Cell: Major Advance! Key Host Molecules Hijacked by Coronaviruses to Infect Human Cells Identified
Dec 09, 2020 07:28
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07:28
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December 9, 2020 / Bioon --- When coronaviruses—including SARS-CoV-2, the virus responsible for coronavirus disease 2019 (COVID-19)—infect humans, they hijack human cells and exploit cellular molecular mechanisms to sustain their own survival and propagation. In a new study, researchers from the Gladstone Institutes and the Chan Zuckerberg Biohub, in collaboration with scientists at the University of California, San Francisco, and Synthego, identified key molecular processes in human cells that coronaviruses exploit for survival. They reported that targeting these processes with drugs could not only treat COVID-19 infections but also address other existing and future coronavirus infections. The related findings were published online in the journal Cell on December 8, 2020, under the title “Genetic screens identify host factors for SARS-CoV-2 and common cold coronaviruses.”
“Dr. Melanie Ott, Director of the Gladstone Institute of Virology and co-corresponding author of the paper, stated, ‘The uniqueness of our study lies in the fact that we did not solely investigate SARS-CoV-2 but simultaneously examined other coronaviruses. This approach has provided us with valuable insights into drug targets capable of broadly inhibiting a wide range of coronaviruses.’”
As a large family of viruses, coronaviruses include those that cause the common cold as well as those that lead to more severe symptoms. The SARS-CoV virus, which caused the fatal SARS outbreak in 2002, is a coronavirus, and the MERS-CoV virus, responsible for the MERS outbreak in the Middle East, is also a coronavirus.
Dr. Andreas Puschnik, a co-corresponding author of the paper and a principal investigator at the Chan Zuckerberg Biohub, stated, “There have been multiple coronavirus outbreaks, so it is clear that this virus family has high epidemic potential. COVID-19 is not the last coronavirus infection we will face.”
Comparison and Contrast of Coronaviruses
Like all viruses, coronaviruses can only replicate within host cells, relying on the host cell’s molecular machinery for proliferation. For this reason, the authors aimed to target human molecules that the virus exploits for survival, rather than targeting the viral components themselves.
In this new study, they infected human cells with SARS-CoV-2 or two other coronaviruses that cause the common cold (HCoV-229E and HCoV-OC43), all three of which were capable of killing these cells. Next, they used CRISPR-Cas9 gene-editing technology to induce mutations in these cells and investigated which mutations conferred resistance to damage from these coronaviruses.
Puschnik explained, “We inferred that the few cells able to survive these infections likely harbored mutations in the host molecules that these coronaviruses use to infect them or replicate.”
Some results are not surprising. For example, it is well known that SARS-CoV-2 requires the human ACE2 receptor to enter human cells. Therefore, cells with mutations in the ACE2 gene are no longer infected or killed by SARS-CoV-2.
However, other findings were unexpected. The authors discovered that certain genetic mutations prevented these three coronaviruses from successfully infecting and killing human cells. These mutations occurred in genes known to regulate the balance of two lipid molecules in human cells—cholesterol and phosphatidylinositol phosphate (PIP).
Cholesterol is required for the entry of certain viruses into cells; however, at the outset of this study, it had not yet been investigated in the context of coronaviruses. Similarly, while phosphatidylinositol phosphates (PIPs) are known to play a role in the formation of small vesicles that viruses frequently exploit to enter and navigate within cells, they had not previously been directly linked to SARS-CoV-2.
The Path to Drug Development
To validate the importance of cholesterol- and PIP-related genes in coronavirus infection, the authors engineered human cells completely lacking these genes and infected them with coronaviruses. Cells deficient in these genes were protected from infection by all three coronaviruses. Similarly, when existing compounds were used to disrupt PIP or cholesterol homeostasis, the cells became less susceptible to infection by any of the coronaviruses. These results suggest that targeting cholesterol or PIP may be a promising strategy for combating multiple coronaviruses.
Ott stated, “The conventional view regarding viruses is that we design drugs targeting unique viral elements, which means that developing a new drug takes time whenever a novel virus emerges. If we can develop broader-spectrum antiviral drugs that target host cell molecules, this would significantly enhance our ability to respond effectively to future pandemic viruses.”
However, not all results were consistent across the three coronaviruses studied. Some human molecules required for SARS-CoV-2 infection are not needed by the two common cold coronaviruses, and vice versa. These findings may help explain what makes SARS-CoV-2 more lethal than the other two coronaviruses.
Further research is needed to test the efficacy of drugs targeting PIP and cholesterol, as well as their ability to effectively inhibit coronavirus growth without causing dangerous side effects. The authors also aim to repeat the screening using other coronaviruses, including SARS-CoV and MERS-CoV, to determine how prevalent the newly identified targets are.
Ott and Puschnik agree that this new study was made possible only because researchers from many laboratories readily came together. Puschnik possessed expertise in studying viral host factors but lacked access to the biosafety level 3 (BSL-3) laboratory required for SARS-CoV-2 research. Earlier this year, Ott was leading the establishment of such a laboratory at the Gladstone Institutes and proposed a collaboration. Scientists at Synthego provided the genetically engineered cells necessary for studying these coronaviruses, and Dr. Nevan Krogan, a senior investigator at the Gladstone Institutes, assisted in analyzing the results of the CRISPR-Cas9 screens.
