Biology subjects

Arzt, J.

Publications and source records attributed to Arzt, J..

5 recordsLinked to original sources

bioRxiv2024

Machine learning approaches for estimating cross-neutralization potential among FMD serotype O viruses

In this study, we aimed to develop an algorithm that uses sequence data to estimate cross-neutralization between serotype O foot-and-mouth disease viruses (FMDV) based on r1 values, while identifying key genomic sites associated with high or low r1 values. The ability to estimate cross-neutralization potential among co-circulating FMDVs in silico is significant for vaccine developers, animal health agencies making herd immunization decisions, and disease preparedness. Using published data on virus neutralization titer (VNT) assays and associated VP1 sequences from GenBank, we applied machine learning algorithms (BORUTA and random forest) to predict potential cross-reaction between serum/vaccine-virus pairs for 73 distinct serotype O FMDV strains. Model optimization involved tenfold cross-validation and sub-sampling to address data imbalance and improve performance. Model predictors included amino acid distances, site-wise amino acid polymorphisms, and differences in potential N-glycosylation sites. The dataset comprised 108 observations (serum-virus pairs) from 73 distinct viruses with r1 values. Observations were dichotomized using a 0.3 threshold, yielding putative non-cross-neutralizing (< 0.3 r1 values) and cross-neutralizing groups ([≥] 0.3 r1 values). The best model had a training accuracy, sensitivity, and specificity of 0.96 (95% CI: 0.88-0.99), 0.93, and 0.96, respectively, and an accuracy of 0.94 (95% CI: 0.71-1.00), sensitivity of 1.00, and specificity of 0.93, positive, and negative predictive values of 0.60 and 1.00, respectively, on one testing dataset and an accuracy, AUC, sensitivity, specificity, and predictive values all approaching 1.00 on a second testing dataset. Additionally, amino acid positions 48, 100, 135, 150, and 151 in the VP1 region alongside amino acid distance were found to be important predictors of cross-neutralization. Our study highlights the value of genetic/genomic data for informing immunization strategies in disease management and understanding potential immune-mediated competition amongst related endemic strains of serotype O FMDVs in the field. We also showcase leveraging routinely generated sequence data and applying a parsimonious machine learning model to expedite decision-making in selection of vaccine candidates and application of vaccines for controlling FMD, particularly serotype O. A similar approach can be applied to other serotypes.

immunology↗

bioRxiv2019

Into the deep (sequence) of the foot-and-mouth disease virus gene pool: bottlenecks and adaptation during infection in naïve and vaccinated cattle

Foot-and-mouth disease virus (FMDV), like many RNA viruses, infects hosts as a population of closely related viruses referred to as a quasispecies. The behavior of this quasispecies has not been described in detail over the full course of infection in a natural host species. In this study, virus samples taken from vaccinated and non-vaccinated cattle up to 35 days post experimental infection with FMDV A24-Cruzeiro were analyzed by deep-sequencing. Vaccination induced significant differences compared to viruses from non-vaccinated cattle. in virus substitution rates, entropy, and evidence for adaptation. Genomic variation detected during early infection was found to reflect the diversity inherited from the source virus (inoculum), whereas by 12 days post infection (dpi) dominant viruses were defined by newly acquired mutations. In most serially sampled cattle, mutations conferring recognized fitness gain occurred within numerous genetic backgrounds, often associated with selective sweeps. Persistent infections always included multiple FMDV subpopulations, suggesting independently maintained foci of infection within the nasopharyngeal mucosa. Although vaccination prevented disease, subclinical infection in this group was associated with very early bottlenecks which subsequently reduced the diversity within the virus population. This implies an added consequence of vaccination in the control of foot-and-mouth disease. Viruses sampled from both animal cohorts contained putative antigenic escape mutations. However, these mutations occurred during later stages of infection, at which time transmission between animals is less likely to occur. ImportancePreparedness and control of foot-and-mouth disease virus have substantial, yet distinct implications in endemic and free regions. Viral evolution and emergence of novel strains are of critical concern in both settings. The factors that contribute to the asymptomatic carrier state, a common form of long-term FMDV infection in cattle and other species, are important but not well-understood. This experimental study of foot-and-mouth disease virus in cattle explored the evolution of the pathogen through detailed sampling and analytical methods in both vaccinated and non-vaccinated hosts. Significant differences were identified between the viruses subclinically infecting vaccinated animals and those causing clinical disease in the non-vaccinated cohort. These results can benefit vaccination programs and contribute to the understanding of persistent infection of cattle.

