Biology subjects

O'Connor, S.

Publications and source records attributed to O'Connor, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Fluorescent Ubiquitination-based Trbl Turnover Indicator (FUTTI): A tool to detect activity of the Tribbles pseudokinase in vivo

Targeted protein turnover of the transcription factor C/EBP is enhanced by the Tribbles (Trib) pseudokinase family of adaptor proteins, which bind to a conserved degron motif in C/EBP substrate and recruit a cognate COP1 E3 ligase to ubiquitinate C/EBP for degradation. We identified a conserved degron in the Drosophila C/EBP ortholog Slbo and fused this motif to a fluorescent protein (GFP or RFP) under the control of a constitutive promoter. Transgenic flies expressing this fluorescent protein (FP)::degron transgene, which we call the Fluorescent Ubiquitination-based Trbl Turnover Indicator (or FUTTI) sensor, showed reduced levels of fluorescence in response to increased levels of Drosophila Tribbles (Trbl) and conversely, increased levels when Trbl activity was reduced. Mutations in the Trbl conserved pseudokinase substrate binding pocket and in a divergent PEST-like motif in the C-terminal tail region disrupted Trbl activity in the FUTTI assay. These data indicate that FUTTI will be a valuable tool to identify sites of Trbl activity in vivo and the critical features of the protein required for function.

genetics↗

bioRxiv2025

Tuning the open-close equilibrium of Cereblon with small molecules influences protein degradation

Most PROTACs and molecular glue degraders currently approved or in clinical trials recruit Cereblon (CRBN) as the ubiquitin E3 ligase. Upon binding ligands and molecular glues, CRBN undergoes a significant structural rearrangement from an open to closed state, defined by the positioning of the thalidomide-binding domain (TBD) with respect to the Lon domain. However, the exact molecular basis for this ligand-induced conformational change and its implication to neo-substrate degradation remain elusive. During our campaign to discover novel CRBN binders, we found hits exhibiting distinct biophysical behaviour from classical thalidomide-based ligands. By combining orthogonal biophysical methods of differential scanning fluorimetry, isothermal titration calorimetry, and small-angle X-ray scattering, supported by X-ray crystallography and cryo-EM structures of ligand-bound complexes, we classify CRBN binders between those that can induce CRBN closure, and those that cannot. Mutational studies identify key residues in the CRBN ligand binding pocket and N-terminal belt that are essential for the Lon and TBD domains to come together in the closed state. Finally, we show that the probability to yield active degrader molecules is greatly influenced by whether binders can or cannot induce CRBN closure. Together, our study reveals new molecular insights into the structural basis for how CRBN open-closed equilibrium is directly modulated by compound binding and impact target degradability by CRBN, with important implications to the design of PROTACs and molecular glue degraders.

biochemistry↗

bioRxiv2025

Characterization of quiescent subpopulations and proliferative compartments in glioblastoma

Glioblastoma (GBM) quiescent (Q) cell populations are hypothesized to contain cancer stem-like cells (CSC) that drive tumor growth, cellular heterogeneity, and recurrence. However, GBM tumors do not neatly resolve into developmental hierarchies and Q stem-like activities are difficult to assess. Here, we evaluated tumor Q subpopulations in patient-derived GBM xenograft tumors using live cell reporters, DNA label retention assays, and single cell genomics. Compared to adult neural stems cells (NSCs), GBM Q populations contain hybrid transcriptional states composed of networks found in both dormant and activated adult NSCs, resulting in constitutive expression of key Q egress transcription factors and their targets (e.g., AP-1 and CCND1/2). As a result, even the longest Q-residing cells ([~]12 days) in xenograft tumors continuously cycle and fail to enter dormant Q states. We provide evidence and hypothesize that transient Q states in primary tumors arise as part of distinct proliferative compartments rather than deterministic developmental hierarchies driven by CSC activity. We further speculate that increases in basal translation rates drive Q instability in GBM tumors.

cancer biology↗

bioRxiv2024

Demonstrating Soft X-Ray Tomography in the lab for correlative cryogenic biological imaging using X-rays and light microscopy

