Clearance of a persistent Picornavirus infection is associated with enhanced pro-apoptotic and cellular immune responses

Authors: STENFELDT, CAROLINA - University Of Minnesota; ESCHBAUMER, MICHAEL - Friedrich-Loeffler-institut; Smoliga, George; Rodriguez, Luis; Zhu, James; Arzt, Jonathan

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/4/2017
Publication Date: 12/19/2017
Citation: Stenfeldt, C., Eschbaumer, M., Smoliga, G.R., Rodriguez, L.L., Zhu, J.J., Arzt, J. 2017. Clearance of a persistent Picornavirus infection is associated with enhanced pro-apoptotic and cellular immune responses. Scientific Reports. 7:17800. https://doi.org/10.1038/s41598-017-18112-4.
DOI: https://doi.org/10.1038/s41598-017-18112-4

Interpretive Summary: Foot-and-mouth disease virus (FMDV) is the most important infectious disease limiting global trade in animal products. In cattle, the virus often causes long-term infection which is referred to as the carrier state. The current study investigated the different immune system mechanisms that are involved in clearance of FMDV from the respiratory tract of cattle. The results showed large differences in the immune response of animals that successfully cleared the infection compared to those that became persistently infected carriers of FMDV. It was concluded that mechanisms associated with activation of specific variants of immune cells were induced in the animals that cleared infection. Contrastingly, mechanisms associated with production of antibodies were upregulated in the animals that became carriers of the virus. Additionally, there were differences in activation of programmed cell death (known as “apoptosis”) between the two groups of animals. The findings of the study highlight that activation of immune cells is important for successful clearance of FMDV infection in cattle. This knowledge is important for future development of vaccines that may prevent FMDV persistence and thereby better protect US cattle herds from this virus.

Technical Abstract: Immunomodulatory mechanisms associated with clearance versus persistence of foot-and-mouth disease virus (FMDV) in distinct microanatomic compartments of the bovine nasopharynx were investigated using quantitative RT-PCR and whole transcriptome microarray. Analysis of tissue samples obtained during persistent infection, as well as during the temporal window bridging acute and persistent phases of infection (transitional phase) demonstrated significant differences in transcriptome profiles of animals that cleared infection versus those that became persistently infected carriers. The combined output of the analyses suggested that clearance of FMDV from the nasopharyngeal mucosa is associated with an activated cellular immune response. This was supported by induction of Th1-associated mediators and upregulation of multiple targets associated with activation of T cell-mediated cytotoxicity. Contrastingly, the pattern of gene regulation in FMDV carriers during transitional and persistent phases of infection suggested inhibition of T cell activation and promotion of Th2 polarization. Similarly, markers indicative of continued antigen stimulation and enhanced antibody-mediated immunity were overexpressed in FMDV carriers. Regulation of genes associated with apoptosis or cellular proliferation suggested an inhibition of apoptotic pathways associated with FMDV persistence. Additionally, markers of enhanced cellular proliferation were upregulated in the nasopharyngeal mucosa of FMDV carriers. The findings presented herein emphasize the critical importance of Th1-mediated cellular immunity for clearance of persistent FMDV infection. Additionally, the strong antibody-mediated immune response that is induced during acute infection may impair efficient clearance of intra-cellular virus, thereby promoting FMDV persistence. Thus, a critical balance between Th1 and Th2 mediated immunity is essential for successful clearance of FMDV infection and should be considered for development of next-generation vaccines and antiviral products.