Zika Virus Infection of Sertoli Cells Alters Protein Expression Involved in Activated Immune and Antiviral Response Pathways, Carbohydrate Metabolism and Cardiovascular Disease

Abstract

Zika virus (ZIKV), a re-emerging virus, causes congenital brain abnormalities and Guillain–Barré syndrome. It is mainly transmitted by Aedes mosquitoes, but infections are also linked to sexual transmissions. Infectious ZIKV has been isolated, and viral RNA has been detected in semen over a year after the onset of initial symptoms, but the mode of long-term persistence is not yet understood. ZIKV can proliferate in human Sertoli cells (HSerC) for several weeks in vitro, suggesting that it might be a reservoir for persistent ZIKV infection. This study determined proteomic changes in HSerC during ZIKV infections by TMT-mass spectrometry analysis. Levels of 4416 unique Sertoli cell proteins were significantly altered at 3, 5, and 7 days after ZIKV infection. The significantly altered proteins include enzymes, transcription regulators, transporters, kinases, peptidases, transmembrane receptors, cytokines, ion channels, and growth factors. Many of these proteins are involved in pathways associated with antiviral response, antigen presentation, and immune cell activation. Several immune response pathway proteins were significantly activated during infection, e.g., interferon signaling, T cell receptor signaling, IL-8 signaling, and Th1 signaling. The altered protein levels were linked to predicted activation of immune response in HSerC, which was predicted to suppress ZIKV infection. ZIKV infection also affected the levels of critical regulators of gluconeogenesis and glycolysis pathways such as phosphoglycerate mutase, phosphoglycerate kinase, and enolase. Interestingly, many significantly altered proteins were associated with cardiac hypertrophy, which may induce heart failure in infected patients. In summary, our research contributes to a better understanding of ZIKV replication dynamics and infection in Sertoli cells.

Zika Virus Induces Sex-Dependent Metabolic Changes in Drosophila melanogaster to Promote Viral Replication

“…Noticeably, Dengue virus (DENV), which is closely related to ZIKV, depends on the glycolysis pathway for its replication ( 45 ), and high glucose levels have been shown to restrict ZIKV infection in human kidney cells ( 46 ). In line with our findings, recent studies in human cells also report dramatic changes in carbohydrate concentrations after ZIKV infection ( 47 ). These alterations target proteins including enzymes, transcription regulators, transporters, and kinases associated with energy generation and immune cell activation.…”

Investigation of the Association between the Energy Metabolism of the Insect Vector Laodelphax striatellus and Rice Stripe Virus (RSV)

“…Plant carbohydrate metabolism frequently results in the occurrence of starch lesions or ringspots at the sites of viral infection [ 36 , 37 ]. In humans, carbohydrate metabolism is hijacked by the Zika virus in an effort to usurp the generation of cellular energy [ 38 ]. Fatty acid metabolism contributes to the replication of multiple human viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hepatitis C virus [ 39 , 40 , 41 ].…”

Mechanism of Immune Evasion in Mosquito-Borne Diseases

“…The pathogenesis of cerebral malaria involves the sequestration of infected erythrocytes in the brain microvasculature and the resulting immune response, leading to endothelial damage, vascular leakage, and hypoxia. These pathological changes can ultimately lead to neurological dysfunction and contribute to the high mortality rate associated with cerebral malaria [ 133 ]. Gene expression profiling studies have identified shared pathways and molecular signatures between cerebral malaria and neurodegenerative diseases, suggesting potential common mechanisms.…”

“…Brasil et al reported a potential association of ZIKAV infection with congenital heart disorders in infants [ 226 ]. In a recent study, Rashid et al reported that ZIKAV infection of human Sertoli cells significantly altered several proteins involved in cardiac hypertrophy [ 133 ].…”