Biology subjects

Duong, V.

Publications and source records attributed to Duong, V..

18 recordsLinked to original sources

bioRxiv2026

Early Immune Hypoactivation and Persistent Innate Reprogramming Characterize Chronic Chikungunya Disease

Chikungunya virus (CHIKV) infection causes acute febrile illness and debilitating arthralgia, with up to 40-80% of patients developing chronic chikungunya disease characterized by persistent arthralgia and fatigue lasting months to years. The immunological mechanisms underlying this transition remain poorly understood. We performed longitudinal immune profiling of CHIKV-infected patients stratified by clinical outcome. Single-cell RNA sequencing of peripheral blood mononuclear cells collected during acute infection and six months post-infection was combined with multiplex plasma cytokine and flow cytometric analysis. Patients who later developed chronic symptoms were characterized by early innate immune hypoactivation during acute infection, characterized by reduced monocyte and dendritic cell frequencies, lower circulating IFN-, IL-6 and IL-8, and reduced antigen-presentation and interferon-associated transcriptional programs. This was accompanied by diminished adaptive immune activation, including reduced IL-17 and IL-21 and lower HLA-DR expression across multiple T-cell subsets. Cell-cell communication analysis further indicated impaired acute monocyte-centered immune coordination in chronic progressors, whereas non-chronic patients displayed stronger monocyte-driven innate-to-adaptive signaling. By six months, chronic patients showed persistent innate remodeling, including increased non-classical monocytes, altered plasmacytoid dendritic cell and natural killer cell transcriptional programs, elevated CXCL10, reduced IL-6 and MMP8, and emergence of NK-centered predicted communication networks. Longitudinal transcriptomic analysis further identified divergent immune recovery trajectories, most prominently in non-classical monocytes and plasmacytoid dendritic cells. Together, these findings suggest that chronic chikungunya disease is associated with early innate immune hypoactivation followed by persistent innate immune remodeling, providing insight into immune mechanisms that may contribute to post-viral chronic inflammatory syndromes.

immunology↗

bioRxiv2026

XL-MS and De Novo Protein Design Identified a Common Motif for TREM2 Binding

Apolipoprotein E (APOE) and Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are the two strongest genetic risk factors of late-onset Alzheimers disease. ApoE binds to the low-density lipoprotein receptor (LDLR) to facilitate the uptake of ApoE-lipoprotein particles. TREM2 is a cell surface receptor expressed on microglia in the brain. The activation of TREM2 is essential for microglia to carry out protective functions against AD pathology. Several studies have shown that TREM2 signaling is activated through direct interaction between TREM2 and ApoE. In addition to its important role in AD pathogenesis, the ApoE/TREM2 interaction has been shown to induce immunosuppression of neutrophils within the tumor microenvironment. Despite its clinical importance, a high-resolution molecular understanding of the complex remains elusive. Here, we carried out chemical cross-linking mass spectrometry (XL-MS) analysis of the ApoE3/TREM2ECD complex to identify intra- and inter-protein cross-links, which were used as restraints to guide integrative protein-protein docking. Our data support a binding model in which a helix-loop-helix motif within the ApoE3 hinge and C-terminal region forms a transient hydrophobic pocket that wraps around the hydrophobic tip of the TREM2 ectodomain. This model is further supported by de novo-designed mini-protein binders, which show the same binding mode as identified by our XL-MS experiment. These results establish a robust framework for developing mini-protein-based TREM2 agonists.

biophysics↗

bioRxiv2026

Sarbecovirus-associated gut microbiome instability in a natural bat reservoir

Sarbecoviruses, a subgenus of Betacoronavirus, display both respiratory and gastrointestinal tropism, suggesting potential interactions with host gut microbial communities. However, ecological signatures of infection in wild bats remain poorly understood. We investigated associations between Sarbecovirus infection status, gut microbiome structure, and diet composition in Rhinolophus shameli roosting in northeastern Cambodia. Fecal samples collected across dry and wet seasons (2023-2024) were subject to full-length 16S rRNA gene sequencing and arthropod DNA metabarcoding. Sarbecovirus-positive bats exhibited stable alpha diversity but consistent shifts in gut community composition and increased interindividual variability consistent with the Anna Karenina Principle, suggesting infection-associated destabilization of community assembly rather than diversity erosion. Infection status was associated with enrichment of Shigella and Escherichia species, taxa linked to inflammatory or epithelial stress states in bats. In contrast, dietary composition showed no strong global structuring by infection status and weak coupling with bacterial community structure, suggesting that trophic ecology is unlikely to be the main driver of the infection-associated microbiome signal. Although causal directionality cannot be inferred, our results reveal measurable and consistent microbiome restructuring associated with Sarbecovirus detection in a natural reservoir host and highlight the potential of microbiome profiling for monitoring wildlife disease processes.

