Reduction of infection by inhibiting mTOR pathway is associated with reversing repression of type I IFN by PRRSV

Authors: LIU, QINFANG - KANSAS STATE UNIVERSITY; MILLER, LAURA; BLECHA, FRANK - KANSAS STATE UNIVERSITY; SANG, YONGMING - TENNESSEE STATE UNIVERSITY

Submitted to: Journal of General Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/7/2017
Publication Date: 6/14/2017
Citation: Liu, Q., Miller, L.C., Blecha, F., Sang, Y. 2017. Reduction of infection by inhibiting mTOR pathway is associated with reversed repression of type I interferon by porcine reproductive and respiratory syndrome virus. Journal of General Virology. 98(6):1316-1328. doi:10.1099/jgv.0.000802.

Interpretive Summary: Infectious diseases cause significant economic loss to US pork producers. Although treating sick animals can help reduce this loss, prevention of disease is the first choice. The best method to prevent transmission of a livestock disease is to induce a protective immune response in susceptible animals through vaccination. For some diseases, current technology is adequate for producing safe and efficacious vaccines. However, for other diseases, vaccines produced from current technology are not adequate. In these cases, understanding the complex nature of the protective immune response may be critical to improving vaccines which requires basic research into how the immune system functions. One important part of the immune response is the activation of different types of cells within the animal's immune system. Monocytic cells, such as macrophages, are one of these cell types that are intricately involved in the animal's response to disease. They have role in the innate responses as well as in development and maintenance of adaptive immunity against invading pathogens. Following infection, the macrophage becomes activated which can occur by direct contact with an infectious agent, or indirectly through stimulation of the cell by specific proteins produced by other cells in the body. Here, through examination of porcine reproductive and respiratory syndrome virus (PRRSV) infection, targeting on macrophages, we elaborate the direct involvement of a signaling pathway, mTOR, during infection. Comprehensive understanding of the immunological impact may become increasingly important to understand host-virus interactions of existing and emerging pathogens, with application to the development of novel therapies and vaccine strategies.

Technical Abstract: Type I interferons (IFNs) are critical in animal antiviral regulation. IFN-mediated signaling regulates hundreds of genes that are directly associated with antiviral, immune and other physiological responses. The signaling pathway mediated by mechanistic target of rapamycin (mTOR), a serine/threonine kinase regulated by IFNs, is key in regulation of cellular metabolism and recently implicated in host antiviral responses. However, little is known about how animal type I IFN signaling coordinates immunometabolic reactions during antiviral defense. Here, using porcine reproductive and respiratory syndrome virus (PRRSV), we found that the genes in the mTOR signaling pathway were differently regulated in PRRSV-infected porcine alveolar macrophages at different activation statuses. Moreover, mTOR signaling regulated PRRSV infection in MARC-145 and primary porcine cells, in part, through modulating the production and signaling of type I IFNs. Taken together, we determined that the mTOR signaling pathway involves PRRSV infection and regulates expression and signaling of type I IFNs against viral infection. These findings suggest that the mTOR signaling pathway has a bi-directional loop with the type I IFN system and imply that some components in the mTOR signaling pathway can be utilized as targets for studying antiviral immunity and for designing therapeutic reagents.