Review
2020 Jun 29;18(1):261.
Affiliations
PMID:
32600410
PMCID: PMC7322393
DOI: 10.1186/s12967-020-02433-6
Free PMC article
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.
Keywords:
Bisphosphonates; Glycoproteins; Immune response; SARS Coronavirus.
Conflict of interest statement
AB is a paid consultant for Novartis, Amgen, and Sandoz. MTL, JG, and AR have no competing interests.
Zoledronic acid (ZA) acts as immunostimulant and endosomal disruptor of dendritic cell in SARS-CoV-2 infection. Inhaled SARS-CoV-2 particles are internalized by the DC (top). In COVID-19 disease, there is depletion of γδ T cells (bottom-left). In addition, virion release depends on prenylation signaling derived from the mevalonate pathway. On the other hand, ZA (bottom-right) inhibits the conversion of geranyl pyrophosphate (GPP) to farnesyl pyrophosphate (FPP), increasing the concentrations of isopentenyl pyrophosphate (IPP). Release of IPP induces γ9δ2 T-cell expansion by phosphoantigen recognition, mediated by butyrophilin-presentation. Downstream inhibition of prenylation reduces the activity of GTPases, decreasing the release of SARS-CoV-2. ZA also affects differentiation of the DC with downregulation of the expression of CD1a, CD11c, CD83, CD86, DC-SIGN, and HLA-DR and enhancement of the expression of CD80. Figure was created using BioRender https://biorender.com/
Zoledronic acid (ZA) acts as immunostimulant and endosomal disruptor of dendritic cell in SARS-CoV-2 infection. Inhaled SARS-CoV-2 particles are internalized by the DC (top). In COVID-19 disease, there is depletion of γδ T cells (bottom-left). In addition, virion release depends on prenylation signaling derived from the mevalonate pathway. On the other hand, ZA (bottom-right) inhibits the conversion of geranyl pyrophosphate (GPP) to farnesyl pyrophosphate (FPP), increasing the concentrations of isopentenyl pyrophosphate (IPP). Release of IPP induces γ9δ2 T-cell expansion by phosphoantigen recognition, mediated by butyrophilin-presentation. Downstream inhibition of prenylation reduces the activity of GTPases, decreasing the release of SARS-CoV-2. ZA also affects differentiation of the DC with downregulation of the expression of CD1a, CD11c, CD83, CD86, DC-SIGN, and HLA-DR and enhancement of the expression of CD80. Figure was created using BioRender https://biorender.com/
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