Search

African buffalo are the natural reservoirs of the SAT serotypes of foot-and-mouth disease virus (FMDV) in sub-Saharan Africa. Most buffalo are exposed to multiple FMDV serotypes early in life, and a proportion of them become persistently infected carriers. Understanding the genetic diversity and evolution of FMDV in carrier animals is critical to elucidate how FMDV persists in buffalo populations. In this study, we obtained oropharyngeal (OPF) fluid from naturally infected African buffalo, and characterized the genetic diversity of FMDV. Out of 54 FMDV-positive OPF, 5 were co-infected with SAT1 and SAT2 serotypes. From the five co-infected buffalo, we obtained eighty-nine plaque-purified isolates. Isolates obtained directly from OPF and plaque purification were sequenced using next-generation sequencing (NGS). Phylogenetic analyses of the sequences obtained from recombination-free protein-coding regions revealed a discrepancy in the topology of capsid proteins and non-structural proteins. Despite the high divergence in the capsid phylogeny between SAT1 and SAT2 serotypes, viruses from different serotypes that were collected from the same host had a high genetic similarity in non-structural protein-coding regions P2 and P3, suggesting interserotypic recombination. In two of the SAT1 and SAT2 co-infected buffalo identified at the first passage of viral isolation, the plaque-derived SAT2 genomes were distinctly grouped in two different genotypes. These genotypes were not initially detected with the NGS from the first passage (non-purified) virus isolation sample. In one animal with two SAT2 haplotypes, one plaque-derived chimeric sequence was found. These findings demonstrate within-host evolution through recombination and point mutation contributing to broad viral diversity in the wildlife reservoir. These mechanisms may be critical to FMDV persistence at the individual animal and population levels, and may contribute to the emergence of new viruses that have the abil

Venetoclax is approved as monotherapy and in combination with rituximab for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Two Phase 1 studies (M12-175 [NCT01328626]; M13-365 [NCT01682616]) were conducted in which patients who initially responded and then progressed on venetoclax monotherapy could receive added rituximab. Ten patients were evaluated (M12-175, n = 8; M13-365, n = 2), and five (50%) responded again upon addition of rituximab, including three complete and two partial responses. Responses were ongoing after 5-10 months of follow-up. Addition of rituximab was well tolerated. These findings indicate potential clinical benefit with rituximab added to venetoclax post-progression in some patients with R/R CLL.

Continuous surveillance for foot-and-mouth disease (FMD) in endemic settings such as West Africa is imperative to support improved local and regional control plans, with the long-term goal of regional eradication. This paper describes the genetic characterization of FMD viruses (FMDV) obtained from outbreaks in Nigeria (n = 45) and Cameroon (n = 15) during 2016 and from archival samples (n = 3) retrieved from a 2014 outbreak in Nigeria. These viruses were analyzed in the context of previously published FMDV sequences from the region. Four FMDV serotypes: O, A, SAT1 and SAT2 were detected. Phylogenetic analyses of the VP1 coding sequences indicate the continuity of FMDV serotype O East Africa-3 (O/EA-3), serotype A AFRICA genotype G-IV (A/AFRICA/G-IV), and serotype South African Territories (SAT) 2 lineage VII (SAT2/VII). The FMDV SAT1 topotype X (SAT1/X), which emerged in Nigeria in 2015, continued to be associated with outbreaks in the region during 2016, and SAT1 is reported for the first time from Cameroon. Additionally, a re-emergence or re-introduction of the serotype O West Africa (O/WA) topotype in Nigeria is described herein. Our findings indicate a consistent, pan-serotypic relationship between FMDV strains detected in Cameroon and Nigeria. Additionally, FMDV strains from West Africa obtained in this study were genetically related to those occurring in East and North Africa. These phylogenetic relationships suggest that animal movements (pastoralism and/or trade) are important factors for virus spread across the African continent. These data provide critical baselines which are a necessary component of Stage 0 and 1 of the Progressive Control Pathway of FMD (PCP-FMD). Specifically, characterizing the existing virus strains (risk) provides the basis for the comprehensive risk-based control plan which is the requisite criteria for Nigeria's transition to Stage 2 of PCP-FMD, and for coordinated regional control of FMD.

