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

Abstract

Long-term persistent viral infections cause substantial morbidity and associated economic losses in human and veterinary contexts. Yet, the mechanisms associated with establishment of persistent infections are poorly elucidated. We investigated immunomodulatory mechanisms associated with clearance versus persistence of foot-and-mouth disease virus (FMDV) in micro-dissected compartments of the bovine nasopharynx by microarray. The use of laser-capture microdissection allowed elucidation of differential gene regulation within distinct anatomic compartments critical to FMDV infection. Analysis of samples from transitional and persistent phases of infection demonstrated significant differences in transcriptome profiles of animals that cleared infection versus those that became persistently infected carriers. Specifically, it was demonstrated that clearance of FMDV from the nasopharyngeal mucosa was associated with upregulation of targets associated with activation of T cell-mediated immunity. Contrastingly, gene regulation in FMDV carriers suggested inhibition of T cell activation and promotion of Th2 polarization. These findings were corroborated by immunofluorescence microscopy which demonstrated relative abundance of CD8 + T cells in the nasopharyngeal mucosa in association with clearance of FMDV. The findings presented herein emphasize that 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.Foot-and-mouth disease virus (FMDV), the prototype Aphthovirus within the Picornaviridae family, is the causal agent of foot-and-mouth disease (FMD), a highly contagious disease of cloven-hoofed animals 1 . The endemic presence of FMD in large regions of the world compromises food security and animal welfare. Additionally, as a country's official FMD status defines access to international markets for export of animal products, this disease has a substantial global economic impact on agricultural production and trade.Control and eradication of FMD is impeded by the existence of a prolonged subclinical persistent phase of infection in ruminant species 2-4 . This concept, generally referred to as the FMDV carrier state, is specifically problematic when vaccination is used to control FMD in non-endemic regions as vaccinated cattle may maintain subclinical FMDV persistence following virus exposure, despite having been protected against the clinical disease 5-12 . Confirmed evidence of FMDV transmission from persistently infected cattle is lacking. However, because infectious FMDV is detectable in oropharyngeal fluid (OPF) and nasopharyngeal tissues of carriers for prolonged periods of time, the presence of such animals precludes achieving an official status as FMD-free by the international organization for animal health (OIE) 13 .In cattle, persistent FMDV has been localized to the follicle-associated epithelium (FAE) of the nasopharyngeal mucosa 10,11 or associated lymph nodes ...

Genetic and antigenic variation of foot-and-mouth disease virus during persistent infection in naturally infected cattle and Asian buffalo in India

“…These results suggest that viral determinants may have some role, but are not likely to be solely responsible for determining persistent FMD infection or for FMDV evolution within carrier animals. The selection pressure acting on the viral genome varies among individual persistently infected animals, suggesting that host factors are similarly important to the viral determinants, as has been suggested by some authors (61, 62).…”

The evolution of a super-swarm of foot-and-mouth disease virus in cattle

“…Contrastingly, clade shifts were largely absent during persistent infection. This finding also may relate to the recent finding that cell-mediated killing as well as inflammatory- and apoptotic pathways are reduced in carriers [34, 42], potentially facilitating the stabilization of surviving virus populations.…”

“…Thus, viruses that transiently emerged in non-vaccinated animals did not re-occur at later time points. This superiority of clade-specific clearance in non-vaccinated animals may reflect differences in the host immune response during early [22] or late [28, 34] infection. One possible explanation is that a primed immune response in vaccinated animals led to fewer clades successfully seeding infection (i.e.…”

“…Consequently, FMDV clade shifts occurred in every animal that was sampled through the transitional phase of infection. Recent investigations have suggested that virus clearance is associated with an activated cellular immune response [34, 42]. It is possible that transitional phase clade shifts are a result of this activated host response, and that virus populations unable to effectively evade this pressure are those that allow for complete clearance.…”

“…These findings have led to the definition of the transitional phase of FMDV infection, which corresponds to the temporal window during which FMDV is cleared from cattle that do not become carriers [28]. Transitional phase events thus comprise a critical stage of FMDV pathogenesis wherein pivotal virus-host interactions determine the outcome of the FMDV carrier state divergence [28, 34].…”