COVID-19 Research: University Of Illinois Study Shows That Nonstructural Proteins Of SARS-CoV-2 Dysregulates Immune Responses And Cell Signaling
: 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. https://www.cell.com/trends/microbiology/fulltext/S0966-842X(20)30324-3?#%20
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, and NSPs 10, 14, and 15 proofread the nascent genome.
While the genome is replicating, multiple viral proteins – such as NSP1, NSP3, NSPs 12-14, ORF3, ORF6, and ORF7a/b – antagonize host immune responses by targeting the innate immune system, in particular the type 1 interferon (IFN) pathway. However, the virus activates certain host Toll-like receptors (TLRs) during infection, which stimulates the release of numerous proinflammatory cytokines, including interleukin (IL)-1β, IL-2, IL-6, IL-7, granulocyte-colony stimulating factor (GCSF), IFN-γ, and tumor necrosis factor-alpha (TNF-α).
Analysis of peripheral blood from severely infected patients revealed decreased CD4 and CD8 T cell counts, but the fractions of hyperactivated T cells increased. Furthermore, the concentrations of T helper (Th)17 cells and perforin and granulysin-expressing CD8 T cells were enhanced, both of which contribute to hyperinflammation. Host Th17 responses are major contributors to cytokine storms, a hallmark of severe coronavirus disease 2019 (COVID-19) infections.
Subsequently, the viral structural proteins and the viral genome assemble into the virion, which travels to the host cell surface using vesicles and is released via lysosomal, Arl8b-dependent exocytosis. The host endoplasmic reticulum (ER) chaperone GRP78/BiP is cotrafficked with the virion and released during this process as well. Alternatively, immature virions use the nucleocapsid (N) protein to localize to a glycosylated envelope (E) protein at the cell surface.This interaction allows for a reorientation of the virion, followed by budding from the host cell. Finally, the destruction of host organelles can lead to the release of lysosomal contents, triggering cell death and the release of viral progeny.
During infection, viruses tend to exploit host machinery to create a permissive host microenvironment. A phosphoproteomic analysis of SARS-CoV-2-infected Vero cells revealed regulation of 97 cellular kinases. The activated kinases include some of those involved in p38-mediated signaling and guanosine monophosphate-dependent protein kinases. Downregulated kinases include those involved in cell growth, the cell cycle, and cytoskeleton regulators. The most highly activated transcription factors, such as nuclear factor-κB (NF-ĸB), monocyte-specific enhancer factor 2C, and c-Jun, are downstream of the p38/MAPK (mitogen activated protein kinase) pathway which is known to mediate stimulation of proinflammatory cytokines, including IL-6, TNF-α, CCL2, CCL20, and CXCL8.
Additionally, cell cycle arrest at the S/G2 transition is highly correlated with productive SARS-CoV-2 infection, whereas M phase progression is negatively correlated. S/G2 arrest during infection may be due to a dysregulation of cyclin-dependent kinase 2 (CDK2) activity during viral infection. Studies have found atypical, delayed induction of host immune response to SARS-CoV-2 infection which favors virus replication in the absence of type I and III IFN responses and simultaneously induces high levels of chemokines.
An integrated immune analysis on a cohort of 50 COVID-19 patients with various levels of disease severity has shown that NF-κB partially drives the inflammation. Such inflammatory responses are the outcome of increased TNF-α and IL-6 signaling. Recent work shows that TNF-α and IFN-γ induce inflammatory cell death and tissue damage through extensive crosstalk among different modes of cell death, including pyroptosis, apoptosis, and necroptosis, together termed PANoptosis.
Treatment with a combination of TNF-α and IFN-γ was found to activate the Janus kinase (JAK)/STAT1(signal transducer and activator of transcription 1)/IRF1 (interferon regulatory factor 1) axis, leading to nitric oxide production that drives caspase-8/FADD-mediated PANoptosis. Interestingly, TNF-α and IFN-γ together induce a SARS-CoV-2-like cytokine storm in mice, which can be reversed using PANoptosis inhibitors.
Furthermore, treatment of SARS-CoV-2-infected mice with neutralizing antibodies against TNF-α and IFN-γ protects mice from death. This emphasizes the clinical significance of cytokine-mediated inflammatory cell death signaling pathways.
Importantly as well, when immune activation is delayed, it prolongs infection and promotes viral replication. A substantial IFN production may ensue, leading to a cytokine storm that may lead to acute tissue injury.
The study shows that it is clear that individual factors of SARS coronaviruses have diverse roles in disruption of cellular programs, and additional research focus directed in the areas outlined here may help in delineating the underlying mechanism of pathogenesis and spread in humans and will be instrumental in our quest for curative therapeutics.
Properly comprehending how SARS-CoV-2 affects the body can help in the development of vaccines and therapies to fight the ongoing COVID-19 pandemic.
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