ecology↗

bioRxiv2025

Repetitive Levodopa Treatment Drives Cell Type-Specific Striatal Adaptations Associated With Progressive Dyskinesia in Parkinsonian Mice

The use of levodopa to manage Parkinsons disease (PD) symptoms leads to levodopa-induced dyskinesia (LID) and other motor fluctuations, which worsen with disease progression and repeated treatment. Aberrant activity of striatal D1- and D2-expressing medium spiny neurons (D1-/D2-MSNs) underlies LID, but the mechanisms driving its progression remain unclear. Using the 6-OHDA mouse model of PD/LID, we combined in vivo and ex vivo recordings to isolate the effect of repeated treatment in LID worsening and other motor fluctuation-related phenotypes. We found that LID worsening is linked to potentiation of levodopa-evoked responses in both D1-/D2-MSNs, independent of changes in dopamine release or MSN intrinsic excitability. Instead, strengthening of glutamatergic synapses onto D1-MSNs emerged as a key driver. Moreover, we found changes in D2-MSN activity that specifically influenced LID duration, potentially contributing to motor fluctuations, which paralleled a reduction in D2R sensitivity. These findings reveal striatal adaptations contributing to worsening of levodopa-related complications.

neuroscience↗

bioRxiv2025

Characterization and evolutionary history of novel SARS-CoV-2-related viruses in bats from Cambodia

Circulating bat coronaviruses present a significant pandemic threat, yet our understanding of their genetic diversity and evolutionary dynamics remains limited. Over 3 years, we sampled 1,462 bats in Cambodias Steung Treng province, identifying extensive and diverse coronaviruses co-circulation. Using metatranscriptomic and amplicon sequencing, we generated 33 complete sarbecovirus genomes, revealing novel lineages that cluster into four distinct groups, each associated with different Rhinolophus bat species. Our analysis highlights rapid migration and recombination of sarbecovirus lineages over short distances and timescales. Of note, the receptor-binding domains of two novel viral groups exhibit high similarity to SARS-CoV-2, and pseudovirus assays confirmed the ability of this spike protein to mediate entry into cells expressing human ACE2, suggesting a potential zoonotic risk. The observed genetic diversity underscores the urgent need for continuous surveillance to identify high-risk animal-to-human interfaces and inform pandemic preparedness.

microbiology↗

bioRxiv2024

Monosynaptic ventral tegmental area glutamate projections to the locus coeruleus enhance aversive processing

Distinct excitatory synaptic inputs to the locus coeruleus (LC) modulate behavioral flexibility. Here we identify a novel monosynaptic glutamatergic input to the LC from the ventral tegmental area (VTA). We show robust VTA axonal projections provide direct glutamatergic transmission to LC. Despite weak synaptic summation, optogenetic activation of these axons enhances LC tonic firing and facilitates real-time and conditioned aversive behaviors. We hypothesized this projection may modulate synaptic integration with other excitatory inputs. We then used coincident VTA-LC photostimulation with local electrical stimulation and observed enhanced LC burst induction. To determine whether this integration also occurs in vivo, we took an analogous approach measuring reward-seeking behavior during unpredictable probabilistic punishment. Here, glutamatergic VTA-LC photostimulation during a concurrent noxious stimulus did not delay reward-seeking behavior, but increased probability of task failure. Together, we identified a novel VTA-LC glutamatergic projection that drives concurrent synaptic summation during salient stimuli to promote behavioral avoidance.

