Major Histocompatibility Complex Class I Chain-Related α (MICA) STR Polymorphisms in COVID-19 Patients

Abstract

The SARS-CoV-2 disease presents different phenotypes of severity. Comorbidities, age, and being overweight are well established risk factors for severe disease. However, innate immunity plays a key role in the early control of viral infections and may condition the gravity of COVID-19. Natural Killer (NK) cells are part of innate immunity and are important in the control of virus infection by killing infected cells and participating in the development of adaptive immunity. Therefore, we studied the short tandem repeat (STR) transmembrane polymorphisms of the major histocompatibility complex class I chain-related A (MICA), an NKG2D ligand that induces activation of NK cells, among other cells. We compared the alleles and genotypes of MICA in COVID-19 patients versus healthy controls and analyzed their relation to disease severity. Our results indicate that the MICA*A9 allele is related to infection as well as to symptomatic disease but not to severe disease. The MICA*A9 allele may be a risk factor for SARS-CoV-2 infection and symptomatic disease.

Keywords: MICA; MICA STR polymorphisms; NK cells; SARS-CoV-2; innate immunity.

Figure 1

Graphic representation of the MICA-NKG2D interaction depending on the Met/Val polymorphism at 129 and the production of sMICA by ADAM17: (A) The Met/Val polymorphism at 129 of the MICA molecules influences binding to NKG2D. Alleles with Met¹²⁹ have high affinity for the ligand, while those with Val¹²⁹ have low affinity. The MICA*A4 and *A9 alleles have Met¹²⁹, MICA*A5 present Val¹²⁹, and the MICA*5.1 and *A6 alleles can have both polymorphisms [20]. (B) In COVID-19 infection, the metalloprotease ADAM17 hydrolyzes MICA generating sMICA, which binds to NKG2D causing inhibition. In the case of the MICA alleles with the Met129 variant, the inhibition will be greater, and there will be a worse control of the infection by the NK and T cells. Abbreviations—ACE2: angiotensin-converting enzyme 2; S1: S1 subunit of spike protein; S2: S2 subunit of spike protein; TMPRSS2: transmembrane protease serine 2; ADAM17: ADAM metallopeptidase domain 17.