Majority Of Post-COVID-19 Individuals Have Immune And Clotting Dysfunction Which Can Be Detected Via Plasma And Saliva

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A new study by researchers from J. Craig Venter Institute-California, Agilent, Technologies, Inc-California, University of Delaware, Maine Medical Center and University of California-San Diego have found that majority of POSt-COVID-19 individuals have immune and clotting dysfunction which ca be detected via plasma and saliva samples.

The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.03.18.484814v1

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has had devastating impacts on global health 1,2. Blood (e.g., serum, plasma and peripheral mononuclear cells) and lungs of COVID-19 patients have been extensively investigated to reveal the acute phase immunopathogenesis and discover diagnostic and protective markers 3–6.

Of the blood components evaluated, the induction of antibodies and T cells play crucial roles in the neutralization and clearance of SARS-CoV-2 viruses, crucial to prevent the infection and reduce disease severity 7–9. Also, the dysregulated neutrophil functions and blood clot process in the early infection phase has been reported to be associated with severe sequelae of COVID-19 10–15.

As millions of people have been recovered from the SARS-CoV-2 infection, there have been an increasing number of long-term complications of the COVID-1916,17. Recent reports warrant that the immunopathogenesis of COVID-19 is beyond the acute-phase systemic or pulmonary disease (<2weeks).

A recent case-control study of 31 individuals with post-acute sequalae of SARS-CoV-2 infection (PACS) found elevated levels of T cell immunoglobulin mucin domains and elevated cytokines in both PACS cases and non-PACS convalescent controls 18, suggesting a sustained inflammatory response were present independent of the clinical manifestation of the PASC.

While millions of people are suffering from lingering symptoms after the COVID-19, even a clear diagnostic definition has not been established Early responses of immune dysfunction remain unknown and early factors to anticipate COVID-19 sequelae are needed 19 , 20. Understanding “how” and “why’’ inflammatory responses persist over multiple organs, is needed to detect the early signs and develop intervening strategies 4,21.

Inter-related multiple biological factors have been reported to be associated with the establishment of the PACS, including host immune dysregulation and dysbiosis in the microbiome at mucosal surfaces 21–23.

It is now known that aberrant innate immune signaling cascades, resulting in a viscous loop of inflammation sustained after clearance of virus, drive the early stage to long-term actions24.

Yet, the early drivers that govern molecular dysbiosis and tissue damage at the mucosal surface are not completely dissected. For a better understanding on the pathophysiology before PASC developers, a novel approach is needed to define normal vs. pathologic convalescent process and to detect initiation of aberrant innate immune activation, especially at mucosal surfaces that are in direct contact with the viral particles.

Saliva is an important vehicle for the silent spread of the SARS-CoV-2 viruses and a critical target to end the explosive transmission of the SARS-CoV-2 variants25. In addition, saliva is a practical and optimal target to monitor alterations of mucosal immune system by respiratory infection, as being:

1) a direct surrogate for antibody response derived from bronchial-alveolar lymphoid tissues (BALT) to the SARS-CoV-2 viral infection26,

2) a reflection of systemic reactions to infection as more than 90% of body protein components are detected from saliva 27,

3) containing oral commensals which shape the host immune profile 28, and 4) oral inflammation can influence on the severity of systemic inflammatory responses 29–31.

Recent studies reported the association of the oral/gastrointestinal mucosal alterations with the pathophysiology of PASC 21,23,32, underpinning the potential of saliva to discover molecular mechanisms and early indicators.

This study was designed to capture the chronic inflammatory response during the start of the convalescent phase (>2 weeks after clinical symptom) and investigate the correlation among biological, and demographic factors. To increase the credibility of the comparative analyses, we first analyzed the plasma antibody levels, the golden standard to measure immune response to the viral infection. We then expanded to the mucosal antibody response and proteomic alterations at both systemic and mucosal levels.

Overall, our results demonstrate that saliva is not only a fluid for viral monitoring but also a reliable source in evaluating the immune responses in the short term and longitudinally. The immune dysfunctions found here are key determining protective and aberrant immune mechanisms at the mucosal level.

The salivary proteome reflected such immunopathogenesis mediated by interactions among IgA, neutrophil, and fibrinogen, which was not observed in plasma proteome. Elevated fibrinogen appears to be an indicator of severity of inflammatory response in both systemic and mucosal responses.

Our study reveals that immune dysfunction can be detected in saliva in persons who have recovered from COVID-19. Such biomarkers may be a good way to screen for PASC and may identify novel pathways and mechanisms that can be targeted therapeutically.

In this report we further demonstrate that salivary IgA antibody responses to SARS-COV-2 could be involved in the neutrophil-fibrinogen interactions at the oral mucosal surface.

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