Long COVID News: T Cell Dysregulation, Inflammation And A Dysfunctional Adaptive Immune Response To Persistent SARS-CoV-2 Occurs In Long COVID!
Long COVID News
: A new study by researchers from University of California, San Francisco-USA and Ulm University Medical Center-Germany has found that Long COVID typically manifest T cell dysregulation, inflammation and a dysfunctional adaptive immune response to persistent SARS-CoV-2!
According to their study abstract,” Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood.”
The study team utilized multiple “omics” assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear Long COVID and non-Long COVID clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine.
Their analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis.
The study findings showed that individuals with Long COVID exhibited systemic inflammation and immune dysregulation.
This finding was evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets.
It was found that individuals with Long COVID harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells.
These Long COVID individuals also harbored significantly higher levels of SARS-CoV2 antibodies, and in contrast to non-Long COVID individuals.
The LONG COVID individuals also exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses.
The study findings clearly showed that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in Long COVID, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.
The study findings were published on a preprint server and are currently being peer reviewed.
Thailand Medical News had already warned in our previous Long COVID News
coverages that many Post COVID individuals are suffering form either immune dysfunctions or COVID-19 induced immunodeficiency!
The study findings from the teams at University of California-San Francisco And ULM University show that individuals with Long COVID exhibit perturbations in both total and SARS-CoV-2-specific T cells, which manifests at a global level as mis-coordination between the two main arms of adaptive immunity and overall changes in gene expression.
The study’s CyTOF data revealed profound changes in classical subset distribution among total CD4+ T cells in individuals with Long COVID, specifically a significantly higher proportion of CD4+ Tcm, Tfh, and Treg cells.
Elevated frequencies of Tcm, Tfh, and Treg in individuals with Long COVID indicate an ongoing immune response persisting at 8 months post-infection. This immune response, however, may not necessarily be directed against SARS-CoV-2, and could potentially be directed against other viruses (e.g., reactivated EBV or other herpes viruses) or auto-antigens.
Interestingly, one aspect highly consistent between all studies to date is the ability to detect SARS-CoV-2-specific T cells in both Long COVID and non-Long COVID individuals, months after infection. This could simply be attributed to the long-term persistence of memory T cells elicited by SARS-CoV-2, but may also indicate the persistence of a long-lived tissue viral reservoir.
The study team found that in Long COVID relative to non-Long COVID individuals, SARS-CoV-2-specific CD8+ T cells, but not total CD8+ T cells, more frequently expressed the exhaustion markers PD1 and CTLA4, which is consistent with ongoing stimulation with viral antigens.
Also in support of a potential persistent reservoir is the observation of higher SARS-CoV-2 antibody levels in Long COVID as compared to non-Long COVID individuals, which has also been previously seen with Spike-specific IgG levels.
The study data revealed that the individuals with the highest frequencies of exhausted (PD1+CTLA4+) SARS-CoV-2-specific CD8+ T cells were not those with the highest SARS-CoV-2 antibody levels, suggesting that there may be multiple endotypes of Long COVID being driven by persisting virus.
Although SARS-CoV-2-specific CD8+ T cells from individuals with Long COVIDC showed signs of exhaustion, their CD4+ counterparts preferentially expressed the tissue-homing receptors CXCR4, CXCR5, and CCR6.
The study team found elevated expression of CXCR4 not only on SARS-CoV-2-specific but also total CD4+ T cells in the context of Long COVID, targeting of this receptor as well as other chemokine receptors may be useful to limit immune cell infiltration into the lung, which may persist in an elevated state of inflammation in individuals with Long COVID.
The study team also found that the SARS-CoV-2-specific CD4+ T cells from individuals with Long COVID produces IL6 in response to spike peptide stimulation.
Though this was observed in only a small minority of individuals with Long COVID, it suggests that a highly inflammatory response directed against the virus, persisting for at least 8 months post-infection, could be a driver of the sequelae.
Most striking from the study was the finding that while fully recovered individuals exhibited coordinated humoral and cellular immune responses to SARS-CoV-2, this coordination was lost in the Long COVID group. That improper crosstalk between T and B cells may be involved in the etiology of Long COVID is also supported by the RNAseq data, which showed that a cluster of genes including both immunoglobulin synthesis and T cell function were co-upregulated in those without Long COVID, but not in individuals with Long COVID.
How the humoral response becomes divorced from the cellular response is unclear, and could potentially involve a mis-alignment between IL4 and IL5 production by Th2 cells which emerged from the Olink analysis.
Potential upstream initiators leading to the miscoordination include a long-lived SARS-CoV-2 reservoir, reactivation of viral co-infections, or autoimmune responses.
The study datasets taken together point to not only a dysregulated but also a highly pro-inflammatory signature in Long COVID, consistent with prior data suggesting elevated and persistent inflammation in Long COVID.
Of particular interest was the elevation of the SGALS9 gene product in Long COVID. LGALS9 encodes for Galectin 9, which has previously been shown to be upregulated during acute COVID-19 and may be a contributing factor in cytokine release and subsequent disease severity.
The high inflammatory state observed in individuals with Long COVID may be in part driven by immune dysregulation, which could initiate from improper cross-talk between T and B cells as discussed above, or potentially faulty regulatory mechanisms as supported by the observation that the individuals with Long COVID with the highest frequencies of exhausted SARS-CoV-2-specific CD8+ T cells were those that had the lowest frequencies SARS-CoV-2-specific CD4+ Treg cells.
Interestingly the study findings also found higher expression of genes involved in heme biosynthesis during acute COVID-19, and that SARS-CoV-2 can bind hemoglobin and dysregulate heme metabolism. It is also possible that increased heme synthesis may reflect fibrin amyloid microclot formation that has been observed in individuals with Long COVID.
These microclots appear to be resistant to fibrinolizes and may trap potential circulating biomarkers of the coagulopathy. As a result, heme synthesis may play a useful role in determining the extent of microclot formation. Further studies of iron metabolism and red blood cell function, and their relationships to coagulopathy in the setting of Long COVID, are warranted.
The study findings using multiple analytical approaches in a carefully selected cohort of individuals with consistent post-COVID symptom trajectories showed that that Long COVID is associated with dysregulation between humoral and cellular immunity. While Long COVID exhibits both clinical and biological complexity, this work contributes to a growing understanding of the potential pathophysiological contributors and suggests several mechanisms warranting further exploration and/or disruption in future therapeutic trials.
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