Abstract S05-03: Preserving innate memory to overcome SARS-CoV-2 infection through the mevalonate pathway
Authors: Gomez Juan Luis , Brufsky Adam 
Published: December 2020

Background: Easily accessible therapies have been proposed to treat SARS-CoV-2 infection. Given that the mevalonate pathway is critical in preventing nonspecific inflammation, events that interfere in this pathway in mononuclear or epithelial lung cells might determine the outcome of infected patients. Based on its mechanism of action, we hypothesize that in patients with metastatic cancer (MC), zoledronic acid (ZA) may influence the severity of COVID-19 disease.

Methods: In silico analysis compared normalized expression levels of prenylation-related genes in mononuclear and epithelial cells, between infected and noninfected SARS-CoV and SARS-CoV-2 samples, from available GEO datasets. RNA analysis was done using R v3.6.3. Counts were normalized with EdgeR, and ggpubr package and was used to compute t-tests. For analyzing samples from GSE150728, Partek Flow was used to align and normalize reads from single-cell RNA.

Results: Analysis of data from the 2003 SARS outbreak (GSE1739) showed that PBMCs isolated from infected patients expressed lower levels of HMGCR, FNTA, COX10, and PGGT1B (&lt;0.05). In vitro results from SARS-CoV-infected Calu-3 cells (GSE17400) showed a trend of downregulation of MVK, RABGGTA, FDFT1, FNTA, and RAB27A (n=3/group). Next, we analyzed the transcriptional response to SARS-CoV-2 in Calu-3 and A549-infected cells in vitro (GSE147507). Differential downregulation of FNTA, MVK, HMGCR, and FDPS (p&lt;0.05), and only upregulation of FNTA and PGGT1B (p&lt;0.05), was observed in Calu-3 cells. The same dataset offered expression data from autopsy-derived, COVID-19-infected bronchial tissue from 2 patients. Here, we found that FDFT1, FNTA, HMGCR, RABGGTA, and FDPS were downregulated &gt;1.5-fold as compared to their healthy controls. Infected A549 cells showed decreased levels of MVK and RABGGTA (p&lt;0.05). In SARS-CoV-2-infected A549 cells, ACE2 transduction upregulated RABGGTA, HMGCR, COX10, and RAB27B when compared to non-transduced infected cells. This suggested that downregulation of prenylation might occur upon binding of the viral spike protein to the ACE2 receptor. Finally, we analyzed single-cell RNA-seq transcripts from uninfected PBMCs (no SARS reads) isolated from acutely ill SARS-CoV-2 patients (GSE150728). Here, we found no differences in the expression of any of these genes. This suggests that disruption of the mevalonate pathway may only account to infected cells.

Conclusion: In light of these findings, coronaviruses may hijack the mevalonate pathway and induce autoimmunity. Response to coronavirus infection may differ in patients with MC under treatment with ZA, statins, or other substances that interfere with prenylation-mediated small vesicle trafficking (i.e., hydroxychloroquine, nicotine). Hence, studies that investigate SARS-CoV-2 disease severity in patients under treatment with ZA are strongly needed.

Citation Format: Juan Luis Gomez, Adam Brufsky. Preserving innate memory to overcome SARS-CoV-2 infection through the mevalonate pathway [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S05-03.