Picornaviruses are major etiological agents of human diseases, including the common cold, poliomyelitis, encephalitis, meningitis, myocarditis, and hepatitis. They are the most common causes of viral illnesses worldwide and the most common causes of infections of humans in the developed world. Yet they are among the most genetically simple of all mammalian viruses, harboring small, positive-sense genomic RNAs with critical regulatory elements contained within their long 5' noncoding regions (NCRs). This apparent conundrum can, in part, be explained by the way these viruses hijack host cell functions and modify the cytoplasmic environment to favor viral replication. Picornaviruses have evolved complex mechanisms for key steps in their replication cycles, including IRES-mediated translation initiation, the switch in template use from translation to RNA replication, and the evasion of host anti-viral responses that all involve, directly or indirectly, the genomic 5' NCR. Unraveling these mechanisms is the over-arching theme of the experiments proposed in this renewal application. Using poliovirus, human rhinovirus, and coxsackievirus in cell culture models and an array of in vitro experimental approaches, this application will address the fundamental nature of viral processes that are directed by the 5' NCRs of genomic RNAs by proposing to (i) determine how host protein SRp20 interacts with the 40S ribosomal subunit to mediate formation of poliovirus IRES-mediated translation initiation complexes, (ii) define the steps used by human rhinovirus to switch template usage from translation to viral RNA synthesis, and (iii) determine the mechanism of AUF1 negative regulation of viral infections. Results from the proposed studies will reveal important insights into how the 5' NCRs of picornavirus RNAs control a myriad of interactions with host and viral proteins, all in the name of survival of a genetically-challenged family of RNA viruses. Such insights should be broadly applicable to other positive-strand RNA viruses that replicate in the cytoplasm of infected human cells and may help to identify unique virus-host interfaces to be developed as targets for anti-viral therapeutics.
Picornaviruses are major pathogens worldwide, inflicting some of the highest prevalence of human morbidity of all known viruses. They include human rhinovirus, poliovirus, coxsackievirus, and many others. This project will explore how these viruses exploit host cell functions and overcome anti-viral defense strategies through instructions encrypted in a noncoding region of their genomic RNAs.
|Ullmer, Wendy; Semler, Bert L (2018) Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells. MBio 9:|
|Lévêque, Nicolas; Garcia, Magali; Bouin, Alexis et al. (2017) Functional Consequences of RNA 5'-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation. J Virol 91:|
|Ullmer, Wendy; Semler, Bert L (2016) Diverse Strategies Used by Picornaviruses to Escape Host RNA Decay Pathways. Viruses 8:|
|Lévêque, Nicolas; Semler, Bert L (2015) A 21st century perspective of poliovirus replication. PLoS Pathog 11:e1004825|
|Flather, Dylan; Semler, Bert L (2015) Picornaviruses and nuclear functions: targeting a cellular compartment distinct from the replication site of a positive-strand RNA virus. Front Microbiol 6:594|
|Tsai, Becky Pinjou; Jimenez, Judith; Lim, Sharon et al. (2014) A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1. Open Biol 4:140180|
|Chase, Amanda J; Daijogo, Sarah; Semler, Bert L (2014) Inhibition of poliovirus-induced cleavage of cellular protein PCBP2 reduces the levels of viral RNA replication. J Virol 88:3192-201|
|Chase, Amanda J; Semler, Bert L (2014) Differential cleavage of IRES trans-acting factors (ITAFs) in cells infected by human rhinovirus. Virology 449:35-44|
|Cathcart, Andrea L; Semler, Bert L (2014) Differential restriction patterns of mRNA decay factor AUF1 during picornavirus infections. J Gen Virol 95:1488-92|
|Langereis, Martijn A; Feng, Qian; Nelissen, Frank H T et al. (2014) Modification of picornavirus genomic RNA using 'click' chemistry shows that unlinking of the VPg peptide is dispensable for translation and replication of the incoming viral RNA. Nucleic Acids Res 42:2473-82|
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