Virus News: University Of Alabama Study Alarmingly Shows That Individuals Recovering From COVID-19 Exhibit Sustained Cellular Immune Dysregulation

Virus News: Scientists from University of Alabama have in a new study found that individuals recovering from COVID-19 exhibit sustained cellular immune dysregulation.


 
To date it has been found that the SARS-CoV-2 coronavirus causes a wide spectrum of clinical manifestations and significant mortality.
 
Research investigating underlying immune characteristics is needed to understand disease pathogenesis and inform vaccine design.
 
The study team examined immune cell subsets in hospitalized and non-hospitalized individuals. In hospitalized patients, many adaptive and innate immune cells were decreased in frequency compared to healthy and convalescent individuals, with the exception of B lymphocytes which increased.
 
The study findings show increased frequencies of T-cell activation markers (CD69, OX40, HLA-DR and CD154) in hospitalized patients, with other T-cell activation/exhaustion markers (PD-L1 and TIGIT) remaining elevated in hospitalized and non-hospitalized individuals. B cells had a similar pattern of activation/exhaustion, with increased frequency of CD69 and CD95 during hospitalization, followed by an increase in PD1 frequencies in non-hospitalized individuals.
 
Alarmingly, many of these changes were found to increase over time in non-hospitalized longitudinal samples, suggesting a prolonged period of immune dysregulation following SARS-CoV-2 infection.
 
Changes in T-cell activation/exhaustion in non-hospitalized patients were found to positively correlate with age. Severely infected individuals had increased expression of activation and exhaustion markers. These data suggest a prolonged period of immune dysregulation following SARS-CoV-2 infection highlighting the need for additional studies investigating immune dysregulation in convalescent individuals.
 
The study findings were published in the peer reviewed journal: JCI or Journal Of Clinical Investigation. https://www.jci.org/articles/view/140491
 
The current COVID-19 pandemic which has killed almost 1.8 million people worldwide does not follow a uniform path.
 
Majority of SARS-CoV-2 infected patients remain asymptomatic or have mild symptoms. Others, especially those with comorbidities, can develop severe clinical disease with atypical pneumonia and multiple system organ failure.
 
Ever since the first cases were reported in December 2019 in Wuhan China the SARS-CoV-2 virus that causes COVID-19 has surged into a pandemic, with cases and deaths still mounting. Ongoing observational clinical research has become a priority to better understand how this previously unknown virus acts, and findings from this research can better inform treatment and vaccine design.
 
The study team led by first-author Dr Jacob "Jake" Files and co-senior authors Dr Nathan Erdmann, M.D., Ph.D., and Dr Paul Goepfert, M.D., have now reported their observational study.
 
Dr Phillip Mudd, M.D., Ph.D., and Dr Kenneth Remy, M.D., both of Washington University told Thailand Medical News, "The importance of these studies to provide context for the interpretation of immune responses generated by participants in COVID-19 vaccine trials, including how those responses change over time, cannot be over-emphasized. This information will be key in potenti al modifications to existing COVID-19 vaccines and treatments."
 
Their opinions were also published as a commentary in the same journal, accompanying the study findings.
 
The study team obtained blood samples and clinical data from 46 hospitalized COVID-19 patients and 39 non-hospitalized individuals who had recovered from confirmed COVID-19 infection.
 
Both groups were compared to healthy, COVID-19-negative controls. Importantly, most individuals in the hospitalized group had active SAR-CoV-2 viruses in their blood and were in the hospital at the time of sample collection.
 
Also, all individuals in the non-hospitalized group were convalescent at the time of sample collection.
 
The study team was able to separate specific immune cell subsets and analyze cell surface markers from the blood samples.
 
From this complex information, immunologists can analyze how each individual's immune system is responding during infection and during convalescence.
 
Furthermore some of these results can reveal whether immune cells have become activated and exhausted by the infection. Exhausted immune cells may increase susceptibility to a secondary infection or hamper development of protective immunity to COVID-19.
 
