Inferred Causal Mechanisms of Persistent FMDV Infection from Differential Gene Expression during the Transitional Phase from Acute to Persistent Infection

Authors: Zhu, James; STENFELDT, CAROLINA - University Of Kansas; BISHOP, ELIZABETH - US Department Of Agriculture (USDA); CANTER, JESSICA - Oak Ridge Institute For Science And Education (ORISE); ESCHBAUMER, MICHAEL - Friedrich-Loeffler-institut; Rodriguez, Luis; Arzt, Jonathan

Submitted to: Pathogens
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/18/2022
Publication Date: 7/22/2022
Citation: Zhu, J.J., Stenfeldt, C., Bishop, E.A., Canter, J.A., Eschbaumer, M., Rodriguez, L.L., Arzt, J. 2022. Inferred Causal Mechanisms of Persistent FMDV Infection from Differential Gene Expression during the Transitional Phase from Acute to Persistent Infection. Pathogens. 11:8:822. https://doi.org/10.3390/pathogens11080822.
DOI: https://doi.org/10.3390/pathogens11080822

Interpretive Summary: Foot-and-mouth disease is one of the most contagious and economically devastating viral diseases of cloven-hoofed animals such as ruminants and pigs. It is caused by foot-and-mouth disease virus (FMDV). Although the mortality of this disease is very low, FMDV can persist for a long time in a high percentage of infected ruminants but not in pigs after acute infection. The mechanisms causing FMDV to persistence are unknown. To understand the mechanisms involved, we applied a transcriptomic approach to identify gene differentially expressed between virus carriers and terminators. We previously reported mechanisms involved in maintaining FMDV persistent infection using micro-dissected tissues collected during the persistent infection phase (virus persist for > 28 days after infection). In this study, we analyzed the genes differentially expressed during the transitional phase from acute to persistent infection. The results of analyses indicated that the differential gene expression between carriers and terminators could affect several immune mechanisms including one known to be regulated by some substances (ligands of a receptor named AHR in the signaling pathway or xenobiotics) produced in the rumens. One example of excessive production of such substances is a disease in cattle called fog fever also named as bovine pulmonary emphysema and edema and bovine atypical interstitial pneumonia. Therefore, we proposed that these ligands in the rumens could be one of the causative factors of FMDV persistent infection. The inferred mechanisms could explain why this virus persists in some ruminants but not in pigs. This study provides novel insightful information for further investigation of FMDV persistent infection and eventually development of a control method.

Technical Abstract: Foot-and-mouth disease virus (FMDV) can persistently infect pharyngeal epithelia in ruminants but not in pigs, by incompletely elucidated causal mechanisms. Our previous studies demonstrated that FMDV persistent infection in cattle was associated with under-expression of several chemokines that recruit immune cells, which contribute to pathogen clearance. This report focuses on the analysis of differentially expressed genes (DEG) identified during the transitional phase between acute and persistent infection to understand the causal mechanisms of persistent infection. During this phase, Th17-stimulating cytokines (IL6 and IL23A) and Th17-recruiting chemokines (CCL14 and CCL20) were upregulated in animals that were still infected (transitional carriers) compared to those that had recently cleared infection (terminators), whereas chemokines recruiting neutrophils and CD8+ T effector cells (CCL3 and ELR+CXCLs) were downregulated. Upregulated Th17-specific receptor, CCR6, and Th17 associated-genes, CD146, MIR155 and ThPOK, provided additional support for increased Th17 cell activity in the tissues of transitional carriers. However, complex interplay of the Th17 regulatory axis was indicated in transitional carriers by non-significant upregulation of IL17A and downregulation of IL17F, that are two hallmarks of TH17 activity and are critical for clearing pathogens. Other DEG indicated that transitional carriers had upregulated aryl hydrocarbon receptor (AHR), non-canonical NF'B signaling, and downregulated canonical NF'B signaling. AHR signaling is well-known for its role in regulating NFkB signaling pathways and Th17 response including stimulating trans-differentiation of Th17 to Treg. The results described herein provide novel insights to the mechanisms of establishment of the FMDV carrier state. Additionally, the fact that ruminants, unlike pigs, produce a large amount of AHR ligands suggests a plausible explanation of why FMDV persists in ruminants, but not in pigs.