microbiology↗

bioRxiv2019

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

The role of foot-and-mouth disease virus (FMDV) persistently infected ruminants in initiating new outbreaks remains controversial, and the perceived threat posed by such animals hinders international trade in FMD-endemic countries. In this study we report longitudinal analyses of genetic and antigenic variations of FMDV serotype O/ME-SA/Ind2001d sublineage during naturally occurring, persistent infection in cattle and buffalo at an organised dairy farm in India. The proportion of animals from which FMDV RNA was recovered was not significantly different between convalescent (post-clinical) and sub-clinically infected animals or between cattle and buffalo across the sampling period. However, infectious virus was isolated from a higher proportion of buffalo samples and for a longer duration compared to cattle. Analysis of the P1 sequences from recovered viruses indicated fixation of mutations at the rate of 1.816 x 10-2 substitution/site/year (s/s/y) (95% CI 1.362-2.31 x 10-2 s/s/y). However, the majority of point mutations were transitional substitutions. Within individual animals, the mean dN/dS ({omega}) value for the P1 region varied from 0.076 to 0.357, suggesting the selection pressure acting on viral genomes differed substantially across individual animals. Statistical parsimony analysis indicated that all of the virus isolates from carrier animals originated from the outbreak virus. The antigenic relationship value as determined by 2D-VNT assay revealed fluctuation of antigenic variants within and between carrier animals during the carrier state which suggested that some carrier viruses had diverged substantially from the protection provided by the vaccine strain. This study contributes to understanding the extent of within-host and within-herd evolution that occurs during the carrier state of FMDV.

evolutionary biology↗

bioRxiv2019

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

Foot-and-mouth disease (FMD) is a highly contagious viral disease that severely impacts global food security and is one of the greatest constraints on international trade of animal products. Extensive viral population diversity and rapid, continuous mutation of circulating FMD viruses (FMDVs) pose significant obstacles to the control and ultimate eradication of this important transboundary pathogen. The current study investigated mechanisms contributing to within-host evolution of FMDV in a natural host species (cattle). Specifically, vaccinated and non-vaccinated cattle were infected with FMDV under controlled, experimental conditions and subsequently sampled for up to 35 days to monitor viral genomic changes as related to phases of disease and experimental cohorts. Consensus-level genomic changes across the entire FMDV coding region were characterized through three previously defined stages of infection: early, transitional, and persistent. The overall conclusion was that viral evolution occurred via a combination of two mechanisms: emergence of full-genomic minority haplotypes from within the inoculum super-swarm, and concurrent continuous point mutations. Phylogenetic analysis indicated that individuals were infected with multiple distinct haplogroups that were pre-existent within the ancestral inoculum used to infect all animals. Multiple shifts of dominant viral haplotype took place during the early and transitional phases of infection, whereas few shifts occurred during persistent infection. These insights into FMDV population dynamics have important implications for virus sampling methodology and molecular epidemiology.

microbiology↗

bioRxiv2018

The role of African buffalo in the epidemiology of foot-and-mouth disease in sympatric cattle and buffalo populations in Kenya

Transmission of pathogens at wildlife-livestock interfaces poses a substantial challenge to the control of infectious diseases, including for foot-and-mouth disease virus (FMDV) in African buffalo and cattle. The extent to which buffalo play a role in the epidemiology of this virus in livestock populations remains unresolved in East Africa. Here, we show that FMDV occurs at high seroprevalence (~77%) in Kenyan buffalo. In addition, we recovered 80 FMDV VP1 sequences from buffalo, all of which were serotype SAT1 and SAT2, and seventeen FMDV VP1 sequences from cattle, which included serotypes A, O, SAT1 and SAT2. Notably, six individual buffalo were co-infected with both SAT1 and SAT2 serotypes. Our results suggest that transmission of FMDV between sympatric cattle and buffalo is rare. However, viruses from FMDV outbreaks in cattle elsewhere in Kenya were caused by viruses closely related to SAT1 and SAT2 viruses found in buffalo. We also show that the circulation of FMDV in buffalo is influenced by fine-scale geographic features, such as rivers, and that social segregation amongst sympatric herds may limit between-herd transmission. Our results significantly advance knowledge of the ecology and molecular epidemiology of FMDV at wildlife-livestock interfaces in Eastern Africa, and will help to inform the design of control and surveillance strategies for this disease in the region.

epidemiology↗