Soft X-ray tomography (SXT) enables native-contrast three-dimensional (3D) imaging of fully hydrated, cryogenically preserved biological samples, revealing ultrastructural details without the need for staining, embedding, or sectioning. Traditionally available only at synchrotron facilities, recent advances in laser-driven plasma sources have led to the development of compact soft X-ray microscopes, such as the SXT-100. The SXT-100 achieves imaging resolutions down to 54 nm full-pitch, with tomograms acquired in 30 minutes to two hours. Integrated with an epifluorescence microscope, the SXT-100 facilitates correlative workflows by bridging fluorescence and electron microscopy while preserving the structural integrity of vitrified samples. We demonstrate the capabilities of the SXT-100 through various use cases, including imaging Euglena gracilis, Saccharomyces cerevisiae yeast cells, and nanoparticles in mammalian cells. The relatively short tomogram acquisition times, the virtually non-destructive nature of soft X-ray tomography, and its quantitative imaging capabilities underscore its potential as a powerful tool for advanced biological imaging. Future developments promise enhanced throughput and deeper integration with emerging correlative imaging modalities, and a wider variety of sample types including tissue.

biophysics↗

bioRxiv2024

Ozboneviz: An Australian Precedent in FAIR 3D Imagery and Extended Biodiversity Collections

Billions of specimens are in biodiversity collections worldwide, and this infrastructure is crucial for research on Earths natural history. Three-dimensional (3D) imagery of specimens is an increasingly important part of the Digital Extended Specimen network of metadata. Open access, high fidelity 3D imagery of biodiversity specimens improves researcher efficiency, equity and increases public engagement with collections. We introduce Ozboneviz, an open access collection of FAIR (Findable, Accessible, Interoperable, Reusable) 3D imagery aiming to enhance research capacity in Australasian vertebrate skeletal morphology. Ozboneviz is an Australian test case demonstrating the feasibility of creating multi-institutional, FAIR 3D biodiversity imagery collections. We outline project design, challenges, and use by the international research community. We then discuss the urgent need for investment in infrastructure and curatorial support to progress the digitisation of Australian biodiversity collections in a way that maximises stakeholder benefit and facilitates 3D data discoverability and retrieval.

zoology↗

bioRxiv2024

Postglacial recolonization of the Southern Ocean by elephant seals occurred from multiple glacial refugia

The Southern Ocean is warming more rapidly than other parts of our planet. How this regions endemic biodiversity will respond to such changes can be illuminated by studying past events, through genetic analyses of time-series data sets including historic and fossil remains. Archaeological and subfossil remains show that the southern elephant seal (Mirounga leonina) was common along the coasts of Australia and New Zealand in the recent past. This species is now mostly confined to sub-Antarctic islands and the southern tip of South America. We analysed ancient seal samples from Australia (Tasmania), New Zealand, and the Antarctic mainland to examine how southern elephant seals have responded to a changing climate and anthropogenic pressures during the Holocene. Our analyses show that these seals formed part of a broader Australasian lineage, comprising seals from all sampled locations from the south Pacific sector of the Southern Ocean. Our study demonstrates that southern elephant seal populations have dynamically altered both range and population sizes under climatic and human pressures, over surprisingly short evolutionary timeframes for such a large, long-lived mammal. Significance StatementGenetic data, alongside historic, archaeological, and subfossil remains show that Australasian populations of the southern elephant seal have been shaped by range expansions and contractions following the Last Glacial Maximum, with subsequent contractions during the late Holocene. These expansion and contraction events are likely to have been a direct result of climate change-induced habitat expansion and contraction, along with Indigenous and European sealing. Prehistoric climate change and more recent human pressures have substantially altered the geographic distribution and population size of southern elephant seals over short evolutionary timescales.

