DNA Repair System and Adaptive Immunity

November 4, 2021

A brand new research shows evidence of the spike protein hijacking both the DNA repair system and adaptive immune system, significantly inhibiting the ability of damaged DNA to repair itself and suppressing the host adaptive immunity.

A brand new research shows evidence of the spike protein hijacking the DNA (damage) repair machinery and adaptive immune machinery, significantly inhibiting the ability of damaged DNA to repair itself. New paper by a pair of Sweden scientists, entitled “SARS-CoV-2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro”, has been peer-reviewed and published in the journal “Viruses”.

Authors write: “Clinical studies have indicated that patients with severe covid-19 exhibit delayed and weak adaptive immune responses; however, the mechanism by which SARS–CoV–2 impedes adaptive immunity remains unclear. Here, by using an in vitro cell line, we report that the SARS-CoV-2 spike protein significantly inhibits DNA damage repair, which is required for effective V(D)J recombination in adaptive immunity. Mechanistically, we found that the spike protein localizes in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein BRCA1 (BRCA1 is a tumor suppressor gene often referred to in relation to breast cancer) and 53BP1 recruitment to the damage site. Our findings reveal a potential molecular mechanism by which the spike protein might impede adaptive immunity and underscore the potential side effects of full-length spike-based vaccines.”

“After infection,” they explain, “these viral proteins hijack and dysregulate the host cellular machinery to replicate, assemble, and spread progeny viruses. Recent clinical studies have shown that SARS–CoV–2 infection extraordinarily affects lymphocyte number and function. Compared with mild and moderate survivors, patients with severe COVID–19 manifest a significantly lower number of total T cells, helper T cells, and suppressor T cells.” …

“As two critical host surveillance systems, the immune and DNA repair systems are the primary systems that higher organisms rely on for defense against diverse threats and tissue homeostasis. Emerging evidence indicates that these two systems are interdependent, especially during lymphocyte development and maturation. As one of the major double-strand DNA break (DSB) repair pathways, non-homologous end joining (NHEJ) repair plays a critical role in lymphocyte-specific recombination-activating gene endonuclease (RAG)-mediated V(D)J recombination, which results in a highly diverse repertoire of antibodies in B cell and T cell receptors (TCRs) in T cells. For example, loss of function of key DNA repair proteins (…) leads to defects in the NHEJ repair which inhibit the production of functional B and T cells, leading to immunodeficiency. If DNA damage cannot be properly repaired, it will contribute to the amplification of viral infection-induced pathology.”

“DNA damage repair occurs mainly in the nucleus to ensure genome stability. Although SARS-CoV-2 proteins are synthesized in the cytosol, some viral proteins are also detectable in the nucleus. … We investigated whether these nuclear-localized SARS–CoV–2 proteins affect the host cell DNA damage repair system. … Surprisingly, we found the abundance of the spike protein in the nucleus. NHEJ repair and homologous recombination (HR) repair are two major DNA repair pathways that not only continuously monitor and ensure genome integrity but are also vital for adaptive immune cell functions. … Interestingly, overexpressed spike protein did not affect cell morphology or proliferation but significantly suppressed both HR and NHEJ repair.”

They conclude: “Our findings provide evidence of the spike protein hijacking the DNA damage repair machinery and adaptive immune machinery in vitro. We propose a potential mechanism by which spike proteins may impair adaptive immunity by inhibiting DNA damage repair. Although no evidence has been published that SARS-CoV-2 can infect thymocytes or bone marrow lymphoid cells, our in vitro V(D)J reporter assay shows that the spike protein intensely impeded V(D)J recombination.” …

“In contrast, our data provide valuable details on the involvement of spike protein subunits in DNA damage repair, indicating that full-length spik-based vaccines may inhibit the recombination of V(D)J in B cells. … Taken together, we identified one of the potentially important mechanisms of SARS-CoV-2 suppression of the host adaptive immune machinery. Furthermore, our findings also imply a potential side effect of the full-length spike-based vaccine.”

Full Study, entitled “SARS–CoV–2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro”