Unlocking the Secrets of COVID-19: Why Some Populations Are Hit Harder Than Others

Decoding the Enigma of COVID-19 Disparities: Unraveling the Varied Impact on Different Populations

A group of researchers has illuminated the factors behind the diverse immune responses to SARS-CoV-2 observed in populations across Central Africa, Western Europe, and East Asia. The intricate interplay between latent cytomegalovirus infection and human genetic attributes shaped by natural selection has been identified as influential in shaping these responses. These crucial insights hold the potential to refine patient care strategies in future epidemic scenarios.

Amidst the ongoing COVID-19 pandemic, the spectrum of clinical outcomes among individuals afflicted by SARS-CoV-2 infection has displayed remarkable variability, ranging from complete absence of symptoms to fatal consequences. Collaborative efforts between the Institut Pasteur, CNRS, Collège de France, and global scientists delved into investigating the dissimilarities in immune responses to SARS-CoV-2 prevalent within populations from Central Africa, Western Europe, and East Asia.

The outcomes of their study emphasize the pivotal roles played by latent cytomegalovirus infections and specific human genetic factors that have evolved due to natural selection. These elements contribute significantly to the divergence in immune responses and severity of COVID-19 experienced across various populations. A comprehensive comprehension of the driving forces behind these variations could potentially enhance the management of patients during future outbreaks. The study’s findings were recently published in the esteemed journal Nature.

Led by Lluis Quintana-Murci, the Human Evolutionary Genetics Unit at the Institut Pasteur is dedicated to unraveling the distinctive immune responses exhibited by diverse human populations when confronted with infections. These responses could stem from differing environmental exposures or historical population dynamics, including the imprint of natural selection on the genetic diversity of various human groups. Their investigation, detailed in the Nature publication, closely scrutinized the extent and underpinnings of variations in responses to the SARS-CoV-2 virus, focusing on populations with distinct geographical and ethnic origins.

The SARS-CoV-2 virus, responsible for the COVID-19 pandemic, elicited a wide array of clinical manifestations, spanning from asymptomatic infection to life-threatening disease. While advanced age remains a primary risk factor, gender, underlying health conditions, and an array of genetic and immunological factors contribute to the severity of the disease. To discern the diversity in immune responses across human populations, scientists exposed immune blood cells obtained from 222 healthy donors representing Central Africa, Western Europe, and East Asia to the virus.

Through the application of single-cell RNA sequencing, the responses of 22 distinct blood cell types to SARS-CoV-2 were meticulously analyzed. This data was then combined with serological and genetic insights derived from the same individuals, facilitating the assessment of disparities in immune responses to SARS-CoV-2 across populations and the identification of contributing determinants.

A convergence of approximately 900 genes was pinpointed, exhibiting varying responses to SARS-CoV-2 among different populations. Rigorous statistical genetic analyses demonstrated that these disparities primarily arise from discrepancies in the composition of blood cells—relative proportions of distinct cell types vary from one population to another.

It is well-established that environmental factors, such as cytomegalovirus exposure (a herpesvirus infection generally benign in nature), can influence blood cell composition. Notably, cytomegalovirus prevalence varies markedly across populations, with 99% seropositivity among Central Africans, contrasting with 50% among East Asians and 32% among Europeans. Evidently, an individual’s environment, particularly the presence of latent cytomegalovirus infection, significantly influences the immune cell response to SARS-CoV-2.

Furthermore, researchers identified around 1,200 human genes whose response to SARS-CoV-2 is governed by human genetic factors. The frequency of alleles regulating these genes was found to vary among the populations under study. Utilizing population genetics approaches, recurrent selection events impacting genes linked to anti-viral functions were unveiled.

Maxime Rotival, a researcher at the Institut Pasteur’s Human Evolutionary Genetics Unit and co-last author of the study, expounded on the historical influence: “We know that infectious agents have had a strong impact on human survival and exerted massive selective pressures that have shaped population genetic variation. We show that past natural selection has impacted present immune responses to SARS-CoV-2, particularly in people of East Asian ancestry, in whom coronaviruses generated strong selective pressures around 25,000 years ago.”

Approximately 1.5% to 2% of European and Asian genomes trace their origins to Neanderthals. Mounting evidence underscores the connection between Neanderthal ancestry and contemporary immunity to infections. By cross-referencing the 1,200 identified genes with the Neanderthal genome, researchers unveiled a trove of genes that both modulate antiviral mechanisms and result from ancient genetic intermingling between Neanderthals and modern Homo sapiens.

Lluis Quintana-Murci, Head of the Human Evolutionary Genetics Unit at the Institut Pasteur and co-last author of the study, elucidated the ramifications: “Our comprehensive population-based study highlights the direct impact of genetic variants governing immune responses to SARS-CoV-2 on the severity of COVID-19. It also establishes links between past evolutionary events, such as natural selection or Neanderthal admixture, and current population disparities in immune responses and disease risk.”

The study’s implications extend further, as Darragh Duffy, Head of the Institut Pasteur’s Translational Immunology Unit, underscored: “By identifying the precise cellular and molecular pathways of the genetic variants associated with COVID-19 severity, this study paves the way for precision medicine strategies that could either identify high-risk individuals or facilitate the development of new treatments.”

Reference: “Dissecting human population variation in single-cell responses to SARS-CoV-2” by Yann Aquino, Aurélie Bisiaux, Zhi Li, Mary O’Neill, Javier Mendoza-Revilla, Sarah Hélène Merkling, Gaspard Kerner, Milena Hasan, Valentina Libri, Vincent Bondet, Nikaïa Smith, Camille de Cevins, Mickaël Ménager, Francesca Luca, Roger Pique-Regi, Giovanna Barba-Spaeth, Stefano Pietropaoli, Olivier Schwartz, Geert Leroux-Roels, Cheuk-Kwong Lee, Kathy Leung, Joseph T. Wu, Malik Peiris, Roberto Bruzzone, Laurent Abel, Jean-Laurent Casanova, Sophie A. Valkenburg, Darragh Duffy, Etienne Patin, Maxime Rotival and Lluis Quintana-Murci, 9 August 2023, Nature. DOI: 10.1038/s41586-023-06422-9

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