confirmed cases of COVID-19 throughout the world has exceeded 330 million with more than 5.5 million deaths, according to the statistics from Johns Hopkins University [1]. The global outbreak of the epidemic caused by SARS-CoV-2 has been lasting for more than two years, hitting hard nations all around the world. Under the current circumstance of the uncertainty in drug efficacy, vaccination is considered to be the most promising approach to contain the virus spread. At present, the number of vaccines administered worldwide is about to exceed 10 billion doses. However, the newly emerged SARS-CoV-2 variants including omicron and IHU harbor multiple mutations in the spike protein on the surface of the virus, which greatly weakens the immune protection provided by currently existing vaccines. These variants typically carry multiple mutations, especially in the receptor binding domain of the spike protein, requiring constant updates for vaccine design. Therefore, developing effective and quickly scalable approaches has become a scientific problem that needs to be urgently addressed.

On January 12, the research team led by Prof. Hua Naranmandura and Prof. Chih-Hung Hsu from Zhejiang University School of Medicine published a paper entitled Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreses Viral Load online in Research, proposing for the first time that heat treatment specifically degrades the RNA polymerase of SARS-CoV-2 and inhibits virus replication.

RNA-dependent RNA polymerase (RdRp) complex is the main effector involved in the replication and transcription of SARS-CoV-2 genome. Its core component is the catalytic subunit NSP12 protein, which exerts polymerase activity by forming a replication-transcription complex (RdRp complex) with two cofactors including NSP7 and NSP8. Therefore, NSP12 is largely studied as an important target for the development of antiviral drugs (nucleoside analogs such as Remdesivir).

In this study, researchers found for the first time that a relatively mild heat shock (40°C) could significantly induce degradation of the RNA-dependent RNA polymerase (NSP12) of SARS-CoV-2. More importantly, P323L mutant, which is concurrently identified on NSP12 in several SARS-CoV-2 variants including omicron and IHU, displays similar heat sensitivity as wild type NSP12, suggesting that heat treatment could be a potential intervention against SARS-CoV-2 variants regardless of their RNA polymerase mutation status. Further, the team also found that treating cells at 40°C for half an hour every day could maintain low levels of both wild type and P323L mutant of NSP12, indicating strong clinical potential. Mechanistically, heat treatment promotes E3 ubiquitin ligase ZNF598-dependent NSP12 ubiquitination leading to proteasomal degradation and significantly decreases SARS-CoV-2 RNA copy number and viral titer.

The key to validate this finding is to directly determine the effect of heat treatment on viral RNA replication by conducting experiments on SARS-CoV-2 infected cells. Therefore Prof. Naranmandura and his colleagues collaborated with P3 laboratory in Zhejiang Provincial Center for Disease Control and Prevention to conduct viral infection experiments. They found that mild heat treatment (40°C) effectively reduces the RNA level of SARS-CoV-2 virus (about 20 times) and virus titer (reduction by more than 99.5%) without compromising cell viability. These results suggest that heat treatment induced degradation of NSP12 leads to reduction of viral RNA load and downregulation of viral titer. The mechanism by which heat treatment inhibits SARS-CoV-2 virulence is shown in the figure above.

Prof. Naranmandura’s team has been focusing on research in the field of heat treatment for more than ten years. In addition to the current study, the previous publication of the group also revealed the favorable effects of hyperthermia combined with arsenic trioxide in the treatment of refractory relapsed acute promyelocytic leukemia by degrading oncogenic proteins [2]. Currently, research on other refractory diseases is also underway. The team is committed to the basic research oriented by clinical problems, with the goal of promoting basic medicine from bench to bedside, facilitating the transformation of scientific research, and contributing to the greater cause of human health. “Heat treatment could be a powerful weapon to fight against diseases. Our goal is to excavate the potential of heat-based therapies on disease treatment.” said Prof. Naranmandura.

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