neuroscience↗

bioRxiv2024

Breaking free from the clocks tyranny restores memory to brain damaged flies

The relationship between sleep and memory is an active topic of investigation. In this context, we demonstrate that enhancing sleep restores memory to flies with ablated Mushroom Bodies (MB), a key memory center; this is consistent across several memory assays. Mapping the underlying circuitry reveals circadian modulation of a subset of Dopaminergic neurons (DANs) that modulate aversive learning. Using imaging, we show that MB-ablation disrupts, and sleep restores the time of day these neurons are most responsive. Knocking down the receptor for the clock output signal, Pigment-dispersing factor (Pdfr), in this subset of DANs restores memory to MB-ablated flies. Crucially, MB-ablation does not result in memory impairments in the absence of a functioning clock. Our results reveal neuromodulations key role in cognitive restoration, where sleep aids memory in damaged brains, but a functioning clock unexpectedly hinders this process.

neuroscience↗

bioRxiv2023

Photoswitchable binders enable temporal dissection of endogenous protein function

General methods for spatiotemporal control of specific endogenous proteins would be broadly useful for probing protein function in living cells. Synthetic protein binders that bind and inhibit endogenous protein targets can be obtained from nanobodies, designed ankyrin repeat proteins (DARPins), and other small protein scaffolds, but generalizable methods to control their binding activity are lacking. Here, we report robust single-chain photoswitchable DARPins (psDARPins) for bidirectional optical control of endogenous proteins. We created topological variants of the DARPin scaffold by computer-aided design so fusion of photodissociable dimeric Dronpa (pdDronpa) results in occlusion of target binding at baseline. Cyan light induces pdDronpa dissociation to expose the binding surface (paratope), while violet light restores pdDronpa dimerization and paratope caging. Since the DARPin redesign leaves the paratope intact, the approach was easily applied to existing DARPins for GFP, ERK, and Ras, as demonstrated by relocalizing GFP-family proteins and inhibiting endogenous ERK and Ras with optical control. Finally, a Ras-targeted psDARPin was used to determine that, following EGF-activation of EGFR, Ras is required for sustained EGFR to ERK signaling. In summary, psDARPins provide a generalizable strategy for precise spatiotemporal dissection of endogenous protein function.

biochemistry↗

bioRxiv2022

Structural basis for the simultaneous recognition of NEMO and acceptor ubiquitin by the HOIP NZF1 domain

Ubiquitination of NEMO by the linear ubiquitin chain assembly complex (LUBAC) is essential for activating the canonical NF-{kappa}B signaling pathway. While the NZF1 domain of the HOIP subunit of LUBAC recognizes the NEMO substrate, it is unclear how it cooperates with the catalytic domains in the ubiquitination process. Here, we report a crystal structure of NEMO in complex with HOIP NZF1 and linear diubiquitin chains, in which the two proteins bind to distinct sites on NEMO. Moreover, the NZF1 domain simultaneously interacts with NEMO and Ile44 surface of a proximal ubiquitin from a linear diubiquitin chain, where the C-term tail of the ubiquitin is in the proximity of the NEMO ubiquitination site (Lys285). We further propose a model for the linear ubiquitination of NEMO by HOIP. In the model, NZF1 binds the monoubiquitinated NEMO and recruits the catalytic domains to the ubiquitination site, thereby ensuring site-specific ubiquitination of NEMO.

biochemistry↗

bioRxiv2021

Robust and Functional Immunity up to 9 months after SARS-CoV-2 infection: a Southeast Asian longitudinal cohort

Assessing the duration of humoral and cellular immunity remains key to overcome the current SARS-CoV-2 pandemic, especially in understudied populations in least developed countries. Sixty-four Cambodian individuals with laboratory-confirmed infection with asymptomatic or mild/moderate clinical presentation were evaluated for humoral immune response to the viral spike protein and antibody effector functions during acute phase of infection and at 6-9 months follow-up. Antigen-specific B cells, CD4+ and CD8+ T cells were characterized, and T cells were interrogated for functionality at late convalescence. Anti-spike (S) antibody titers decreased over time, but effector functions mediated by S-specific antibodies remained stable. S- and nucleocapsid (N)-specific B cells could be detected in late convalescence in the activated memory B cell compartment and are mostly IgG+. CD4+ and CD8+ T cell immunity was maintained to S and membrane (M) protein. Asymptomatic infection resulted in decreased ADCC and frequency of SARS-CoV-2-specific CD4+ T cells at late convalescence. Whereas anti-S antibodies correlated with S-specific B cells, there was no correlation between T cell response and humoral immunity. Hence, all aspects of a protective immune response are maintained up to nine months after SARS-CoV-2 infection in the absence of re-infection. One sentence summaryFunctional immune memory to SARS-CoV-2, consisting of polyfunctional antibodies, memory B cells and memory T cells are maintained up to nine months in a South-East Asian cohort in the absence of re-infection.

