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

Madalina Elena Carter-Timofte, Sofie Eg Jørgensen, Mette Ratzer Freytag, Michelle Mølgaard Thomsen, Nanna-Sophie Brinck Andersen, Ali Al-Mousawi, Alon Schneider Hait, Trine H Mogensen, Madalina Elena Carter-Timofte, Sofie Eg Jørgensen, Mette Ratzer Freytag, Michelle Mølgaard Thomsen, Nanna-Sophie Brinck Andersen, Ali Al-Mousawi, Alon Schneider Hait, Trine H Mogensen

Abstract

Coronavirus disease-19 (COVID-19) describes a set of symptoms that develop following infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whilst COVID-19 disease is most serious in patients with significant co-morbidities, the reason for healthy individuals succumbing to fulminant infection is largely unexplained. In this review, we discuss the most recent findings in terms of clinical features and the host immune response, and suggest candidate immune pathways that may be compromised in otherwise healthy individuals with fulminating COVID-19. On the basis of this early knowledge we reason a potential genetic effect on host immune response pathways leading to increased susceptibility to SARS-CoV-2 infection. Understanding these pathways may help not only in unraveling disease pathogenesis, but also in suggesting targets for therapy and prophylaxis. Importantly such insight should instruct efforts to identify those at increased risk in order to institute preventative measures, such as prophylactic medication and/or vaccination, when such opportunities arise in the later phases of the current pandemic or during future similar pandemics.

Keywords: SARS-coronavirus 2; host immune defenses; immunopathology; innate immunity; primary immunodeficiency; whole exome sequencing.

Copyright © 2020 Carter-Timofte, Jørgensen, Freytag, Thomsen, Brinck Andersen, Al-Mousawi, Hait and Mogensen.

Figures

Figure 1
Figure 1
Induction of interferons (IFN) and signaling by the type I and III IFN receptors. The presence of microbial or self nucleic acid in the cytosol or within the endosomal compartment activates pattern recognition receptors (PRR)s. RNA activates retinoic acid-inducible receptor (RIG)-I in the cytosol and Toll-like receptor (TLR)3 and TLR7 in the endosomal compartment. These events trigger signaling pathways through the adaptor molecules mitochondrial antiviral signaling protein (MAVS), TIR-domain-containing adapter-inducing interferon-β (TRIF), and Myeloid differentiation primary response (MyD)88 leading to phosphorylation and activation of the TANK binding kinase (TBK)1, which in turn phosphorylates the transcription factors IFN regulatory factor (IRF)3 and IRF7. Whereas IRF3 is constitutively present, IRF7 is only expressed at low levels but may be secondarily induced by Type I IFN. Phosphorylation of IRF3 and IRF7 leads to homodimerization, nuclear translocation, and expression of Type I IFNs (IFNα and IFNβ) and type III IFNs (IFNλ) acting on neighboring cells with type I and III IFN receptors, respectively. Type I IFN binds to IFNα/β receptor composed of IRFNAR1 and IFNAR2, whereas type III IFN binds to the IFNλ receptor composed of IFNLR1 and IL10Rβ. These events activate the downstream receptor-associated Janus-associated kinase (JAK)1 and tyrosine kinase (TYK)2 and subsequent tyrosine phosphorylation of STAT1 and STAT2. These activated transcription factors together with IRF9 form the heterotrimeric transcription factor IFN-stimulated gene factor (ISGF)3 complex which binds to IFN-stimulated regulatory elements (ISRE) in DNA. In addition, STAT1 homodimers form the IFN-γ-activated factor (GAF) complex which binds to γ-activated (GAS) sequences. Altogether, these transcription factors induce a broad spectrum of IFN-stimulated genes (ISG)s that mediate the complex “antiviral state” of IFNs.
Figure 2
Figure 2
Innate immune signaling pathways that are known to be activated during viral infection and replication. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells through the angiotensin-converting enzyme 2 (ACE2 receptor) and the cellular serine protease TMPRSS2 for viral S protein priming. Following cellular entry, the virus RNA genome may be recognized by pattern recognition receptors (PRR)s, including endosomal Toll-like receptor (TLR)3 and TLR7 recognizing double-stranded and single-stranded RNA, respectively. In the cytosol the virus may be recognized by the retinoic acid inducible receptor (RIG)-I or the melanoma differentiation-associated protein (MDA)5. Following viral recognition by PRRs, this triggers signaling through IFN regulatory factor (IRF)3 and NF-κB to induce IFNs and pro-inflammatory cytokines. Similar responses may be activated by extracellular virus through TLR4.

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Source: PubMed

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