1. Genetics and Genomics
  2. Medicine
Download icon

COVID-19: Rare variants increase the risk of severe COVID-19

  1. Frank L van de Veerdonk  Is a corresponding author
  2. Mihai G Netea
  1. Department of Internal Medicine, Radboudumc Center for Infectious Diseases, Netherlands
  2. Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Germany
Insight
  • Cited 0
  • Views 1,370
  • Annotations
Cite this article as: eLife 2021;10:e67860 doi: 10.7554/eLife.67860

Abstract

Evidence is mounting that rare loss-of-function variants in the TLR7 gene predispose men with no medical history to severe forms of COVID-19.

Main text

COVID-19 is a disease that does not strike equally: while most individuals will experience no or only mild respiratory symptoms, a minority – including young patients in their 20s or 30s – will develop severe pneumonia and acute respiratory distress syndrome, sometimes resulting in death. Identifying the underlying factors that predispose to severe COVID-19, especially in young individuals, is crucial to initiate preventive measures and design treatment strategies for at-risk patients.

Accumulating evidence suggests that rare loss-of-function mutations in a single gene known as TLR7 could predispose men under 50 without known risk factors to severe COVID-19. TLR7 codes for a Toll-like receptor that can recognise single-strand RNA present in viruses such as SARS-CoV-2, the agent responsible for COVID-19. Once activated, the receptor helps to switch on the immune response, triggering the production of pro-inflammatory molecules and the release of type I and II interferon proteins that regulate the activity of the immune system.

Now, in eLife, Alessandra Renieri and colleagues at the University of Siena and a number of other institutes in Italy – including Chiara Fallerini, Sergio Daga, and Stefania Mantovani as joint first authors – report five cases of men (three under 50, and two in their mid-60s) with severe COVID-19 who carry rare TLR7 variants (Fallerini et al., 2021). These data validate and extend two other studies we have been involved in: one highlights two sets of two young brothers (median age of 26) carrying a rare TLR7 variant who suffered from severe COVID-19 (van der Made et al., 2020); the other identified TLR7 variants in a selected group of COVID-19 patients (Solanich et al., submitted to medRxiv). In total, these three reports describe eight rare TLR7 variants in 12 male patients with no medical history who still developed severe COVID-19. We are therefore more confident with suggesting that variants of this single gene are responsible for an important proportion of risk factor for severe COVID-19 in men under 50.

Functional studies have started to shed light on the mechanism by which TLR7 variants can lead to severe COVID-19. This work shows that the variants disrupt the production of type I and type II interferon after stimulation of the TLR7 receptor, which suggests that the mutations lead to a loss-of-function in the antiviral response to SARS-CoV-2 (van der Made et al., 2020). However, Fallerini et al. show that some of the rare TLR7 variants only have a marginal effect on the release of type I interferon, indicating that additional pathways influence the body's defence against SARS-CoV-2.

Given these studies, it is somewhat surprising that a global initiative using exome or genome sequencing in 657 patients with severe COVID-19 did not report TLR7 variants, focusing instead on the pathways that allow the recognition of viral infections such as influenza. This initiative identified defects in the TLR3 and IRF7 pathway that could be responsible for up to 3.5% of patients with severe COVID-19 (Zhang et al., 2020). The field is now anxiously waiting for potential TLR7 variants to be identified in this large dataset as well. Indeed, Fallerini et al. suggest that at least 2% of severely ill Italian COVID-19 patients have loss of function TLR7 variants, but this percentage could be even higher in other populations.

Since the first report on TLR7 variants in severe COVID-19, diagnostic pipelines have been developed to discover such mutations. Being aware that this monogenetic factor predisposes young men to severe outcomes has several consequences. First, families of patients with TLR7 variants could be screened, and individuals fast-tracked for vaccination if identified as carriers. Second, unvaccinated carriers of rare TLR7 variants that predispose to severe COVID-19 could benefit from prophylactic interferon gamma treatment, similar to that given to patients with chronic granulomatous disease to prevent severe infection (The International Chronic Granulomatous Disease Cooperative Study Group, 1991; Marciano et al., 2004). Third, patients with these variants should be admitted to hospital earlier, be monitored more closely for complications, and be treated more aggressively once they become critically ill. Indeed, there is an argument for screening all men under 50 who have been admitted to intensive care (and their families) for the TLR7 variants. Together, these measures might have a dramatic impact on clinical outcome.

