Boning up: amino-bisphophonates as immunostimulants and endosomal disruptors of dendritic cell in SARS-CoV-2 infection

Abstract

Amino-bisphosphonates such as zoledronic acid (ZA) can possibly ameliorate or prevent severe COVID-19 disease by at least three distinct mechanisms: (1) as immunostimulants which could boost γδ T cell expansion, important in the acute response in the lung; (2) as DC modulators, limiting their ability to only partially activate T cells; and (3) as prenylation inhibitors of small GTPases in the endosomal pathway of the DC to prevent expulsion of lysosomes containing SARS-CoV-2 virions. Use of ZA or other amino-bisphosphonates as modulators of COVID-19 disease should be considered.

Dysregulation of the mevalonate pathway during SARS‐CoV‐2 infection: An in silico study

“…FDPS and FDFT1 constitute downstream enzymes that may be responsible for cholesterol synthesis and prenylation of small GTPases (Figure 2). FDPS, in particular, constitutes the target for aminobisphosphonates, which were previously proposed by our group to be inducers of innate immune response and prophylactic agents against SARS‐CoV‐2 8 . A recent study has suggested that PBMCs derived from COVID‐19‐infected patients possess increased MVP activity based on increased SREBF‐2 expression.…”

“…Recently, a retrospective study suggested that statin use could improve the clinical outcome of patients admitted to the ICU 7 . We previously proposed the use of aminobisphosphonates as stimulants of trained immunity, which could be utilized as prophylactics for COVID‐19 8 . Bisphosphonates block farnesyl diphosphate synthase ( FDPS ), an essential step for prenylation and cholesterol synthesis, promoting γδ T‐cell expansion and modulating membrane expression in innate immune cells.…”

“…Data could suggest that defective expression of MVP intermediaries inhibits autophagy and prompts tissue inflammation following SARS‐CoV‐2 infection. Disease severity could be reduced by efficient and early reconstitution of this pathway 5 or by use of MVP modulators 7,8 …”

Association between Alzheimer’s disease and COVID-19: A bidirectional Mendelian randomization

“…Taken together, the findings indicated that subjects infected with severe COVID-19 with respiratory failure might be of higher risk of AD after survival of No overlapped genetic variants as IVs for AD and severe COVID-19 was overserved, indicating that AD and severe COVID-19 might be bidirectionally regulated by different pathogenic pathways. The shared pathway of the regulation of GTPase activity might underly the association between AD and severe COVID-19 [29][30][31] , which needed further investigation to get more data support and further experimental study to verify. In conclusion, our study showed that AD may causally affect severe COVID-19, which were of clinical significance for particular attention to individuals with AD during this pandemic.…”

Sterilizing immunity against SARS-CoV-2 in hamsters conferred by a novel recombinant subunit vaccine

“…Zinc ion, one species available to the cellular environments upon adjuvant dissolution, has an immunostimulatory effect and was known to steer the immune response more towards the Th1 pathway (29,30). Although the precise role of nitrogen bisphosphonate was still unknown, previous studies suggested these compounds could stimulate γδ T cells expansion and act as a dendritic cell modulator due to the upstream accumulation of phosphoantigen isopentyl diphosphate as a result of inhibition of farnesyl diphosphate synthetase (31)(32)(33). Notably, the FH002C adjuvant showed more potent effects than Al001 to promote the developments of Tfh and GCB cells and generated antibody-producing plasma cells in the early days after immunization (Figure 2A, 2B, and 2C).…”