Reprogramming of red blood cell metabolism in Zika virus-infected donors.

Abstract

Diseases caused by arthropod-borne viruses remain a burden to global health; in particular, Zika virus (ZIKV) has been reported in 87 countries and territories. In healthy blood donors, ZIKV RNA can be detected in red blood cells (RBCs) months after infection, clearance of detectable nucleic acid in plasma, and seroconversion. However, little information is available on the impact of ZIKV infection to metabolism. We applied mass spectrometry-based metabolomics and lipidomics approaches to investigate the impact of ZIKV infection on RBCs over the course of infection. ZIKV-infected blood donors (n=25) were identified through molecular and serologic methods, which included nucleic acid amplification testing and real-time polymerase chain reaction (PCR) for detection of ZIKV RNA and enzyme-linked immunosorbent assay (ELISA) for detection of flavivirus-specific IgM and IgG. In ZIKV RNA-positive donors, we observed lower glucose and lactate levels, and higher levels of ribose phosphate, suggestive of the activation of the pentose phosphate pathway. The top pathways altered in RBCs from ZIKV-IgM-positive donors include amino acid metabolism and biosynthesis, fatty acid metabolism and biosynthesis, linoleic acid and arachidonate metabolism and glutathione metabolism. RBCs from ZIKV-infected donors had increased levels of early glycolytic metabolites, and higher levels of metabolites of the pentose phosphate pathway. Alterations in acyl-carnitine and fatty acid metabolism are consistent with impaired membrane lipid homeostasis in RBCs from ZIKV IgM positive donors. RBC from healthy blood donors who had been infected by ZIKV are characterized by long-lasting metabolic alterations even months after infection has resolved.