ecology↗

bioRxiv2024

Genome-based discovery of pachysiphine synthases in Tabernaemontana elegans

Plant specialized metabolism represents an inexhaustible source of active molecules, some of which have been used in human health for decades. Among these, monoterpene indole alkaloids (MIAs) include a wide range of valuable compounds with anticancer, antihypertensive, or neuroactive properties. This is particularly the case for the pachysiphine derivatives which show interesting antitumor and anti-alzheimer activities but accumulate at very low levels in several Tabernaemontana species. Unfortunately, genome data in Tabernaemontanaceae are lacking and knowledge on the biogenesis of pachysiphine-related MIAs in planta remains scarce, limiting the prospects for biotechnological supply of many pachysiphine-derived biopharmaceuticals. Here, we report a raw version of the toad tree (Tabernaemontana elegans) genome sequence. These new genomic resources led to the identification and characterization of a couple of genes encoding cytochrome P450 with pachysiphine synthase activity. Our phylogenomic and docking analyses highlights the different evolutionary processes that have been recruited to epoxidize the pachysiphine precursor tabersonine at a specific position and in a dedicated orientation, thus enriching our understanding of the diversification and speciation of the MIA metabolism in plants. These gene discoveries also allowed us to engineer the synthesis of MIAs in yeast through the combinatorial association of metabolic enzymes resulting in the tailor-made synthesis of non-natural MIAs. Overall, this work represents a step forward for the future supply of pachysiphine-derived drugs by microbial cell factories. Significance StatementWhile pachysiphine is a monoterpene indole alkaloid of high interest and the precursor of an anti-Alzheimer compound, its biosynthesis involving the epoxidation of tabersonine remains uncharacterized. By sequencing and assembling the genome of Tabernaemontana elegans, we identified two P450s exhibiting a pachysiphine synthase activity that we modelized to explore the evolutionary scenario leading to the acquisition of this expoxidase activity; and used to engineer yeast cell factories for securing pachysiphine supply and producing new-to-nature alkaloids.

plant biology↗

bioRxiv2024

The genetic origins and impacts of historical Papuan migrations into Wallacea

The tropical archipelago of Wallacea was first settled by anatomically modern humans (AMH) by 50 thousand years ago (kya), with descendent populations thought to have remained genetically isolated prior to the arrival of Austronesian seafarers around 3.5 kya. Modern Wallaceans exhibit a longitudinal countergradient of Papuan- and Asian-related ancestries widely considered as evidence for mixing between local populations and Austronesian seafarers, though converging multidisciplinary evidence suggests that the Papuan-related component instead comes primarily from back-migrations from New Guinea. Here, we reconstruct Wallacean population genetic history using more than 250 newly reported genomes from 12 Wallacean and three West Papuan populations and confirm that the vast majority of Papuan-related ancestry in Wallacea ([~]75-100%) comes from prehistoric migrations originating in New Guinea and only a minor fraction is attributable to the founding AMH settlers. Mixing between Papuan and local Wallacean lineages appear to have been confined to the western and central parts of the archipelago and likely occurred contemporaneously with the widespread introduction of genes from Austronesian seafarers--which now comprise between [~]40-85% of modern Wallacean ancestry--though dating historical admixture events remains challenging due to mixing continuing into the Historical Period. In conjunction with archaeological and linguistic records, our findings point to a dynamic Wallacean population history that was profoundly reshaped by the spread of Papuan genes, languages, and culture in the past 3,500 years.

evolutionary biology↗

bioRxiv2024

Identification of Fasnall as a therapeutically effective Complex I inhibitor

Proliferating cancer cells actively utilize anabolic processes for biomass production, including de novo biosynthesis of amino acids, nucleotides, and fatty acids. The key enzyme of the fatty acid biosynthesis pathway, fatty acid synthase (FASN), is widely recognized as a promising therapeutic target in cancer and other health conditions1,2. Here, we establish a metabolic signature of FASN inhibition using a panel of pharmacological inhibitors (GSK2194069, TVB-2640, TVB-3166, C75, cerulenin, and Fasnall). We find that the activity of commonly used FASN inhibitors is inconsistent with the metabolic signature of FASN inhibition (accumulation of malonate, succinate, malonyl coenzyme A, succinyl coenzyme A, and other metabolic perturbations). Moreover, we show that one of these putative FASN inhibitors, Fasnall, is a respiratory Complex I inhibitor that mimics FASN inhibition through NADH accumulation and consequent depletion of the tricarboxylic acid cycle metabolites. We demonstrate that Fasnall impairs tumor growth in several oxidative phosphorylation-dependent cancer models, including combination therapy-resistant melanoma patient-derived xenografts. Fasnall administration does not reproduce neurological side effects in mice reported for other Complex I inhibitors3,4. Our results have significant implications for understanding the FASN role in human health and disease and provide evidence of therapeutic potential for Complex I inhibitors with fast systemic clearance. Our findings also highlight the continuing need for validation of small molecule inhibitors to distinguish high-quality chemical probes and to expand the understanding of their application.

cancer biology↗

bioRxiv2023

Mathematical modeling indicates that regulatory inhibition of CD8+ T cell cytotoxicity can limit efficacy of IL-15 immunotherapy in cases of high pre-treatment SIV viral load