Also the study team was able to analyze changes over time, in two ways. The first was observing changes in surface markers over time, defined as days since the onset of symptoms for non-hospitalized samples. The second was directly comparing the frequencies of these markers between the first and second clinic visits for non-hospitalized patients who had blood samples collected at two sequential timepoints.
 
Alarmingly, the most surprising finding involved non-hospitalized patients.
 
Although the study team saw upregulated activation markers in hospitalized patients, they also found several activation and exhaustion markers were expressed at higher frequencies in non-hospitalized convalescent samples.
 
Analyzing these markers over time, it was apparent that immune dysregulation in the non-hospitalized individuals did not quickly resolve. Furthermore, the dysregulation of T cell activation and exhaustion markers in the non-hospitalized cohort was more pronounced in the elderly.
 
Corresponding author Dr Nathan Erdmann from the Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham commented, "To our knowledge this is the first description of sustained immune dysregulation due to COVID-19 in a large group of non-hospitalized convalescent patients."
 
A recent study classified immune subsets in SARS-CoV-2 infection and reported increased frequencies of the classical CD14+ monocyte population in a small cohort of COVID-19 recovered patients, while a new report found increased frequencies of “Non-T/Non-B” cells in COVID19 patients. https://pubmed.ncbi.nlm.nih.gov/32377375/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263500/
 
The study findings found decreased frequencies within monocytes, NK cells, and dendritic cells in hospitalized COVID-19 patients, that then returned to baseline in our non-hospitalized individuals. Taken together, these findings may suggest an influx of immature nonclassical immune cells during infection and needs to be investigated further.
 
Also increased percentages of intermediate CD14+CD16+ monocytes in severe SARS-CoV-2 infections have been previously described. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108005/
 
The study team found a trend (p=0.104) towards increased double positive monocytes in our hospitalized group, and also demonstrate that this monocyte population is elevated in non-hospitalized individuals. The intermediate monocyte population was recently shown to be functionally heterogenous, emphasizing the need for more investigation into this subset. https://pubmed.ncbi.nlm.nih.gov/28428369/
 
Lastly the study team shows that the frequency of dendritic cells is decreased in both hospitalized and non-hospitalized patients. Taken together, these data suggest a prolonged impact of SARSCoV-2 on the innate immune system in both hospitalized and non-hospitalized individuals.
 
The team’s  investigation into the CD4+ and CD8+ T-cell compartments clearly shows sustained activation (based on HLA-DR, CD69 and OX40 expression) and exhaustion (based on PD-L1 and TIGIT expression) in both T-cell subsets.
 
As PD1 and TIM3 can be upregulated on both activated and exhausted T cells, their role post COVID-19 infection remains unclear. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125508/
 
https://pubmed.ncbi.nlm.nih.gov/32265932/
 
Regulatory T cells have previously been shown to upregulate OX40 and HLA-DR. https://pubmed.ncbi.nlm.nih.gov/29065175/
 
https://pubmed.ncbi.nlm.nih.gov/30555473/
 
The sustained increase in OX40 and HLA-DR in both hospitalized and non-hospitalized individuals could represent a regulatory T cell population, further emphasizing the need for further classification and functional assessment these subsets. The loss of CD27 and CD28 may suggest increased Tcell senescence, which is of particular relevance to understanding formation of memory responses. CD4+ and CD8+ memory T cells are typically generated following the initial activation and expansion stage that occurs in acute infection. https://pubmed.ncbi.nlm.nih.gov/15140950/
 
As demonstrated previously, establishment of airway memory CD4+ T cells mediated protective immunity against respiratory coronaviruses including SARS and MERS in a mouse model. https://pubmed.ncbi.nlm.nih.gov/27287409/
 
The study team observed sustained expression of T-cell activation and exhaustion markers in non-hospitalized, convalescent SARS-CoV-2 individuals, as well as decreased frequencies of CD27 and CD28 expressing CD8+ T cells.
 
