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Research Project: Intervention Strategies to Support the Global Control and Eradication of Foot-and-Mouth Disease Virus (FMDV)

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Title: Foot-and-mouth disease virus 5’-terminal S fragment is required for replication and modulation of the innate immune response in host cells

item KLOC, ANNA - Oak Ridge Institute For Science And Education (ORISE)
item DIAZ-SAN SEGUNDO, FAYNA - University Of Connecticut
item Schafer, Elizabeth
item RAI, D - University Of Connecticut
item Kenney, Mary
item De Los Santos, Teresa
item Rieder, Aida - Elizabeth

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/31/2017
Publication Date: 9/26/2017
Citation: Kloc, A., Diaz-San Segundo, F., Schafer, E.A., Rai, D.K., Kenney, M.A., De Los Santos, T.B., Rieder, A.E. 2017. Foot-and-mouth disease virus 5’-terminal S fragment is required for replication and modulation of the innate immune response in host cells. Virology. 512:132-143.

Interpretive Summary: Foot-and-mouth disease virus (FMDV) is a devastating disease of cattle and other cloven-hoofed animals that is responsible for millions of dollars in losses around the globe each year, prompting researchers in both the U.S. and other countries to develop more effective vaccines. In this study, we uncover a new role attributed to a small segment of the beginning of the FMDV genome that is responsible for virus replication and also modulating the innate immune response in animals to the virus. This work adds to the knowledge of virus-unique processes that have potential for the development of disease control strategies such as better vaccines.

Technical Abstract: The foot-and-mouth disease virus (FMDV) contains a 5’ untranslated region (5’UTR) with multiple structural domains that regulate viral genome replication, translation, and virus-host interactions. At its 5’terminus, the S fragment of over 360 bp is predicted to form a stable stem-loop that is separated from the rest of the genome by a homopolymeric cytidylic acid tract (polyC). Even though the S fragment is relatively conserved among different FMDV serotypes, little is known about its function. In this study we used site-directed mutagenesis to generate mutant FMD viruses harboring deletions and mutations within the S fragment. The deletion mutants presented three different growth phenotypes: the short truncations from the top of the stem-loop (A24 FMDV-S12 and A24 FMDV-S13) grew in secondary bovine cells at levels similar to the parental virus, whereas the intermediate truncations (A24 FMDV-S11, A24 FMDV-S8, A24 FMDV-S7, and A24 FMDV-S4) had attenuated phenotypes. Truncations larger than A24 FMDV-S4, which had 168 nucleotides removed from the S fragment, were nonviable. In-vitro characterization of the shortest A24 FMDV-S4 mutant virus revealed that infection of primary porcine kidney cells triggered an enhanced innate immune response, as seen by an increase in the IFN-ß mRNA levels and an upregulation of the IFN-ß-stimulating genes and pro-inflammatory cytokines, as compared to the wild-type (WT) virus. Furthermore, the A24 FMDV-S4 truncation failed to induce disease in an FMDV mouse model, indicating that the virus is attenuated in vivo. Animals previously exposed to the A24 FMDV-S4 virus were also protected after a wild type (WT) A24 FMDV challenge. Our findings provide a novel insight into the role of the FMDV S fragment and offer evidence that it is able to modulate the innate immune system response.