© 2018 The Author(s). Recombination of rapidly evolving RNA-viruses provides an important mechanism for diversification, spread, and emergence of new variants with enhanced fitness. Foot-and-mouth disease virus (FMDV) causes an important transboundary disease of livestock that is endemic to most countries in Asia and Africa. Maintenance and spread of FMDV are driven by periods of dominance of specific viral lineages. Current understanding of the molecular epidemiology of FMDV lineages is generally based on the phylogenetic relationship of the capsid-encoding genes, with less attention to the process of recombination and evolution of non-structural proteins. In this study, the putative recombination breakpoints of FMDVs endemic to Southeast Asia were determined using full-open reading frame sequences. Subsequently, the lineages' divergence times of recombination-free genome regions were estimated. These analyses revealed a close relationship between two of the earliest endemic viral lineages that appear unrelated when only considering the phylogeny of their capsid proteins. Contrastingly, one lineage, named O/CATHAY, known for having a particular host predilection (pigs) has evolved independently. Additionally, intra-lineage recombination occurred at different breakpoints compared to the inter-lineage process. These results provide new insights about FMDV recombination patterns and the evolutionary interdependence of FMDV serotypes and lineages.

Several foot-and-mouth disease virus (FMDV) carrier cattle were identified in Vietnam by the recovery of infectious virus from oropharyngeal fluid. This report contains the first near-complete genome sequences of seven viruses from sequential samples from one carrier animal collected over the course of 1 year. The characterization of within-host viral evolution has implications for FMDV control strategies.

© 2017 The Author(s). Foot-and-mouth disease virus (FMDV) is endemic in Vietnam, a country that plays an important role in livestock trade within Southeast Asia. The large populations of FMDV-susceptible species in Vietnam are important components of food production and of the national livelihood. In this study, we investigated the phylogeny of FMDV O/PanAsia in Vietnam, reconstructing the virus' ancestral host species (pig, cattle or buffalo), clinical stage (subclinical carrier or clinically affected) and geographical location. Phylogenetic divergence time estimation and character state reconstruction analyses suggest that movement of viruses between species differ. While inferred transmissions from cattle to buffalo and pigs and from pigs to cattle are well supported, transmission from buffalo to other species, and from pigs to buffalo may be less frequent. Geographical movements of FMDV O/PanAsia virus appears to occur in all directions within the country, with the South Central Coast and the Northeast regions playing a more important role in FMDV O/PanAsia spread. Genetic selection of variants with changes at specific sites within FMDV VP1 coding region was different depending on host groups analyzed. The overall ratio of non-synonymous to synonymous nucleotide changes was greater in pigs compared to cattle and buffalo, whereas a higher number of individual amino acid sites under positive selection were detected in persistently infected, subclinical animals compared to viruses collected from clinically diseased animals. These results provide novel insights to understand FMDV evolution and its association with viral spread within endemic countries. These findings may support animal health organizations in their endeavor to design animal disease control strategies in response to outbreaks.

© 2017 Arzt et al. In 2015, foot-and-mouth disease (FMD) virus lineage Ind-2001 was detected for the first time in Southeast Asia. This report contains the first nearcomplete genome sequence of a viral isolate from this lineage collected from an outbreak in Vietnam. This novel incursion has substantial implications for regional FMD control measures.

In recent years, foot-and-mouth disease virus (FMDV) serotype O, topotype Middle East- South Asia (ME-SA), lineage Ind-2001d has spread from the Indian subcontinent to the Middle East, North Africa, and Southeast Asia. In the current report, we describe the first detection of this lineage in Vietnam in May, 2015 in Dak Nông province. Three subsequent outbreaks caused by genetically related viruses occurred between May-October, 2015 after which the virus was not detected in clinical outbreaks for at least 15 subsequent months. The observed outbreaks affected (in chronological order): Cattle in Dak Nông province, pigs in Dak Lak province and Dak Nông province, and cattle in Ninh Thuân province. The clinical syndromes associated with these outbreaks were consistent with typical FMD in the affected species. Overall attack rate on affected premises was 0.85 in pigs and 0.93 in cattle over the course of the outbreak. Amongst 378 pigs at risk on affected premises, 85 pigs died during the outbreaks; there were no deaths among cattle. The manner in which FMDV/O/ME-SA/Ind-2001d was introduced into Vietnam remains undetermined; however, movement of live cattle is the suspected route. This incursion has substantial implications for epidemiology and control of FMD in Southeast Asia.

The epidemiological significance of asymptomatic persistent foot-and-mouth disease virus (FMDV) infection in carrier animals, specifically its ability to seed new clinical outbreaks, is undetermined, and consistent viral determinants of FMDV persistence have not been identified. We analyzed 114 FMDV O/ME-SA/PanAsia VP1 sequences from naturally infected animals in Vietnam, of which 31 were obtained from persistently infected carrier animals. A site-specific substitution was identified at VP1 residue 172 where arginine was present in all 31 of the carrier-associated viruses, whereas outbreak viruses typically contained glutamine. Additionally, we characterized multiple viruses from a single persistently infected animal that were collected over the course of eight months and at multiple distinct anatomic sites (larynx, dorsal soft palate and dorsal nasopharynx). This work sheds new light on naturally occurring viral mutations within the host and provides a basis for understanding the viral evolution and persistence mechanisms of FMDV.

Understanding the quantitative characteristics of a pathogen's capability to transmit during distinct phases of infection is important to enable accurate predictions of the spread and impact of a disease outbreak. In the current investigation, the potential for transmission of foot-and-mouth disease virus (FMDV) during the incubation (preclinical) period of infection was investigated in seven groups of pigs that were sequentially exposed to a group of donor pigs that were infected by simulated-natural inoculation. Contact-exposed pigs were comingled with infected donors through successive 8-h time slots spanning from 8 to 64 h post-inoculation (hpi) of the donor pigs. The transition from latent to infectious periods in the donor pigs was clearly defined by successful transmission of foot-and-mouth disease (FMD) to all contact pigs that were exposed to the donors from 24 hpi and later. This onset of infectiousness occurred concurrent with detection of viremia, but approximately 24 h prior to the first appearance of clinical signs of FMD in the donors. Thus, the latent period of infection ended approximately 24 h before the end of the incubation period. There were significant differences between contact-exposed groups in the time elapsed from virus exposure to the first detection of FMDV shedding, viremia, and clinical lesions. Specifically, the onset and progression of clinical FMD were more rapid in pigs that had been exposed to the donor pigs during more advanced phases of disease, suggesting that these animals had received a higher effective challenge dose. These results demonstrate transmission and dissemination of FMD within groups of pigs during the incubation period of infection. Furthermore, these findings suggest that under current conditions, shedding of FMDV in oropharyngeal fluids is a more precise proxy for FMDV infectiousness than clinical signs of infection. These findings may impact modeling of the propagation of FMD outbreaks that initiate in pig hol

Foot-and-mouth disease (FMD) is a highly contagious viral disease which affects both domestic and wild biungulate species. This acute disease, caused by the FMD virus (FMDV), usually includes an active replication phase in the respiratory tract for up to 72 h postinfection, followed by hematogenous dissemination and vesicular lesions at oral and foot epithelia. The role of the early local adaptive immunity of the host in the outcome of the infection is not well understood. Here we report the kinetics of appearance of FMDV-specific antibody-secreting cells (ASC) in lymphoid organs along the respiratory tract and the spleen in cattle infected by aerosol exposure. While no responses were observed for up to 3 days postinfection (dpi), all animals developed FMDV-ASC in all the lymphoid organs studied at 4 dpi. Tracheobronchial lymph nodes were the most reactive organs at this time, and IgM was the predominant isotype, followed by IgG1. Numbers of FMDV-ASC were further augmented at 5 and 6 dpi, with an increasing prevalence in upper respiratory organs. Systemic antibody responses were slightly delayed compared with the local reaction. Also, IgM was the dominant isotype in serum at 5 dpi, coinciding with a sharp decrease of viral RNA detection in peripheral blood. These results indicate that following aerogenous administration, cattle develop a rapid and vigorous genuine local antibody response throughout the respiratory tract. Time course and isotype profiles indicate the presence of an efficient T cell-independent antibody response which drives the IgM-mediated virus clearance in cattle infected by FMDV aerosol exposure.