References

    1. Zhang Q
    2. Bastard P
    3. Liu Z
    4. Le Pen J
    5. Moncada-Velez M
    6. Chen J
    7. Ogishi M
    8. Sabli IKD
    9. Hodeib S
    10. Korol C
    11. Rosain J
    12. Bilguvar K
    13. Ye J
    14. Bolze A
    15. Bigio B
    16. Yang R
    17. Arias AA
    18. Zhou Q
    19. Zhang Y
    20. Onodi F
    21. Korniotis S
    22. Karpf L
    23. Philippot Q
    24. Chbihi M
    25. Bonnet-Madin L
    26. Dorgham K
    27. Smith N
    28. Schneider WM
    29. Razooky BS
    30. Hoffmann HH
    31. Michailidis E
    32. Moens L
    33. Han JE
    34. Lorenzo L
    35. Bizien L
    36. Meade P
    37. Neehus AL
    38. Ugurbil AC
    39. Corneau A
    40. Kerner G
    41. Zhang P
    42. Rapaport F
    43. Seeleuthner Y
    44. Manry J
    45. Masson C
    46. Schmitt Y
    47. Schlüter A
    48. Le Voyer T
    49. Khan T
    50. Li J
    51. Fellay J
    52. Roussel L
    53. Shahrooei M
    54. Alosaimi MF
    55. Mansouri D
    56. Al-Saud H
    57. Al-Mulla F
    58. Almourfi F
    59. Al-Muhsen SZ
    60. Alsohime F
    61. Al Turki S
    62. Hasanato R
    63. van de Beek D
    64. Biondi A
    65. Bettini LR
    66. D'Angio' M
    67. Bonfanti P
    68. Imberti L
    69. Sottini A
    70. Paghera S
    71. Quiros-Roldan E
    72. Rossi C
    73. Oler AJ
    74. Tompkins MF
    75. Alba C
    76. Vandernoot I
    77. Goffard JC
    78. Smits G
    79. Migeotte I
    80. Haerynck F
    81. Soler-Palacin P
    82. Martin-Nalda A
    83. Colobran R
    84. Morange PE
    85. Keles S
    86. Çölkesen F
    87. Ozcelik T
    88. Yasar KK
    89. Senoglu S
    90. Karabela ŞN
    91. Rodríguez-Gallego C
    92. Novelli G
    93. Hraiech S
    94. Tandjaoui-Lambiotte Y
    95. Duval X
    96. Laouénan C
    97. Snow AL
    98. Dalgard CL
    99. Milner JD
    100. Vinh DC
    101. Mogensen TH
    102. Marr N
    103. Spaan AN
    104. Boisson B
    105. Boisson-Dupuis S
    106. Bustamante J
    107. Puel A
    108. Ciancanelli MJ
    109. Meyts I
    110. Maniatis T
    111. Soumelis V
    112. Amara A
    113. Nussenzweig M
    114. García-Sastre A
    115. Krammer F
    116. Pujol A
    117. Duffy D
    118. Lifton RP
    119. Zhang SY
    120. Gorochov G
    121. Béziat V
    122. Jouanguy E
    123. Sancho-Shimizu V
    124. Rice CM
    125. Abel L
    126. Notarangelo LD
    127. Cobat A
    128. Su HC
    129. Casanova JL
    130. COVID-STORM Clinicians
    131. COVID Clinicians
    132. Imagine COVID Group
    133. French COVID Cohort Study Group
    134. CoV-Contact Cohort
    135. Amsterdam UMC Covid-19 Biobank
    136. COVID Human Genetic Effort
    137. NIAID-USUHS/TAGC COVID Immunity Group
    (2020) Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
    Science 370:eabd4570.
    https://doi.org/10.1126/science.abd4570

Article and author information

Author details

  1. Frank L van de Veerdonk

    Frank L van de Veerdonk is in the Department of Internal Medicine, Radboudumc Center for Infectious Diseases, Nijmegen, The Netherlands

    For correspondence
    frank.vandeveerdonk@radboudumc.nl
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1121-4894
  2. Mihai G Netea

    Mihai G Netea is in the Department of Internal Medicine, Radboudumc Center for Infectious Diseases, Nijmegen, The Netherlands and the Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany

Publication history

  1. Version of Record published: March 23, 2021 (version 1)

Copyright

© 2021, van de Veerdonk and Netea

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,370
    Page views
  • 123
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Elliott Swanson et al.
    Tools and Resources

    Single-cell measurements of cellular characteristics have been instrumental in understanding the heterogeneous pathways that drive differentiation, cellular responses to signals, and human disease. Recent advances have allowed paired capture of protein abundance and transcriptomic state, but a lack of epigenetic information in these assays has left a missing link to gene regulation. Using the heterogeneous mixture of cells in human peripheral blood as a test case, we developed a novel scATAC-seq workflow that increases signal-to-noise and allows paired measurement of cell surface markers and chromatin accessibility: integrated cellular indexing of chromatin landscape and epitopes, called ICICLE-seq. We extended this approach using a droplet-based multiomics platform to develop a trimodal assay that simultaneously measures transcriptomics (scRNA-seq), epitopes, and chromatin accessibility (scATAC-seq) from thousands of single cells, which we term TEA-seq. Together, these multimodal single-cell assays provide a novel toolkit to identify type-specific gene regulation and expression grounded in phenotypically defined cell types.

    1. Evolutionary Biology
    2. Genetics and Genomics
    Paloma Diaz-Maroto et al.
    Research Article Updated

    The study of South American camelids and their domestication is a highly debated topic in zooarchaeology. Identifying the domestic species (alpaca and llama) in archaeological sites based solely on morphological data is challenging due to their similarity with respect to their wild ancestors. Using genetic methods also presents challenges due to the hybridization history of the domestic species, which are thought to have extensively hybridized following the Spanish conquest of South America that resulted in camelids slaughtered en masse. In this study, we generated mitochondrial genomes for 61 ancient South American camelids dated between 3,500 and 2,400 years before the present (Early Formative period) from two archaeological sites in Northern Chile (Tulán-54 and Tulán-85), as well as 66 modern camelid mitogenomes and 815 modern mitochondrial control region sequences from across South America. In addition, we performed osteometric analyses to differentiate big and small body size camelids. A comparative analysis of these data suggests that a substantial proportion of the ancient vicuña genetic variation has been lost since the Early Formative period, as it is not present in modern specimens. Moreover, we propose a domestication hypothesis that includes an ancient guanaco population that no longer exists. Finally, we find evidence that interbreeding practices were widespread during the domestication process by the early camelid herders in the Atacama during the Early Formative period and predating the Spanish conquest.