Biology subjects

Leung, P.

Publications and source records attributed to Leung, P..

5 recordsLinked to original sources

bioRxiv2026

Census and genetic analysis of the United States marmoset population

The common marmoset (Callithrix jacchus), a small monkey native to Brazil, has been used as a biomedical model in the United States (US) since the 1950s, yet the origins, genomic diversity, and population structure of current colonies remain poorly defined. Through the NIH Marmoset Coordinating Center, we registered and sampled most US research marmosets ([~]2,300 living animals) and assembled pedigrees and historical records for >10,000 individuals. We present a resource of >800 whole-genome sequences, largely from US colonies. These data reveal an unexpected population structure that predates the establishment of research colonies. Indeed, this population structure mirrors variation found in marmosets across Brazil. Leveraging sequenced families, we generate the first pedigree-based recombination map and improved estimates of de novo mutation processes for this species. Our insights into genetic diversity, structure, and inbreeding will guide colony management, inform disease modelling and strengthen the marmosets standing as a biomedical model. Further, this work demonstrates how coordinated efforts across colonies can enable a self-sustaining "living laboratory", supporting data sharing and well-powered studies beyond the reach of single institutions.

genetics↗

bioRxiv2024

Global prevalence of naturally occurring Wolbachia in field-collected Aedes mosquitoes: a systematic review and meta-analysis

BackgroundDengue is one of the leading causes of morbidity worldwide. Wolbachia-mediated dengue biocontrol has emerged as a novel strategy in recent decades and depends on a lack of Wolbachia in the natural populations of Aedes mosquitoes. Through a systematic review of the published literature, this study sought to estimate the natural occurrence of Wolbachia among field-collected Aedes mosquitoes worldwide. MethodsWe conducted hand and systematic searches from PubMed, the Cochrane Library, and Google Scholar for all relevant published articles on Wolbachia infection in Aedes mosquitoes published before September 12, 2024. The prevalence estimates were analysed using a random effects meta-analysis, and a random effects meta-regression was performed to determine sources of heterogeneity in prevalence estimates. ResultsTwenty-three studies with 16,997 field-collected Aedes mosquitoes from different countries worldwide were included. The meta-analysis revealed a global pooled prevalence of natural Wolbachia infection in Aedes mosquitoes of 57.7% (95% CI: 41.0-72.8%), which was six times higher in Ae. albopictus than Ae. aegypti (p <0.001) and ranged from 6.0% (95% CI: 2.6-13.1%) in Ae. aegypti to 87.1% (95% CI: 78.0-92.8%) in Ae. albopictus. Continentally, Asia had the highest percentage of Wolbachia infection in Ae. aegypti (7.1%), followed by Europe (5.0%), North America (1.9%), and Africa (0.7%). Similarly, Asia had the highest prevalence of Wolbachia in Ae. albopictus (95.5%), followed by Europe (94.8%), North America (91.6%), South America (85.2%), and Africa (71.6%). Overall, dengue incidence was negatively related to Wolbachia prevalence (B = -0.0006, p = 0.0281). Species wise, infection rates in Ae. aegypti were significantly higher among females than males (OR = 1.72; 95% CI = 1.01, 2.92, p = 0.046), while there was no difference between males and females in Ae. albopictus (p = 0.098). Furthermore, Wolbachia infection rates in Ae. albopictus were inversely correlated with dengue incidence ({beta} = -0.0013, p <0.01) but not in Ae. aegypti (p = 0.0984). In contrast, higher temperature was negatively associated with Wolbachia prevalence in Ae. aegypti but not in Ae. albopictus. In contrast, higher temperature was negatively associated with Wolbachia prevalence in Ae. aegypti ({beta} = --2.5736, p <0.001) but not in Ae. albopictus (p = 0.7050). ConclusionAedes mosquitoes had a high and variable prevalence of naturally occurring Wolbachia, and this was negatively correlated with dengue incidence across countries. While the natural infection of Ae. albopictus is more common, detection in Ae. aegypti may reflect contamination and require high-quality multicentre studies to verify the above findings.

