ORF8 Breaks Genetic System of Macrophage to Escape Reproductive Immunity by Telomerase and NOS-Like System

30 March 2023, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


There is evidence that SARS-CoV-2 ORF8 may block interferon, change endoplasmic reticulum stress, damage chromatin, cause apoptosis, and hurt the male reproductive system through nitric oxide (NO). The pathogenesis of COVID-19 will be easier to understand if we know what ORF8 does. In this study, the bioinformatics technique of domain searching was used to find out what the ORF8 protein does in the body. ORF8 has domains associated with EF-hand, oxidized low-density lipoprotein cholesterol binding, macrophage-specific clearance receptors, suppression of telomerase transcription, damaged telomeres of  DNA, Cyclin, NOS, ubiquitination, etc., according to the search results. ORF8 binds to oxidized VLDL cholesterol via macrophage-like specialized clearance receptors (SMB and SRCR)  domains and is endocytosed into macrophages in the form of CD14+ receptor-bound VLDL, as revealed by the results. ORF8 colonizes macrophages via domain-like ABC and MlaD functions. ORF8 reaches the nucleus via cholesterol nuclear translocation and binds histones by ubiquitination. Ca2+ binding activates ORF8 NOS activity to produce NO, influencing histone acetylation, and ORF8 binds the CpG island of the telomerase reverse transcriptase gene in order to suppress transcription. ORF8 also binds to DNA telomeres via the TRF domain and telomerase-like activity, catalyzes telomere breaking via ribonuclease II, DNA topoisomerase (TOPEUc), and the Ku protein. And ORF8 activates the S/G2 switch via the cyclin and motor domains. ORF8 interferes with the genetic activity of macrophages and induces the death of immune cells, hence subverting the NO regulating mechanism of the immune system and facilitating virus evasion from the reproductive immune system. We suggested that ORF8 may be the virus's self-destruction mechanisms, which accelerate the death of infected cells owing to chromatin damage and indirectly lead to the demise of the virus when the synthesis of ORF8 being greater than the secretion.


Nitric oxide
Nitric oxide synthase
Specialized clearance receptor


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