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Source: COVID-19 Research  Jan 23, 2021  3 years, 2 months, 3 weeks, 1 day, 22 hours, 48 minutes ago

COVID-19 Research: University Of Illinois Study Shows That Nonstructural Proteins Of SARS-CoV-2 Dysregulates Immune Responses And Cell Signaling

COVID-19 Research: University Of Illinois Study Shows That Nonstructural Proteins Of SARS-CoV-2 Dysregulates Immune Responses And Cell Signaling
Source: COVID-19 Research  Jan 23, 2021  3 years, 2 months, 3 weeks, 1 day, 22 hours, 48 minutes ago
COVID-19 Research: A new study by researchers from the University of Illinois at Chicago shows that the nonstructural proteins of the SARS-CoV-2 coronavirus dysregulates the immune responses and cell signaling of the human host to generate a permissive environment.

According to the study team, the SARS-CoV-2 proteins upregulate or downregulate more than 100 human kinases involved in cellular physiology, metabolism, and immune activation. Targeting specific proviral cellular signaling could make the host microenvironment resistant to virus replication. Most of the nonstructural proteins of SARS-CoV-2 participate in dysregulating the immune response.
The SARS-CoV-2 virus reorganizes the host cytoskeleton for efficient cell entry and controls host transcriptional processes to support viral protein translation. The virus also dysregulates innate cellular defenses using various structural and nonstructural proteins. This results in substantial but delayed hyperinflammation alongside a weakened interferon (IFN) response.
This study provide an overview of SARS-CoV-2 and its uniquely aggressive life cycle and discuss the interactions of various viral proteins with host signaling pathways. The study also address the functional changes in SARS-CoV-2 proteins, relative to SARS-CoV. The comprehensive assessment of host signaling in SARS-CoV-2 pathogenesis provides some complex yet important strategic clues for the development of novel therapeutics against this rapidly emerging worldwide crisis.
Pertaining to the differences in sequence homology, NSP2 may be important in serodiagnosis.
The study findings were published in the peer reviewed journal: Trends In Microbiology.
The SARS-CoV-2, the virus that causes the COVID-19 disease, is a novel pathogen that emerged in December 2019 in China. Since then, it has spread globally to over 221 countries and territories, infecting more than 98.5 million people and claiming over 2.11 million lives.

While the virus continues to spread and new highly infectious variants emerge, understanding the complex pathogen-host interplay is urgently needed to effectively control its spread.
Typically pathogens, such as viruses and bacteria, assume host pathways to trigger a tolerant environment for their proliferation.
Scientists from the Department of Ophthalmology and Visual Sciences, the University of Illinois at Chicago, USA, provided an overview of SARS-CoV-2 and its life cycle pathways.
By doing so, the team addressed the functional changes in the viral proteins, providing important strategic clues to help that may help in the ongoing development of therapies against COVID-19.
The severe acute respiratory syndrome coronavirus (SARS-CoV) and the SARS-CoV-2 belong to the beta subfamily of the coronavirus genus. SARS-CoV-2 contains 29 different proteins, which include 16 nonstructural proteins. These include proteases, RNA-dependent RNA polymerases, a nuclease, helicase, and methyltransferase encoded by 14 open reading frames (ORFs).
The SARS-CoV-2 has the highest transmissi on rate among the coronaviruses that have caused outbreaks in the past. However, it has the lowest mortality rate of about 2.3 percent, compared to SARS-CoV or the Middle East respiratory syndrome coronavirus (MERS-CoV), with a fatality rate of 9.6 percent and 35 percent, respectively.
Interestingly the reason why SARS-CoV-2 has the highest rate of transmissibility is that it has genetic alterations in the various structural and nonstructural proteins.
The study team highlights the importance of understanding the mechanisms by which the virus triggers host cell pathways and functions to cause illness.
The study team discussed genomic variations in viral proteins to determine their roles in the modulation of host cell signaling.
Significantly among the key findings of the study was that SARS-CoV-2 proteins modulate host signaling to produce a permissive or tolerant environment. This way, the environment in the host can support viral proliferation and spread.
In addition, the study team found that viral proteins can boost or lower the activity of about 100 human kinases involved in cellular function, metabolism, and immune activation. This means that the proteins of SARS-CoV-2 alter the body and cellular functions to aid in its spread.
The researchers also noted that targeting particular proviral cellular signaling could help make the host environment resistant to virus replication.
Importantly therapeutics developed for this function can aid in containing virus spread and preventing infection.
These nonstructural proteins of SARS-CoV-2 also participate in dysregulating the immune response. This leads to a weaker activity of the immune system in fighting the infection. The virus alters innate cellular defenses using many of its proteins, leading to a delayed hyper inflammation along with a weakened interferon (IFN) response.
They are altogether 17 nonstructural proteins proteins playing a key role in this dyregulation of the cell signaling and immune response.
The life cycle of SARS-CoV-2 begins with the priming of the viral spike (S) protein by host proteases or the transmembrane protease serine 2 (TMPRSS2) to ensure fusion of the viral envelope with the host cell membrane and entry of the viral genome into the cell. Alternatively, SARS-CoV-2 virions can be endocytosed by the cell after attaching to the angiotensin-converting enzyme 2 (ACE2) receptor. Once internalized, host enzyme cathepsin L can cleave the S protein that results in a similar release of the viral genome to the cell.
Once inside the cell, the positive-sense ssRNA genome becomes translated using host ribosomes. The primary viral gene ORF1ab codes for the polyproteins pp1a and pp1ab which autocleaves the papain-like protease (PLpro) and 3C-like protease (3CL-pro) from itself.

PLpro further processes the viral polyprotein and releases nonstructural proteins (NSPs) 1–3, while 3CL-pro releases the remaining NSPs 4–16.Certain SARS-CoV-2 NSPs form an RNA replication complex, such as the RNA-dependent RNA polymerase (RdRp) NSP12 and the helicase NSP13. NSPs 10, 13, 14, and 16 participate in mRNA capping,