Source: SARS-CoV-2 M Proteins   Jan 24, 2022  4 months ago
BREAKING! U.S. NIH Study Reveals That Membrane(M) Proteins Of SARS-CoV-2 Induce Altered CD4+ T Cells That Dysregulate Interferon Signaling!
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BREAKING! U.S. NIH Study Reveals That Membrane(M) Proteins Of SARS-CoV-2 Induce Altered CD4+ T Cells That Dysregulate Interferon Signaling!
Source: SARS-CoV-2 M Proteins   Jan 24, 2022  4 months ago

A new study by researchers from U.S NIH, NIAID and La Jolla Institute for Immunology has found that SARS-CoV-2 M Proteins or membrane proteins induce altered CD4+ T cells that dysregulate interferon signaling!
The study team generated CD4+ T cell lines (TCLs) reactive to either SARSCoV-2 spike (S) or membrane (M) proteins from unexposed naive T cells from six healthy donor volunteers to understand in fine detail whether the S and M structural proteins have intrinsic differences in driving antigen-specific CD4+ T cell responses.
Having shown that each of the TCLs were antigen-specific and antigen-reactive, single cell mRNA analyses demonstrated that SARS-CoV-2 S and M proteins drive strikingly distinct molecular signatures. The SARS-CoV-2 M Proteins or membrane proteins was found to induce altered CD4+ T cells that dysregulate interferon signaling!
The study fining showed that  while the S-specific responses are virtually indistinguishable from those responses induced by other viral antigens (e.g. CMV), the M protein-specific CD4+ TCLs have a transcriptomic signature that indicate a marked suppression of interferon signaling, characterized by a downregulation of the genes encoding ISG15, IFITM1, IFI6, MX1, STAT1, OAS1, IFI35, IFIT3 and IRF7 (a molecular signature which is not dissimilar to that found in severe COVID-19).
The study findings suggest a potential link between the antigen specificity of the SARS-CoV-2-reactive CD4+ T cells and the development of specific sets of adaptive immune responses. Moreover, the balance between T cells of significantly different specificities may be the key to understand how CD4+ T cell dysregulation can determine the clinical outcomes of COVID-19.
The study findings were published on a preprint server and are currently being peer reviewed.
 Typically, SARS-CoV-2 infected-patients develop specific antibodies, CD4+ T cells, and CD8+ T cells in response to the infection, although, CD4+ T cells had the strongest association with diminished COVID-19 disease severity compared with the other two arms (B cells, CD8+ T cells) of the adaptive immunity.
Importantly, the absence of SARS-CoV-2-specific CD4+Tcells was associated with severe or fatal COVID-19.
Data from other another coronavirus ie SARS-CoV-1 reported that SARS-CoV-1 spike protein was responsible for nearly two-thirds of the CD4+ T cell reactivity with limited reactivity for M and N proteins.
 However, it seems that the pattern of antigen predominance of SARS-Cov-2-driven immune responses is different from SARS-CoV-1 in that there is strong reactivity of CD4+ T cells to viral S, M and N structural proteins, as well as, to other non-structural proteins and open reading frames, including ORF3 and NSP3.
The correlation between antigen-specific CD4+ T cell responses and COVID-19 severity remains unclear. First it has been demonstrated that mild COVID-19 patients, who typically recover without special treatment, showed broad SARS-CoV-2-specific CD4+ T cell responses to S and N proteins, responses that were highly correlated with specific antibody titers.
T cell responses were however imbalanced in critical ICU patients with a functionally impaired CD4+ T cell response showing reduced production of IFN-g and TNF-a.
In fact, an inflammatory cytokine and chemokine signature (elevated CXCL10, IL-6, and IL-8) accompanied by ineffective interferon responses has been strongly associated with failure to control a primary SARS-CoV-2 infection and with a higher risk of fatal COVID-19.
Also, impaired, and delayed type I and type III IFN responses have been associated with a higher risk of severe COVID-19.
Interferons (IFNs), including type I (IFN-α and IFN-β) and type III (IFN-λ) are central to both combating virus infection and modulating the antiviral immune response.
Although type I IFNs are widely expressed and can result in immune mediated pathology during viral infections, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are associated with protection to viruses without driving damaging proinflammatory responses.
Interestingly, coronaviruses develop efficient immune evasion mechanisms by manipulating immune responses and by interfering with the IFN-related pathways.
Indeed, several structural (M and N) and non-structural (NSP1 and NSP3) proteins from SARS-CoV and MERS-CoV can act as interferon antagonists.
Notwithstanding, SARS-CoV-2 M protein has also been implicated to antagonize type I and III IFN production by affecting the formation of the RIG-I/MDA-5–MAVS–TRAF3–TBK1 signalosome that has been shown to attenuate antiviral immunity and enhance viral replication.
 The study team using single-cell transcriptomes of human CD4+ TCLs reactive to either S protein or M protein, have shown that SARS-CoV-2 M protein-reactive CD4+ TCLs in comparison with S protein, expressed higher levels of the inflammatory genes FOS, JUNB and lower levels of ISGs, including ISG15, IFI6, IFI35, IFI44, IFIT3, IFITM1, STAT1, OAS1, and interferon regulatory factors, including (IRF7).
Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. ISGs have a central role to regulate the type I interferon. Among these ISGs, ubiquitin-like protein ISG15 is one of the most strongly and rapidly induced, and recent work has shown that it can directly inhibit viral replication and modulate host immunity.
It has also been observed that the molecular signature of SARS-CoV-2 M protein-reactive CD4+ TCLs, is characterized by suppression in the interferon pathways, genetically associates with the transcriptional profile of severe COVID-19.
Notably, through signal cell RNAseq analysis of T-cell dysregulation in severe COVID-19 it has been demonstrated that CD4+T cells from severe COVID-19 patients expressed higher levels of a set of inflammatory genes that include FOS, FOSB, JUN and others, gene expression not dissimilar to those found in our M-specific TCLs derived from SARS-CoV-2 unexposed individuals.
In parallel, this same study showed that CD4+ T cells from patients with severe COVID-19 showed decreased expression of interferon-induced genes including IFIT1, IFIT2, 226 IFIT3, and IFITM1 and those downstream from interferon signaling, again striking similar to the molecular signature seen in the M protein-reactive CD4+ TCLs in this present study.
The mechanisms by how the peptide megapools of M and S proteins underlies different responses of naïve CD4+ T cells remains unclear.
Detailed future studies are needed to elucidate if the M driven dysregulation of interferon signaling pathway in the adaptive immunity resemble to the mechanisms already described including the interaction with pattern recognition receptors  (PRRs)-downstream molecules of innate cells, or if it is induced by the interaction of the class II  MHC-peptide complex with the restricted TCR repertoire of naïve T cells.
In conclusion, although it has been poorly understood how CD4+ T cell dysregulation can contribute to the immunopathogenesis of severe COVID-19, the study findings suggest a potential link between the antigen specificity of the reactive CD4+ T cells to SARS-CoV-2 with the development of a functional and efficient adaptive immune response.
The discordant response to S compared to M proteins suggest that the balance between the T cells of different specificities may alter immune evasion mechanisms that may, in turn, drive disease severity. Hence, one could envision therapeutic approaches that also targets the SARS-CoV-2 M protein may also be important for amelioration of severity of COVID-19.
For more about SARS-CoV-2 M-Proteins and Dysregulated Interferon Signaling, keep on logging to Thailand Medical News.


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