immunology↗

bioRxiv2021

The dengue virus NS1 protein conveys pro-inflammatory signals by docking onto human high-density lipoproteins

The nonstructural NS1 protein is a virulence factor secreted by dengue virus (DENV)-infected cells. NS1 is known to alter the complement system, activate immune cells and perturb endothelial barriers. Here we show that pro-inflammatory signals are triggered by a high affinity complex formed between NS1 and human high-density lipoproteins (HDL). Electron microscopy images of the NS1-HDL complexes show spherical HDL particles with rod-shaped NS1 protrusions on their surface. These complexes are readily detectable in the plasma of hospitalized dengue patients using anti-apolipoprotein A-I (ApoA-I) antibodies specific of the HDL moiety. The functional reprogramming of HDL particles by the NS1 protein as a means to exacerbate systemic inflammation during DENV infection provides a new paradigm linking the human lipoprotein network to dengue pathogenesis.

microbiology↗

bioRxiv2021

A novel SARS-CoV-2 related coronavirus in bats from Cambodia

Knowledge of the origin and reservoir of the coronavirus responsible for the ongoing COVID-19 pandemic is still fragmentary. To date, the closest relatives to SARS-CoV-2 have been detected in Rhinolophus bats sampled in the Yunnan province, China. Here we describe the identification of SARS-CoV-2 related coronaviruses in two Rhinolophus shameli bats sampled in Cambodia in 2010. Metagenomic sequencing identified nearly identical viruses sharing 92.6% nucleotide identity with SARS-CoV-2. Most genomic regions are closely related to SARS-CoV-2, with the exception of a small region corresponding to the spike N terminal domain. The discovery of these viruses in a bat species not found in China indicates that SARS-CoV-2 related viruses have a much wider geographic distribution than previously understood, and suggests that Southeast Asia represents a key area to consider in the ongoing search for the origins of SARS-CoV-2, and in future surveillance for coronaviruses.

microbiology↗

bioRxiv2020

Coronavirus surveillance of wildlife in the Lao People's Democratic Republic detects viral RNA in rodents

Coronaviruses can become zoonotic as in the case of COVID-19, and hunting, sale, and consumption of wild animals in Southeast Asia facilitates an increased risk for such incidents. We sampled and tested rodents (851) and other mammals, and found Betacoronavirus RNA in 12 rodents. The sequences belong to two separate genetic clusters, and relate closely to known rodent coronaviruses detected in the region, and distantly to human coronaviruses OC43 and HKU1. Considering close human-wildlife contact with many species in and beyond the region, a better understanding of virus diversity is urgently needed for the mitigation of future risks.

microbiology↗

bioRxiv2020

Rapid metagenomic characterization of a case of imported COVID-19 in Cambodia

Rapid production and publication of pathogen genome sequences during emerging disease outbreaks provide crucial public health information. In resource-limited settings, especially near an outbreak epicenter, conventional deep sequencing or bioinformatics are often challenging. Here we successfully used metagenomic next generation sequencing on an iSeq100 Illumina platform paired with an open-source bioinformatics pipeline to quickly characterize Cambodias first case of COVID-2019.

microbiology↗

bioRxiv2019

A new high-throughput tool to screen mosquito-borne viruses in Zika virus endemic/epidemic areas

Mosquitoes are vectors of arboviruses affecting animal and human health. Arboviruses circulate primarily within an enzootic cycle and recurrent spillovers contribute to the emergence of human-adapted viruses able to initiate an urban cycle involving anthropophilic mosquitoes. The increasing volume of travel and trade offers multiple opportunities for arbovirus introduction in new regions. This scenario has been exemplified recently with the Zika pandemic. To incriminate a mosquito as vector of a pathogen, several criteria are required such as the detection of natural infections in mosquitoes. In this study, we used a high-throughput chip based on the BioMarkTM Dynamic arrays system capable of detecting 64 arboviruses in a single experiment. A total of 17,958 mosquitoes collected in Zika-endemic/epidemic countries (Brazil, French Guiana, Guadeloupe, Suriname, Senegal, and Cambodia) were analyzed. Here we show that this new tool can detect endemic and epidemic viruses in different mosquito species in an epidemic context. Thus, this fast and low-cost method can be suggested as a novel epidemiological surveillance tool to identify circulating arboviruses.

