COVID-19 Research: Study Shows SARS-COV-2 Infections Causes Dysregulation Of Numerous Host Cellular Processes
Source: COVID-19 Research Jul 25, 2020 4 years, 3 months, 3 weeks, 6 days, 6 hours, 39 minutes ago
COVID-19 Research: A study led by researchers at Karolinska Institutet published in
Emerging Microbes & Infections gives new insights into the virus-host interplay enabling newer perspectives about how to tackle the virus.
https://www.tandfonline.com/doi/full/10.1080/22221751.2020.1799723
The prevailing COVID-19 pandemic caused by the novel coronavirus has created an unprecedented public health challenge globally. Little was known about how the infecting cells respond to the virus and how the virus hijacks the host cellular machinery.
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The researchers discovered a variety of host cellular response against SARS-CoV-2 in vitro. After assessing the cellular host response to the virus infection, they found that 2622 genes and 1819 proteins were increased whereas 2856 genes and 1743 proteins were decreased significantly (false discovery rate <0.05) over the time despite distinct coverage (19997 protein-coding genes vs 7757 proteins quantified) compared to control.
The researchers identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, the study team also found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production.
The study team also identified that mammalian/mechanistic target of rapamycin (mTOR) signaling pathways were markedly modulated during SARS-CoV-2 infection.
Dr Ujjwal Neogi, Associate Professor of Virology at the Department of Laboratory Medicine at Karolinska Institutet, "The study illustrates a comprehensive picture of the host cellular response and provides a platform for further studies on drug candidate targeting mTOR pathway for a potential therapy alone or preferably in combination with antivirals for the management of severe COVID-19 patients."
The detailed analysis revealed that the SARS-CoV-2 causes distinct changes to the cellular pathways and suggests one of many plausible basis of high pathogenicity of SARS-CoV-2. Hijacking the mTOR pathway can render the virus highly pathogenic, as was observed for the highly pathogenic 1918 influenza virus and the Middle East respiratory syndrome coronavirus (MERS-CoV).
The mTOR pathway also plays a central role in the overall functioning of the cells and considered a central regulator of lifespan and aging by changing the host metabolism.
Dr Ujjwal Neogi added, "The effect of SARS-CoV-2 in the metabolic health, particularly in severely ill patients who were in ventilators and a group of patients with long-term illness need further attention to understand the metabolic impairments and recover their impaired metabolism."
Currently, there are three clinical trials&nb
sp;including one in phase III ongoing in the United States targeting mTOR pathway in the Severe COVID-19 patients and the results are expected in September.
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