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The seven enigmas of SARS-CoV-2: from the past to the future

Evangelos Andreakos1, Lisa Arkin2, Paul Bastard3,4,5,6

  • 1Laboratory of Immunobiology, Center for Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.

Journal of Human Immunity
|December 5, 2025
PubMed

Insights

The COVID Human Genetic Effort identified genetic and immune factors explaining severe COVID-19 and related conditions. This research advances understanding of infectious disease variability and pandemic preparedness.

Area of Science:

  • Immunology
  • Genetics
  • Infectious Diseases

Background:

  • Clinical variability in SARS-CoV-2 infection suggests underlying genetic and immune factors.
  • Inborn errors of immunity (IEI) can predispose individuals to severe infectious diseases.

Purpose of the Study:

  • To investigate the genetic and immunological basis of clinical variability in SARS-CoV-2 infection.
  • To identify monogenic IEI and phenocopies contributing to severe COVID-19 phenotypes.

Main Methods:

  • Patient-based research leveraging the COVID Human Genetic Effort.
  • International collaboration to analyze genetic and immunological data.

Main Results:

  • Deciphered pathogenesis of critical COVID-19 pneumonia (~15%) and multisystemic inflammatory syndrome in children (MIS-C, ~2%).
  • Genetically and immunologically defined neuro-COVID-19 in a child.
  • Delineated immunological mechanisms of COVID-toes.

Conclusions:

  • Patient-based research and international collaboration are powerful tools for discovering genetic drivers of infectious disease.
  • Findings have implications for developing medical strategies against future pandemics.

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