Comparative in vitro transcriptomic analyses of COVID-19 candidate therapy hydroxychloroquine suggest limited immunomodulatory evidence of SARS-CoV-2 host response genes.

Michael Jay Corley; Christopher Sugai; Michael Schotsaert; Robert E. Schwartz; Lishomwa C Ndhlovu

Low Density Lipoprotein Receptor (LDLR) genes, which were transcriptionally altered in the HCQ treatment of PBMC transcriptional dataset (Fig.1c ,f) and in the SARS-CoV-2 in vitro infection of NHBE cells transcriptional dataset (Fig.1d,g) . Interestingly, the NDRG2 and LDLR genes were not altered upon SARS-CoV-2 in vitro infection of A549 cells (Fig.1e,h) , suggesting different in vitro SARS-CoV-2 infection models vary in transcriptional responses which will be critical for identifying relevant host genes impacted by viral infection. The NDRG2 gene has been identified as a novel factor for the regulation of IL-10 in myeloid cells [16] and a factor in macrophage polarization [17] , suggesting HCQ may impact myeloid cell inflammation that has been hypothesized as a driver of severe COVID-19 [18] . We observed that NDRG2 was significantly upregulated in the SARS-CoV-2 in vitro infection dataset (Fig.1d ) and significantly downregulated in the in vitro hydroxychloroquine treatment dataset (Fig.1c) , suggesting that HCQ may restore host transcription of NDRG2 and exert anti-inflammatory effects. We found that the LDLR gene was significantly upregulated in both the in vitro hydroxychloroquine treatment and SARS-CoV-2 infection datasets ( Fig.1f ,g), suggesting both HCQ treatment and SARS-CoV-2 infection alter lipid metabolism transcription. We acknowledge these observations are associative and further casual studies are needed. Previous work has shown HCQ impacts lipid profiles [19] by potentially altering intracellular pH leading to lipid uptake and increased receptor expression.