evolutionary biology↗

bioRxiv2024

Temporal dynamics of viral fitness and the adaptive immune response in HCV infection

Numerous studies have shown that viral variants that elude the host immune response may incur a fitness expense, diminishing the survival of the viral strain within the host, and the capacity of the variant to survive future transmission events. However, this generic definition can be further divided into two categories where intrinsic fitness describes the viral fitness without the influence of any immune pressure and effective fitness considers both intrinsic fitness with the influence of host immune pressure. Furthermore, co-occurring mutations outside the epitope regions targeted by the immune response may increase or decrease the likelihood of survival of the variant (known as epistasis). Analysis of viral fitness and epistasis over the non-structural protein regions is lacking for hepatitis C virus (HCV). Here, using a rare cohort of subjects very recently infected with HCV, we build upon our prior investigations by integrating mathematical modelling and experimental data to examine the interplay between the evolving transmitted/founder (T/F) viruses, the adaptive immune response, viral fitness, and co-occurring mutations. We show that viral fitness decreases during the first 90 days post-infection (DPI) associated with the magnitude of CD8+ T-cell responses and the initial level of diversification. Thereafter, viral fitness rebounds in a complex pattern of evolution characterized by multiple sets of co-occurring mutations. Finally, we show that an early and strong CD8+ T-cell response in the absence of neutralizing antibodies (nAbs) imposes a strong selective force on the T/F virus population, enabling the virus to escape and establish chronic infection. Understanding these dynamics is highly relevant for HCV vaccine design and supports a vaccine strategy that induces broad immunity targeting both T and B cell responses.

immunology↗

bioRxiv2021

Single cell multi-omics reveals early elevated function and multiple fates within human progenitor exhausted CD8+ T cells

T-cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of subjects with primary infection using single cell multi-omics to identify the functions and phenotypes of HCV-specific CD8+ T cells. Early elevated IFN-{gamma} response against the transmitted virus was associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome we discovered progenitors of early-exhaustion with intermediate expression of PD-1. Intra clonal analysis revealed distinct trajectories with multiple fates suggesting evolutionary plasticity of precursor cells. These findings challenge current paradigm on the contribution of CD8+ T cells to HCV disease outcome and provide data for future studies on T-cell differentiation in human infections. One sentence summaryProgenitors of T-cell exhaustion in acute HCV infection

immunology↗

bioRxiv2018

TCR-pMHC bond length controls TCR ligand discrimination

T-cell receptors (TCRs) detect specifically and sensitively a small number of agonist peptide-major histocompatibility complexes (pMHCs) from an ocean of structurally similar self-pMHCs to trigger antigen-specific adaptive immune responses1-4. Despite intense efforts, the mechanism underlying TCR ligand discrimination remains a major unanswered question in immunology. Here we show that a TCR discriminates between closely related peptides by forming TCR-pMHC bonds with different lengths, which precisely control the accessibility of CD3{zeta} immunoreceptor tyrosine-based activation motifs (ITAMs) for phosphorylation. Using in situ fluorescence resonance energy transfer (FRET)3,5, we measured the intermolecular length of single TCR-pMHC bonds and the intramolecular distance of individual TCR-CD3{zeta} complexes at the membrane of live primary T cells. We found that an agonist forms a short TCR-pMHC bond to pull the otherwise sequestered CD3{zeta} off the inner leaflet of the plasma membrane, leading to full exposure of its ITAMs for strong phosphorylation. By contrast, a structurally similar weaker peptide forms a longer bond with the TCR, resulting in partial dissociation of CD3{zeta} from the membrane and weak phosphorylation. Furthermore, we found that TCR-pMHC bond length determines 2D TCR binding kinetics and affinity, T-cell calcium signaling and T-cell proliferation, governing the entire process of signal reception, transduction and regulation. Thus, our data reveal the fundamental mechanism by which a TCR deciphers the structural differences between foreign antigens and self-peptides via TCR-pMHC bond length to initiate different TCR signaling for ligand discrimination.

immunology↗