Puschnik said, “Everyone is fully willing to roll up their sleeves, pool resources, and work together to help contribute to a better understanding of COVID-19.” (Bioon.com)
References:
1.Ruofan Wang et al. Genetic screens identify host factors for SARS-CoV-2 and common cold coronaviruses. Cell, 2020, doi:10.1016/j.cell.2020.12.004.
2.Researchers identify critical molecules that coronaviruses hijack to infect human cells
https://medicalxpress.com/news/2020-12-critical-molecules-coronaviruses-hijack-infect.html
Image from Cell, 2020, doi:10.1016/j.cell.2020.12.004.
“Dr. Melanie Ott, Director of the Gladstone Institute of Virology and co-corresponding author of the paper, stated, ‘The uniqueness of our study lies in the fact that we did not solely investigate SARS-CoV-2 but simultaneously examined other coronaviruses. This approach has provided us with valuable insights into drug targets capable of broadly inhibiting a wide range of coronaviruses.’”
As a large family of viruses, coronaviruses include those that cause the common cold as well as those that lead to more severe symptoms. The SARS-CoV virus, which caused the fatal SARS outbreak in 2002, is a coronavirus, and the MERS-CoV virus, responsible for the MERS outbreak in the Middle East, is also a coronavirus.
Dr. Andreas Puschnik, a co-corresponding author of the paper and a principal investigator at the Chan Zuckerberg Biohub, stated, “There have been multiple coronavirus outbreaks, so it is clear that this virus family has high epidemic potential. COVID-19 is not the last coronavirus infection we will face.”
Comparison and Contrast of Coronaviruses
Like all viruses, coronaviruses can only replicate within host cells, relying on the host cell’s molecular machinery for proliferation. For this reason, the authors aimed to target human molecules that the virus exploits for survival, rather than targeting the viral components themselves.
In this new study, they infected human cells with SARS-CoV-2 or two other coronaviruses that cause the common cold (HCoV-229E and HCoV-OC43), all three of which were capable of killing these cells. Next, they used CRISPR-Cas9 gene-editing technology to induce mutations in these cells and investigated which mutations conferred resistance to damage from these coronaviruses.
Puschnik explained, “We inferred that the few cells able to survive these infections likely harbored mutations in the host molecules that these coronaviruses use to infect them or replicate.”
Some results are not surprising. For example, it is well known that SARS-CoV-2 requires the human ACE2 receptor to enter human cells. Therefore, cells with mutations in the ACE2 gene are no longer infected or killed by SARS-CoV-2.
However, other findings were unexpected. The authors discovered that certain genetic mutations prevented these three coronaviruses from successfully infecting and killing human cells. These mutations occurred in genes known to regulate the balance of two lipid molecules in human cells—cholesterol and phosphatidylinositol phosphate (PIP).
Cholesterol is required for the entry of certain viruses into cells; however, at the outset of this study, it had not yet been investigated in the context of coronaviruses. Similarly, while phosphatidylinositol phosphates (PIPs) are known to play a role in the formation of small vesicles that viruses frequently exploit to enter and navigate within cells, they had not previously been directly linked to SARS-CoV-2.
The Path to Drug Development
To validate the importance of cholesterol- and PIP-related genes in coronavirus infection, the authors engineered human cells completely lacking these genes and infected them with coronaviruses. Cells deficient in these genes were protected from infection by all three coronaviruses. Similarly, when existing compounds were used to disrupt PIP or cholesterol homeostasis, the cells became less susceptible to infection by any of the coronaviruses. These results suggest that targeting cholesterol or PIP may be a promising strategy for combating multiple coronaviruses.
Ott stated, “The conventional view regarding viruses is that we design drugs targeting unique viral elements, which means that developing a new drug takes time whenever a novel virus emerges. If we can develop broader-spectrum antiviral drugs that target host cell molecules, this would significantly enhance our ability to respond effectively to future pandemic viruses.”
However, not all results were consistent across the three coronaviruses studied. Some human molecules required for SARS-CoV-2 infection are not needed by the two common cold coronaviruses, and vice versa. These findings may help explain what makes SARS-CoV-2 more lethal than the other two coronaviruses.
Further research is needed to test the efficacy of drugs targeting PIP and cholesterol, as well as their ability to effectively inhibit coronavirus growth without causing dangerous side effects. The authors also aim to repeat the screening using other coronaviruses, including SARS-CoV and MERS-CoV, to determine how prevalent the newly identified targets are.
Ott and Puschnik agree that this new study was made possible only because researchers from many laboratories readily came together. Puschnik possessed expertise in studying viral host factors but lacked access to the biosafety level 3 (BSL-3) laboratory required for SARS-CoV-2 research. Earlier this year, Ott was leading the establishment of such a laboratory at the Gladstone Institutes and proposed a collaboration. Scientists at Synthego provided the genetically engineered cells necessary for studying these coronaviruses, and Dr. Nevan Krogan, a senior investigator at the Gladstone Institutes, assisted in analyzing the results of the CRISPR-Cas9 screens.
Puschnik said, “Everyone is fully willing to roll up their sleeves, pool resources, and work together to help contribute to a better understanding of COVID-19.” (Bioon.com)
References:
1.Ruofan Wang et al. Genetic screens identify host factors for SARS-CoV-2 and common cold coronaviruses. Cell, 2020, doi:10.1016/j.cell.2020.12.004.
2.Researchers identify critical molecules that coronaviruses hijack to infect human cells
https://medicalxpress.com/news/2020-12-critical-molecules-coronaviruses-hijack-infect.html