These findings may represent an impaired ability to form memory T cells. This is supported by prior observations on IL-10 production in SARS and SARS-CoV-2 individuals where IL-10 production by regulatory CD4+ T cells was shown to be necessary for memory CD8+ T cell development in mice . In SARS patients, there was shown to been an increase in IL-10 production during the convalescent phase of infection. https://pubmed.ncbi.nlm.nih.gov/15271897/
 
However, a recent report on SARS-CoV-2 infected individuals has found that serum levels of IL-10 were highest during acute infection and decreased in convalescence. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205903/
 
Overall, these study findings provide a possible etiology for how the sustained immune dysfunction observed during convalescence could impair the formation of long-term memory T cells, emphasizing the need to explore memory and regulatory T cell development and function in SARS-CoV-2 infected individuals. There was substantial B cell activation demonstrated by increased frequencies of CD95+, CD69+, and PD1+ B cells in the hospitalized group. This may reflect both the presence of SARSCoV-2 specific B cells responding to antigen and/or bystander B-cell activation. B-cell markers were found to generally return to levels similar to healthy controls, although the sustained presence of FCRL4+ and PD1+ B cells suggests persistence of some degree of B-cell dysregulation.
 
How this dysregulation relates to SARS-CoV-2 antibody responses is unknown.
 
The finding of more pronounced T-cell activation/exhaustion in elderly non-hospitalized SARS-CoV-2 individuals has many potential implications.
 
In acute disease, these findings suggest this group may be at heightened risk for inflammation-mediated pathology. This immune dysfunction may also lead to suboptimal SARS-CoV-2-specific memory responses and increased susceptibility of re-infection.
 
Additional longitudinal studies are needed to better understand the impact of T-cell activation on long term immunity.
 
The study team extended their analysis to separate hospitalized patients that did or did not require intensive care. This revealed several differences in surface markers on T and B cell populations. Not surprisingly, activation markers were more frequently observed in severely infected individuals, in support of recent observations on the expression of HLA-DR and CD38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263500/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402634/
 
The study findings are the first report of upregulated PD-L1 in severe COVID-19 patients. Interestingly, it was observed that non-ICU patients had increased expression of CD137.
 
Prior studies observed that CD137 can augment immune responses in acute viral infections, and that blocking CD137 with anti-CD137 antibodies led to increased LCMV infection in the mouse model. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1974869/
 
The findings suggest CD137 expression may be associated with COVID-19 disease outcomes.
 
Finally, the team found that severely infected COVID-19 patients have increased B-cell expression of CD95 and CD27, and decreased expression of HLA-DR. These findings need to be investigated further to explore possible therapeutic interventions. The prolonged activation we observed, particularly of T cells and monocytes, may be due to the persistence of antigen, either viral RNA and/or protein, despite resolution of symptoms. Support of this can be found from the studies that identified the persistence of viral RNA in SARSCoV-2 patients during the convalescent period. https://pubmed.ncbi.nlm.nih.gov/32147538/
 
https://pubmed.ncbi.nlm.nih.gov/32235945/
 
Antigen presenting cells (APCs) that present viral RNA can cross-prime and activate CD8+ T cells through a TLR3 mechanism, which could be similar to what is occurring in SARS-CoV-2 infected individuals. These data open the door to many interesting mechanistic studies to determine what factors are causing and prolonging immune cell activation https://pubmed.ncbi.nlm.nih.gov/15711573/
 
The B and T cells from both patient cohorts had phenotypes consistent with activation and cellular exhaustion throughout the first two months of infection. And in the non-hospitalized individuals, the activation markers and cellular exhaustion increased over time.
 
 "These findings," Dr Mudd and Dr Remy said in their commentary, "illustrate the persistent nature of the adaptive immune system changes that have been noted in COVID-19 and suggest longer-term effects that may shape the maintenance of immunity to SARS-CoV-2."
 
A key question now being explored, the study team says, is whether these observed immunologic changes are associated with symptoms experienced well beyond the acute infection, often described as "Long COVID."
 
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