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ABSTRACT:
In the past decade, 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. In the United States, Rift Valley fever virus (RVFV) is a Select Agent and a Category A priority pathogen due to its potential to cause severe economic distress and major health issues, as it has in Africa and the Arabian Peninsula for many years. Furthermore, there has been increasing evidence that the U.S. and Europe are vulnerable to RVFV transmission due to the widespread range of competent vectors. 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. ILK signaling, which influences cytoskeletal reorganization and cell motility, was shown to be highly upregulated following infection. Compound 22, an ILK inhibitor, reduced viral replication and protein production despite the NSs-induced mRNA export block, indicating that this pathway is still playing a role in viral pathogenesis. Additional assays have shown that Compound 22 decreases RVFV entry into cells as well as egress out of the host cell. Other phenotypes seen with treatment include the restriction of caveolae to the Golgi and disruption of the actin cytoskeleton. Overall, this study 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. This work also sheds light on the potential mechanism of viral-induced ILK signaling.