A potential bimodal interplay between heme and complement factor H 402H in the deregulation of the complement alternative pathway by SARS-CoV-2.

The recent discovery that the trimeric SARS-CoV-2 spike S glycoprotein carries heme within an NTD domain pocket of the S1 subunits, suggested that this virus may be cleverly utilizing heme, in addition to the S1 RBD domains, for invading target cells carrying a specific entry receptor like ACE2, TMEM106B and others. Studies during the COVID-19 pandemic revealed that the infectivity of this virus depends on cell surface heparan sulfate and that the infection induces non-canonical activation of the Complement Alternative pathway (AP) on the surface of infected cells. In our recent COVID-19 genomic studies, among the coding SNPs of interest we also detected the presence of the CFH rs1061170, rs800292 and rs1065489 within all the infected patient subgroups examined. The minor C allele of rs1061170 encodes CFH 402H that over the years has been associated with diseases characterized by complement dysregulation namely the age-related macular degeneration (AMD) and the atypical haemolytic uremic syndrome (aHUS). Also, more recently with the diminishment of CD4 T cell responses with ageing. The rs800292 minor allele A encodes CFH 62I that supports enhanced cofactor activity for Complement factor I (CFI). Also, the rs1065489 minor allele T encodes CFH 936D and is located within the CCP16 domain that influences the affinity of CFH with extracellular laminins. A subsequent computational analysis revealed that the CFH residue 402 is located centrally within a heme-binding motif (HBM) in domain CCP7 (YNQNYGRKF). Heme on the viral spike glycoprotein S1 subunit could recruit CFH 402H for masking free viral particles from opsonisation, and when in proximity to cell surface, act as a bait disrupting CFH 402H from the heparan sulphate coat of the target cells. Publicly available genetic data for European populations indicate that the minor C allele of rs1061170 is present only in haplotypes that carry the major alleles of rs800292 and rs1065489. This combination encodes for CFH 402H that exhibits increased biochemical affinity for heme in proximity, without enhanced cofactor activity for CFI and weaker association with the extracellular matrix. In the theatre of infection, this combination can promote heme-mediated viral infection with weaker complement opsonisation and potential AP deregulation. This strategy may be evolutionary conserved among various classes of infectious agents.