key: cord-0844906-dnwfwj5l
authors: Mogensen, Trine H.
title: Human genetics of SARS-CoV-2 infection and critical COVID-19
date: 2022-02-24
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2022.02.022
sha: 34f704bdbeb923dbc488999d4fcdcb3c2bfeb460
doc_id: 844906
cord_uid: dnwfwj5l

BACKGROUND: During the past two years studies on patients with SARS-CoV-2 infection have revealed rare inborn errors of immunity (IEI) in type interferon (IFN) pathways underlying critical COVID-19 pneumonia. This has provided insights into pathophysiological mechanisms and immune signaling circuits regulating antiviral responses to SARS-CoV-2 and governing susceptibility and outcome of SARS-CoV-2 infection in humans. OBJECTIVES: In this review the current knowledge on IEIs underlying critical COVID-19 are presented, and the clinical implications of these findings for individualized prophylaxis and treatment are outlined. SOURCES: The review is based on a broad literature search, including primarily studies on whole exome sequencing, and to a lesser extent genome-wide association studies, of patients with critical COVID-19, as well as retrospective descriptive studies of the SARS-CoV-2 disease course in individuals with known IEIs. CONTENT: The review describes the discovery of monogenic IEI in 9 genetic loci related to the production or responses to type I IFN in patients with critical COVID-19 pneumonia and the surprising finding of phenocopies of these, represented by neutralizing autoantibodies to type IFN in a significant proportion of patients with critical pneumonia, particularly in elderly men, and further enriched in patients with lethal disease course. Moreover insights gained from studies on SARS-CoV-2 infection, disease course, and outcome in patients with known IEI is presented. Finally, some hypotheses for a possible genetic basis of autoimmune, inflammatory, and long-term complications of SARS-CoV-2 infection are presented and discussed. IMPLICATIONS: Uncovering IEI underlying critical COVID-19 or other severe SARS-CoV-2 disease manifestations provide valuable insights into the basic principles of antiviral immune responses and pathophysiology related to SARS-CoV-2 infection. Such knowledge has important clinical implications for identification of susceptible individuals and for diagnosis, prophylaxis, and treatment of patients to reduce disease burden and improve preparedness against viral pandemics with known or emerging viruses in the future.

In late 2019, an increasing number of cases of acute respiratory distress syndrome (ARDS) were reported in 45

China, followed in March 2020, by the World Health Organization (WHO) declaring the outbreak a global 46 pandemic and attributing coronavirus disease 2019 (COVID-19) to a novel coronavirus named severe acute 47 respiratory syndrome-coronavirus (SARS-CoV)-2 (1). This viral pandemic turned out to spread to all 48 continents of the globe, be highly transmissible, and lead to millions of cases and deaths, particularly in 49 vulnerable subjects with old age or medical co-morbidities, such as pulmonary disease, hypertension, 50 diabetes, obesity or secondary immunosuppression by medications or malignant disease (2). Although 51 severe/critical COVID-19 pneumonia mostly affects these groups of patients, it has become apparent that 52 supposedly otherwise healthy individuals in rare cases may experience a severe, sometimes fulminant, 53 disease course. Moreover in the course of the pandemic, unexpected new disease manifestations have 54 emerged, including postinfectious multisystem inflammatory disease in children and adults (MIS-C and MIS-55 A9 (3) as well as more subtle longterm neurocognitive, pulmonary and musculoskeletal sequels named 56

LongCOVID or post-acute COVID-19 syndrome (PACS) (4). 57 58 Sensing and activation of the immune system by SARS-CoV-2 59

The newly emerged SARS-CoV-2 is a beta-coronavirus and related to the previously identified SARS-1, the 60 etiological source of Mediterranean respiratory syndrome (MERS). SARS-CoV-2 is a single stranded (ss)RNA 61 virus that infects cells through the ACE2 surface receptor and is dependent upon the cellular protease 62 TMPRRS2 to establish productive infection (5). The innate host immune system senses the viral RNA genome 63 or ssRNA or double-stranded (ds)RNA replication intermediates through membrane-bound endosomal TLR3 64 

The clinical observation of extensive inter-individual disease presentation of SARS-CoV-2 infection has led to 78 efforts to define and understand the human genetic and immunological basis of susceptibility to this virus. 79

Among these, the COVID Human Genetic Effort (http://www.covidhge.com) consortium was the first to 80 report major novel insights into human genetic susceptibility to severe COVID-19 (8), by the identification of 81 23 patients with critical COVID-19 pneumonia and IEI at eight genetic loci that govern TLR3-dependent type 82 I IFN induction, amplification or response to IFN, implicating defects in TLR3, UNC93B, TRIF, TBK1, IRF3, IRF7, 83 and IFNAR1/2 (9). (Figure 1 ). Although rare, these patients with IEI showed that type I IFN immunity is 84 indispensable for the control of SARS-CoV-2 infection and that defects in these circuits predispose to critical 85 pneumonia, particularly in the young and middle-aged, where an estimated 3-5% of cases may be attributed 86 to these genetic defects. The genetic landscape has been expanded by two independent reports of X-linked 87 TLR7 deficiency in males with severe COVID-19 accounting for 1% of critical COVID-19 in males under 60 years 88 (10, 11). Importantly, the study of TLR7 deficiency demonstrated that this defect was due to insufficient IFN 89 production from pDCs (expressing high levels of TLR7 and IRF7), and formally proving the longstanding 90 concept of the essential role of pDCs in type I IFN production in humans (10). Thus, during critical SARS-CoV-91 J o u r n a l P r e -p r o o f 2 infection pDCs are responsible for TLR7-driven type I IFN production, whereas TLR3-dependent pathways 92 govern mucosal type I IFN production by respiratory epithelial cells (12). Within the genes so far 93 demonstrated to confer susceptibility to critical COVID-19 there is a striking lack of genetic defects within 94 adaptive immunity. This may suggest that viral restriction and control to avoid severe acute infection is 95 particularly exerted by early innate antiviral pathways, whereas humoral and cellular defects play a more 96 modest if any role, in analogy to the situation in influenza. On a theoretical basis, genetic defects in adaptive 97 immunity if existing, may be found rather in patients with prolonged infection or among those developing 98 critical COVID-19 despite vaccination, so called "breakthrough cases". 99 100

