The pathogenesis of foot-and-mouth disease virus: current understandings and knowledge gaps.

Foot-and-mouth disease (FMD) continues to be one of the most important diseases of livestock globally based upon both biological features and regulatory aspects. Few pathogens have had comparable impact on global livestock production and regulation of international trade in animal-derived products. The pathogenesis (interaction between pathogen and host) is central to the importance of the disease ranging from how the causal pathogen, FMD virus (FMDV), transmits between hosts and is maintained in populations. Key accomplishments over the last decade include description of the primary sites of infection in domestic species, delineating critical differences in temporo-anatomic progression in different host species and emphasizing that knowledge gained regarding FMDV pathogenesis in one host cannot necessarily be extrapolated and applied to a different host. Host responses to infection and viral genomics have been characterized with ever-increasing granularity. Yet, the numerous knowledge gaps that remain in understanding FMDV pathogenesis impede advancements in FMD control and eradication. For instance, it remains unclear if long-term asymptomatic FMDV carriers are biologically relevant (contagious) and the manner in which host genomics and transcriptomics affect pathogenesis during different phases of infection. The characterization of neoteric subclinical infection as a disease stage that is distinct from the persistent "FMDV carrier state" has emphasized the importance of sample collection from clinically unaffected animals for FMDV surveillance. Similarly, incorporating a phase of pre-clinical infectiousness in simulation modeling can dramatically improve prediction of FMD outbreaks in non-endemic regions. The outcome of FMDV infection with regards to viral persistence differs between host species as well as between individuals of the same species. Yet, we lack a satisfactory explanation of the host factors that drive the FMDV carrier state divergence. This review was based upon a gap-analysis workshop organized by the Global Foot-and-Mouth Disease Research Alliance (GFRA) in Buenos Aires, Argentina, in December of 2022. The purpose of this work is to summarize the current understanding of the distinct compartments of FMD pathogenesis with an emphasis on progress made within the last decade and present the critical knowledge gaps that continue to limit FMD control and eradication.