SARS-CoV-2 infection in patients with inborn errors of immunity due to DNA repair defects

Abstract

Clinical information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with inborn errors of immunity (IEI) during the current Coronavirus disease 2019 (COVID-19) pandemic is still limited. Proper DNA repair machinery is required for the development of the adaptive immune system, which provides specific and long-term protection against SARS-CoV-2. This review highlights the impact of SARS-CoV-2 infections on IEI patients with DNA repair disorders and summarizes susceptibility risk factors, pathogenic mechanisms, clinical manifestations and management strategies of COVID-19 in this special patient population.

Keywords: COVID-19; DNA repair mechanism; inborn errors of immunity; primary immunodeficiency.

Figure 1

Comparison of the innate immune response to SARS-CoV-2 between normal host cells and DNA repair protein defective host cells In normal host cells (left), following infection of SARS-CoV-2, RIG-1-MDA-5 senses cytosolic dsRNA, TLR7/8/3 sense ssRNA and dsRNA, respectively. Subsequently MYD88 and TBK1-IKK activate IRF3/IRF7 and regulate ISRE7/8 expression, leading to the expression of type I IFN. Type I IFN then primes an antiviral programme in both infected cells and neighboring cells through IFNAR1/2 by regulating the expression of IFN-stimulated genes. In DNA repair protein defective host cells (right), before SARS-CoV-2 infection, unrepaired DNA damages induce cytoplasmic DNA accumulation. Following the recognition by the RAD50-CARD9 and DNA-PK-Ku complexes, the type I IFN system is primed via the STING pathway. Overactivation of type I IFN promotes antiviral activity and reduces virus replication. IRF3: transcription factors interferon (IFN)-regulatory factor 3; TLR: Toll-like receptors (TLRs); IFNAR1/2: interferon-α receptor; TBK1: TANK-binding kinase 1; IKK: IkappaB kinase; DNA-PK: DNA-dependent protein kinase; Ku: Ku70-Ku80 heterodimer; RAD50: DNA repair protein RAD50; CARD9: Caspase recruitment domain family member 9; cGMP-AMP: cyclic guanosine monophosphate-adenosine monophosphate; STING: Stimulator of interferon genes.

Figure 2

Comparison of the adaptive immune responses to SARS-CoV-2 between normal host cells and DNA repair protein defective host cells (A) The process of SARS-CoV-2 priming of the adaptive immune response in the lung is depicted. (B) The comparison of adaptive immune responses in normal immune cells and DNA repair protein-deficient cells is highlighted. Tfh: T follicular helper cells; TCR: T cell receptor; MHC: major histocompatibility complex.

Figure 3

Comparison of the infected patients and deceased patients with IEI associated with DNA repair gene defects (detailed in Supplementary Table S1)