The identification of genetic defects in antiviral type I IFN circuits in critical COVID-19 was accompanied by 102 the almost simultaneous discovery of pre-existing neutralizing auto-antibodies against type I IFNs (most 103 notably against IFN and IFN) as a phenocopy of the type I IFN-related IEI (13). Although the presence of 104 auto-antibodies to type I IFN were previously reported in some patients receiving IFN therapy, in systemic 105 lupus erythematosus, myastenia gravis, thymoma, autoimmune polyendocrine syndrome (APS)-1, 106 incontinentia pigmenti and others, the impact on infection susceptibility was previously largely unexplored 107 (14). However, while the discovery of auto-antibodies to type I IFNs in COVID-19 patients was novel and 108 unexpected, such phenocopies of genetically well-defined IEI exerted by the existence of specific auto-109 antibodies to these same mediators has been described previously in the case of auto-antibodies against IFN 110 in mycobacterial infection, against IL17 in chronic mucocutaneous candidiasis, and against IL6 in Hyper-IgE 111 syndrome (8). In subsequent studies, neutralizing auto-antibodies against type I IFNs were confirmed in 112 independent cohorts in over 10% of patients with severe COVID-19 (15). Moreover, neutralizing auto- antibody deficiencies and only 15% combined and 3% innate immunodeficiency, and the morbidity and 198 mortality was not striking at around 10% of these (25). Another study including 121 individuals concluded 199 that the specific IEI was not a factor predicting severity, and the identified predictors, such as bronchiectasis 200 and cardiopathy, were similar as those established in the general population (26). An Israeli study found that 201 the COVID-19 pandemic did not have a major impact on individuals with IEI and even suggested that in some 202 cases lack of strong inflammatory immune responses may be paradoxically a protective measure against the 203 development of severe disease and sequelae (27). Finally, a Danish study of patients with common variable 204 immunodeficiency of mixed genetic background also reported only mild disease/low morbidity (28). 205

Collectively, larger cohorts of (unvaccinated) individuals are needed in order to ascertain associations 206 between genetically well-defined IEIs and risk of severe COVID-19. In particular these studies should focus 207 on patients predicted to experience increased vulnerability to SARS-CoV-2, such as innate deficiencies in type 208 I IFN induction and signaling, T cell defects or combined immunodeficiencies. A recent review of the 209 characteristics of SARS-CoV-2 infection in 648 patients with different IEI found that combined 210 immunodeficiencies, immune dysregulation disorders, and innate immune defects impairing type I IFN 211 responses were associated with severe disease course in some patients (29). However, for most patients, the 212 underlying IEI did not represent an independent risk factor for severe COVID-19 -on the contrary some IEI 213 might be protective due to impaired inflammation and consequently less severe immunopathology. 

The author has no conflicts of interest to declare 256 

A Novel Coronavirus from Patients with 284 Pneumonia in China

Novel Coronavirus-Infected Pneumonia in Wuhan

A key to the viral and genetic causes of Kawasaki disease?

Post-acute 290 COVID-19 syndrome

Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Innate immunological pathways in COVID-19 pathogenesis

Activation and evasion of type I interferon 297 responses by SARS-CoV-2

A Global Effort to Define the Human Genetics of Protective 299 Immunity to SARS-CoV-2 Infection

Inborn errors of type I IFN 301 immunity in patients with life-threatening COVID-19

305 11. van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, 306 et al. Presence of Genetic Variants Among Young Men With Severe COVID-19

Mechanisms of viral inflammation and disease in humans

Autoantibodies 310 against type I IFNs in patients with life-threatening COVID-19

Autoantibodies 317 neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% 318 of COVID-19 deaths

Auto-antibodies 320 to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine

SARS-CoV-2 and viral sepsis: observations and 322 hypotheses

Deciphering the Role of Host Genetics in Susceptibility to Severe COVID-19

Polyclonal expansion of TCR Vbeta 21.3(+) CD4(+) and CD8(+) T cells is a hallmark of Multisystem 328 Inflammatory Syndrome in

Antiviral Immune Responses in Adult Patients With Multisystem Inflammatory Syndrome

The association between ABO blood group and 333 SARS-CoV-2 infection: A meta-analysis

Genomewide 335 Association Study of Severe Covid-19 with Respiratory Failure

Coronavirus disease 2019 in 339 patients with inborn errors of immunity: An international study

Outcome of SARS-CoV-2 Infection in 121 Patients with Inborn Errors of Immunity: A Cross-Sectional Study

Minor Clinical Impact of 344 COVID-19 Pandemic on Patients With Primary Immunodeficiency in Israel

Low morbidity 346 in Danish patients with common variable immunodeficiency disorder infected with severe acute respiratory 347 syndrome coronavirus 2

Coronavirus disease 2019 in patients with inborn errors of 349 immunity: lessons learned

IFN-alpha2a Therapy in Two 351 Patients with Inborn Errors of TLR3 and IRF3 Infected with SARS-CoV-2

Interferon-beta Therapy 353 in a Patient with Incontinentia Pigmenti and Autoantibodies against Type I IFNs Infected with SARS-CoV-2

Early nasal 356 type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs