ORCID Profile
0000-0002-2882-1420
Current Organisations
Brown University
,
Oxford University Clinical Research Unit - Nepal, Patan Academy Of Health Sciences
,
University of Oxford
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Related Links
Publications
Burden of enteric fever at three urban sites in Africa and Asia: a multicentre population-based study
Publisher: Elsevier BV
Date: 12-2021
Genomic epidemiology and antimicrobial resistance transmission ofSalmonellaTyphi and Paratyphi A at three urban sites in Africa and Asia
Publisher: Cold Spring Harbor Laboratory
Date: 16-03-2023
DOI: 10.1101/2023.03.11.23286741
Abstract: Enteric fever is a serious public health concern. The causative agents, Salmonella enterica serovars Typhi and Paratyphi A, are frequently antimicrobial resistant (AMR), leading to limited treatment options and poorer clinical outcomes. We investigated the genomic epidemiology, resistance mechanisms and transmission dynamics of these pathogens at three urban sites in Africa and Asia. Bacteria isolated from febrile children and adults at study sites in Dhaka, Kathmandu, and Blantyre were sequenced and AMR determinants identified. Phylogenomic analyses incorporating globally-representative genome data, and ancestral state reconstruction, were used to differentiate locally-circulating from imported pathogen variants. S . Paratyphi A was present in Dhaka and Kathmandu but not Blantyre. S . Typhi genotype 4.3.1 (H58) was common in all sites, but with different dominant variants (4.3.1.1.EA1 in Blantyre 4.3.1.1 in Dhaka 4.3.1.2 in Kathmandu). Resistance to first-line antimicrobials was common in Blantyre (98%) and Dhaka (32%) but not Kathmandu (1.4%). Quinolone-resistance mutations were common in Dhaka (99.8%) and Kathmandu (89%) but not Blantyre (2.1%). AcrB azithromycin-resistance mutations were rare (Dhaka only n=5, 1.1%). Phylogenetic analyses showed that (a) most cases derived from pre-existing, locally- established pathogen variants (b) nearly all (98%) drug-resistant infections resulted from local circulation of AMR variants, not imported variants or recent de novo emergence (c) pathogen variants circulated across age groups. Most cases (67%) clustered with others that were indistinguishable by point mutations in idual clusters included multiple age groups and persisted for up to 2.3 years, and AMR determinants were invariant within clusters. Enteric fever was associated with locally-established pathogen variants that circulate across age groups. AMR infections resulted from local transmission of resistant strains. These results form a baseline against which to monitor the impacts of control measures. Wellcome Trust, Bill & Melinda Gates Foundation, European Union’s Horizon 2020, NIHR. Current knowledge of the enteric fever pathogen populations in Dhaka, Kathmandu, and Blantyre comes from retrospective analysis of isolates captured from routine diagnostics or treatment trials. Due to these study designs, most focus on either adult or paediatric cohorts, which complicates assessment of pathogen variant transmission across age groups. Many studies report prevalence of antimicrobial resistance (AMR) and associated mechanisms amongst enteric fever cases. Genomic studies at these sites and elsewhere have identified the spread of AMR clones, and a recent genomic study quantified the inter- and intra-continental spread of resistant S . Typhi between countries. However, PubMed search of “(typhoid OR (enteric fever)) AND (genom*)” identified no studies quantifying the relative proportion of resistant infections that is attributable to local transmission of resistant variants vs imported strains or de novo emergence of AMR. We estimate the vast majority (98%) of drug-resistant enteric fever cases identified in our study resulted from local circulation of resistant variants. Further, we show genetically indistinguishable pathogen variants (either resistant or susceptible) persisting for up to 2.3 years and causing infections across all age groups (under 5 years 5-15 years ≥15 years). While inter-country transfer of resistant enteric fever pathogens does occur and is concerning, the burden of drug-resistant enteric fever at the study sites is currently caused mainly by transmission of locally-established variants, and transmits across age groups. These data confirm assumptions made in models of vaccine impact regarding heterogeneity of pathogen variants and AMR across age groups, and support that childhood immunisation programmes can be expected to reduce the overall burden of resistant infections in endemic settings.
The STRATAA study protocol: A programme to assess the burden of enteric fever in Bangladesh, Malawi and Nepal using prospective population census, passive surveillance, serological studies and healthcare utilisation surveys
Publisher: BMJ
Date: 06-2017
Direct inference and control of genetic population structure from RNA sequencing data
Publisher: Cold Spring Harbor Laboratory
Date: 16-09-2022
DOI: 10.1101/2022.09.16.508259
Abstract: RNAseq data can be used to infer genetic variants, yet its use for estimating genetic population structure remains underexplored. Here, we construct a freely available computational tool (RGStraP) to estimate RNAseq-based genetic principal components (RG-PCs) and assess whether RG-PCs can be used to control for population structure in gene expression analyses. Using whole blood s les from understudied Nepalese populations and the Geuvadis study, we show that RG-PCs had comparable results to paired array-based genotypes, with high genotype concordance and high correlations of genetic principal components, capturing subpopulations within the dataset. In differential gene expression analysis, we found that inclusion of RG-PCs as covariates reduced test statistic inflation. Our paper demonstrates that genetic population structure can be directly inferred and controlled for using RNAseq data, thus facilitating improved retrospective and future analyses of transcriptomic data.
Association of Antibody-Dependent Neutrophil Phagocytosis With Distinct Antibody Glycosylation Profiles Following Typhoid Vaccination
Publisher: Frontiers Media SA
Date: 16-09-2021
Abstract: Typhoid Vi-conjugate vaccines (Vi-TCV) have been developed to control typhoid fever in children in endemic regions. Previously, in a human challenge model of typhoid, Vi-TCV was administered prior to deliberate ingestion of Salmonella Typhi by healthy adult volunteers in the UK. Vi-specific antibody-dependent neutrophil phagocytosis (ADNP) was associated with protection against enteric fever in this model, but it is not known if ADNP is induced by vaccination of children. We measured ADNP in a cohort of Nepalese children receiving a Vi-TCV in a field study to investigate whether functional antibody responses were also present in children in an endemic setting. Furthermore, we investigated relationships between the functional antibody measures and other properties of the antibody response, including Vi-IgG and IgA titres, and Fc region glycosylation. Antibody-dependent neutrophil phagocytosis significantly increased in children aged 9 months to 15 years between the day of vaccination and 28 days following administration of Vi-TCV (D28). The magnitude of ADNP was also comparable with the levels of ADNP induced by plasma from vaccinated UK adults. Neither IgG nor IgA antibody titres significantly correlated with ADNP scores at D28 however, increased vaccine-induced ADNP was associated with decreased levels of IgG1 sialylation. These data suggest that vaccination with Vi-TCV produces functional antibody responses in children, which associate with specific glycosylation patterns of the Fc region.
Related Organisations
Oxford University Clinical Research Unit - Nepal, Patan Academy Of Health Sciences
Location: Nepal
University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Mila Shakya.