Study offers comprehensive longitudinal roadmap of immune activation and resolution in mild COVID-19

Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) is a novel human betacoronavirus that emerged in Wuhan, China, in late 2019. It has since spread across the world, causing an unprecedented pandemic leading to severe morbidity and mortality and economic impact.

COVID-19, the disease caused by SARS-CoV-2 infection, often leads to respiratory illness and other symptoms such as fever, fatigue, and often loss of smell and taste. The severity of symptoms varies from asymptomatic or mild symptoms to severe symptoms leading to hospitalization and death in some cases.

Post-acute sequelae or long COVID in patients with mild COVID-19

While over 80% of infected individuals experience mild symptoms and recover without hospitalization, there is considerable heterogeneity in disease severity. Given the scale of the global impact of this pandemic, a better understanding of the immune response of humans to SARS-CoV-2 in the case of individuals with mild COVID-19, who may experience persistent or recurrent symptoms in the post-recovery phase, is crucial.

Studies show that about 30% to >70% of patients with mild COVID-19 develop post-acute sequelae of SARS-CoV2 infection or long COVID, which is the name given to clinical symptoms that persist for weeks to months after infection.

Analyzing the longitudinal immune response in mild COVID-19 patients

Researchers from the US recently profiled the longitudinal immune response in mild COVID-19 patients starting with early time points of 1-15 days post-infection through convalescence to over 100 days after onset of symptoms. This study's findings have been released as a preprint on the bioRxiv* server.

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The researchers correlated data obtained from serum proteomics, single-cell analyses of peripheral blood cells, clinical metadata, and virus-specific cellular and humoral immune responses. They found that acute infection involved vigorous coordinated innate and adaptive immune activation, including an early cellular and proteomic response correlating with the amount of virus-specific humoral responses post day 30 from symptom onset.

They also characterized signals associated with recovery and convalescence to define new signatures of gene expression, inflammatory cytokines, and chromatin accessibility that persisted in individuals experiencing post-acute sequelae of SARS-CoV-2 infection.

Mild COVID-19 shows heterogeneity in clinical presentation and magnitude of acute and SARS-CoV-2-specific immune responses

To summarize, the study's findings showed that mild COVID-19 shows heterogeneity in clinical presentation as well as the magnitude of acute and SARS-CoV-2-specific immune responses. Early acute viral infection involves an activated, inflammatory state that includes age-enhanced IFN responses and plasmablast expansion. Longitudinal analysis by the authors showed that a reduction in activated and pro-inflammatory immune responses correlated with an increase in convalescent homeostasis and repair pathways.

Individuals with post-acute sequelae had distinct diminished IFN and antiviral responses to acute infection and persistent, unresolved inflammatory signaling during convalescence. An increase in early acute interferon and antiviral signaling was associated with stronger humoral responses to the virus during convalescence. With the help of integrative analysis, the researchers were able to reveal the key network nodes in acute SARS-CoV-2 infection and their longitudinal resolution and persistence in post-acute sequelae.

Findings offer a possible mechanism for age-dependent effect on immune responses

Overall, the study results offer a comprehensive longitudinal roadmap of immune activation and resolution in patients with mild COVID-19. It also provides a possible mechanism for an age-dependent effect on immune responses. The study observed a strong plasmablast response that identified important early correlates of antibody and B cell responses and may be regulated by early IFN responses. A subset of study participants who progressed to post-acute sequelae showed innate immune-centric hyperactivation and novel inflammatory and non-inflammatory signatures in serum proteins.

While the analyses nominate multiple potential therapeutic targets in post-acute sequelae, the authors believe that serum protein biomarkers may offer an objective diagnosis of inflammatory and non-inflammatory post-acute sequelae once the findings are validated in larger cohorts. According to the authors, a more personalized approach to immunomonitoring and therapy will help improve outcomes across the COVID-19 and post-acute sequelae spectrum.

The team concludes:

To our knowledge, this is the deepest longitudinal systems immunology study to-date in mild COVID-19, and reveals numerous new insights."

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Susha Cheriyedath

Susha has a Bachelor of Science (B.Sc.) degree in Chemistry and Master of Science (M.Sc) degree in Biochemistry from the University of Calicut, India. She always had a keen interest in medical and health science. As part of her masters degree, she specialized in Biochemistry, with an emphasis on Microbiology, Physiology, Biotechnology, and Nutrition. In her spare time, she loves to cook up a storm in the kitchen with her super-messy baking experiments.