Alterations in the host transcriptome in vitro following Rift Valley fever virus infection

Chelsea Pinkham,Bibha Dahal,Connie Schmaljohn,Brett Beitzel,Gustavo Palacios,Kylene Kehn-Hall,Michael Lindquist,Nicole Bracci,Aura Garrison,Aarthi Narayanan,Catherine E Campbell,Cynthia L De La Fuente

doi:10.1038/s41598-017-14800-3

Abstract

Rift Valley fever virus (RVFV) causes major outbreaks among livestock, characterized by “abortion storms” in which spontaneous abortion occurs in almost 100% of pregnant ruminants. Humans can also become infected with mild symptoms that can progress to more severe symptoms, such as hepatitis, encephalitis, and hemorrhagic fever. The goal of this study was to use RNA-sequencing (RNA-seq) to analyze the host transcriptome in response to RVFV infection. G2/M DNA damage checkpoint, ATM signaling, mitochondrial dysfunction, regulation of the antiviral response, and integrin-linked kinase (ILK) signaling were among the top altered canonical pathways with both the attenuated MP12 strain and the fully virulent ZH548 strain. Although several mRNA transcripts were highly upregulated, an increase at the protein level was not observed for the selected genes, which was at least partially due to the NSs dependent block in mRNA export. Inhibition of ILK signaling, which is involved in cell motility and cytoskeletal reorganization, resulted in reduced RVFV replication, indicating that this pathway is important for viral replication. Overall, this is the first global transcriptomic analysis of the human host response following RVFV infection, which could give insight into novel host responses that have not yet been explored.

Highlights

In the past decade, there has been an emergence of arbovirus-related diseases
It is imperative that we develop a better understanding of pathways essential for Rift Valley fever virus (RVFV) replication and pathogenesis to aid in the development of necessary therapeutics and vaccines, which are vital to preventing the spread of this disease
actinin 2 (ACTN2), ARHGEF6, and myosin heavy chain 3 (MYH3) all demonstrated a time-dependent increase in gene expression, while thymosin beta-10 (TMSB10) decreased in gene expression over time. These results indicate that the RNA-seq data was generally reproducible by RT-qPCR, and confirm that the Integrin-linked kinase (ILK) signaling pathway is altered at the mRNA level following RVFV infection

Summary

Introduction

There has been an emergence of arbovirus-related diseases. With the increase in cases of arboviruses such as Zika, chikungunya, and West Nile viruses, there has been an effort to uncover the mechanisms of pathogenesis for these viruses, as well as develop appropriate therapeutics[1]. Overall, increased mortality rates, along with increased vector plasticity, demonstrates that the threat of RVFV spread to new nations is discernible and could have serious implications. To this day, a suitable FDA-approved treatment or vaccine remains outstanding. A global RNA-seq analysis of Schmallenburg virus (SBV), another member of the Bunyavirales order showed differential gene expression between SBV and SBV lacking the nonstructural protein NSs10 They found that NSs is efficient in shutting down the host immune response, there are many antiviral genes that are still upregulated following infection, identifying potential new antiviral factors that may be important for restricting infection. Our work is the first global transcriptomic analysis of the human host response following RVFV infection, yielding insight into novel host responses that have not yet been explored

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