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

Mahamud-Ur Rashid,Kevin M Coombs,Victor Spicer,Ying Lao

doi:10.3390/v14020377

Mahamud-Ur Rashid, Kevin M Coombs + Show 2 more

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https://doi.org/10.3390/v14020377

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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.

Highlights

In order to better understand the mechanism(s) of viral persistence and its impact on the male genital tract, we extended the previous study by using a complementary tandem mass tag (TMT)-based 2D LC/MS/MS mass spectrometry-based approach to investigate Sertoli cell proteomic alterations after Zika virus (ZIKV) infection
After infecting human Sertoli cells (HSerC) with ZIKV at multiplicity of infection (MOI) = 3, viral protein expression levels, which could result from increased expression, lower protein turnover, or a combination of both, and cytopathic effects were monitored at 3, 5 and 7 dpi, ZIKV infection did not induce any cytopathic effects (Figure 1A)
Understanding the mechanisms of ZIKV persistence in the male genital tract is critical for treatment of the disease, antiviral/vaccine development and overall control of viral transmission

Summary

Introduction

Zika virus (ZIKV) belongs to the family Flaviviridae, and is a single-stranded positivesense RNA virus. Other members of the family include Japanese encephalitis virus (JEV), Yellow fever virus (YFV), West Nile virus (WNV) and Dengue virus (DENV). ZIKV was first discovered in Rhesus monkeys in Uganda’s Zika rainforest in 1947 [1]. The virus remained undiagnosed for a long time due to the disease’s nonspecific flu-like symptoms and a lack of diagnostic screening [2,3]. In 2007, ZIKV re-emerged in the Pacific islands, spreading to over 80 countries/territories, including Latin America, the United States, and Southeast Asia [4–8]. The virus has been linked to microcephaly in babies [9] and Guillain–Barré syndrome (GBS) in adults [10,11].

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