molecular biology↗

bioRxiv2018

Worldwide survey reveals lower susceptibility of African Aedes aegypti mosquitoes to diverse strains of Zika virus

Zika virus (ZIKV) is a flavivirus mainly transmitted to humans through the bite of infected Aedes aegypti mosquitoes. First isolated in Uganda in 1947, ZIKV was shown to circulate in enzootic sylvatic cycles in Africa and Asia for at least half a century before the first reported human epidemic occurred in 2007 on the Pacific island of Yap, Micronesia. Subsequently, larger ZIKV outbreaks were recorded in French Polynesia and other South Pacific islands during 2013-2014. In 2015, ZIKV reached Brazil from where it rapidly spread across the Americas and the Caribbean, causing hundreds of thousands of human cases. The factors that have fueled the explosiveness and magnitude of ZIKV emergence in the Pacific and the Americas are poorly understood. Reciprocally, the lack of major human epidemics of ZIKV in regions with seemingly favorable conditions, such as Africa or Asia, remains largely unexplained. To evaluate the potential contribution of vector population diversity to ZIKV epidemiological patterns, we established dose-response curves for eight field-derived Ae. aegypti populations representing the global range of the species, following experimental exposure to six low-passage ZIKV strains spanning the current viral genetic diversity. Our results reveal that African Ae. aegypti are significantly less susceptible than non-African Ae. aegypti across all ZIKV strains tested. We suggest that low susceptibility of vector populations may have contributed to prevent large-scale human transmission of ZIKV in Africa.

epidemiology↗

bioRxiv2017

Dengue modeling in rural Cambodia: statistical performance versus epidemiological relevance

Dengue dynamics are shaped by the complex interplay between several factors, including vector seasonality, interaction between four virus serotypes, and inapparent infections. However, paucity or quality of data do not allow for all of these to be taken into account in mathematical models. In order to explore separately the importance of these factors in models, we combined surveillance data with a local-scale cluster study in the rural province of Kampong Cham (Cambodia), in which serotypes and asymptomatic infections were documented. We formulate several mechanistic models, each one relying on a different set of hypotheses, such as explicit vector dynamics, transmission via asymptomatic infections and coexistence of several virus serotypes. Models are confronted with the observed time series using Bayesian inference, through Markov chain Monte Carlo. Model selection is then performed using statistical information criteria, but also by studying the coherence of epidemiological characteristics (reproduction numbers, incidence proportion, dynamics of the susceptible class) in each model. Considering the available data, our analyses on transmission dynamics in a rural endemic setting highlight both the importance of using two-strain models with interacting effects and the lack of added value of incorporating vector and explicit asymptomatic components.

epidemiology↗

bioRxiv2017

Diverse laboratory colonies of Aedes aegypti harbor the same adult midgut bacterial microbiome

BackgroundHost-associated microbes, collectively known as the microbiota, play an important role in the biology of multicellular organisms. In mosquito vectors of human pathogens, the gut bacterial microbiota influences vectorial capacity and has become the subject of intense study. In laboratory studies of vector biology, genetic effects are often inferred from differences between geographically and genetically diverse colonies of mosquitoes that are reared in the same insectary. It is unclear, however, to what extent genetic effects can be confounded by uncontrolled differences in the microbiota composition among mosquito colonies. To address this question, we used 16S metagenomics to compare the midgut bacterial microbiome of six recent laboratory colonies of Aedes aegypti representing the geographical range and genetic diversity of the species.\n\nResultsWe found that the diversity, abundance, and community structure of the midgut bacterial microbiome was remarkably similar among the six different colonies of Ae. aegypti, regardless of their geographic origin. We also confirmed the relatively low complexity of bacterial communities inhabiting the mosquito midgut.\n\nConclusionsOur finding that geographically diverse colonies of Ae. aegypti reared in the same insectary harbor a similar gut bacterial microbiome supports the conclusion that the gut microbiota of adult mosquitoes is environmentally determined regardless of the host genotype. Thus, uncontrolled differences in microbiota composition are unlikely to represent a significant confounding factor in genetic studies of vector biology.

genetics↗