Immunotherapeutic cytokines can activate immune cells against cancers and chronic infections. N-803 is an IL-15 superagonist that expands CD8+ T cells and increases their cytotoxicity. N-803 also temporarily reduced viral load in a limited subset of non-human primates infected with simian immunodeficiency virus (SIV), a model of HIV. However, viral suppression has not been observed in all SIV cohorts and may depend on pre-treatment viral load and the corresponding effects on CD8+ T cells. Starting from an existing mechanistic mathematical model of N-803 immunotherapy of SIV, we develop a model that includes activation of SIV-specific and non-SIV-specific CD8+ T cells by antigen, inflammation, and N-803. Also included is a regulatory counter-response that inhibits CD8+ T cell proliferation and function, representing the effects of immune checkpoint molecules and immunosuppressive cells. We simultaneously calibrate the model to two separate SIV cohorts. The first cohort had low viral loads prior to treatment ({approx}3-4 log viral RNA copy equivalents (CEQ)/mL), and N-803 treatment transiently suppressed viral load. The second had higher pre-treatment viral loads ({approx}5-7 log CEQ/mL) and saw no consistent virus suppression with N-803. The mathematical model can replicate the viral and CD8+ T cell dynamics of both cohorts based on different pre-treatment viral loads and different levels of regulatory inhibition of CD8+ T cells due to those viral loads (i.e. initial conditions of model). Our predictions are validated by additional data from these and other SIV cohorts. While both cohorts had high numbers of activated SIV-specific CD8+ T cells in simulations, viral suppression was precluded in the high viral load cohort due to elevated inhibition of cytotoxicity. Thus, we mathematically demonstrate how the pre-treatment viral load can influence immunotherapeutic efficacy, highlighting the in vivo conditions and combination therapies that could maximize efficacy and improve treatment outcomes. Author SummaryImmunotherapy bolsters and redirects the immune system to fight chronic infections and cancers. However, the effectiveness of some immunotherapies may depend on the level of pre-treatment inflammation and the corresponding presence of regulatory cells and immune checkpoint molecules that normally function to prevent immune overreaction. Here, we consider two previously published cohorts of macaques who were given the immunotherapeutic N-803 to treat Simian Immunodeficiency Virus, an analog of Human Immunodeficiency Virus (HIV). One cohort had low viral loads before treatment, and N-803 temporarily suppressed viral loads. The second cohort had high viral loads that did not consistently decrease with N-803 treatment. In this work, we demonstrate with a mathematical model how these two distinct outcomes can arise due only to the different viral loads and the corresponding immune activation and regulatory response. In the model, we find that the key limiting factor is the direct inhibition of the cytotoxic action of immune cells by immune checkpoint molecules. This model indicates that simultaneous blockade of immune checkpoint molecules may be necessary for effective application of N-803 for the treatment of HIV. This and similar models can inform the design of such combination therapies for cancer and chronic infection.

systems biology↗

bioRxiv2022

An international scholastic network to generate LexA enhancer-trap lines for Drosophila

Conditional gene regulation in Drosophila through binary expression systems like the LexA-LexAop system provides a superb tool for investigating gene and tissue function. To increase the availability of defined LexA enhancer trap insertions, we present molecular, genetic and tissue expression studies of 301 novel Stan-X LexA enhancer traps derived from mobilization of the index SX4 line. This includes insertions into distinct loci on the X, II and III chromosomes that were not previously associated with enhancer traps or targeted LexA constructs, an insertion into ptc, and eleven insertions into natural transposons. A subset of enhancer traps was expressed in CNS neurons known to produce and secrete insulin, an essential regulator of growth, development and metabolism. Fly lines described here were generated and characterized through studies by students and teachers in an international network of genetics classes at public, independent high schools, and universities serving a diversity of students, including those underrepresented in science. Thus, a unique partnership between secondary schools and university-based programs has produced and characterized novel resources in Drosophila, establishing instructional paradigms devoted to unscripted experimental science.

genetics↗

bioRxiv2022

KAT5 activity regulates G0-like states in human gliomas

In solid tumors, G0-like states are likely critical for maintaining developmental hierarchies and cellular heterogeneity and promoting tumor growth/recurrence, yet little is known about tumor G0 states or regulation of their ingress/egress. To discover G0-like states and their regulators for glioblastoma (GBM), we analyzed G0 populations in an orthotopic model of GBM using single cell RNA-seq and performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) for genes that trap cells in G0 when inhibited. We identify the protein acetyltransferase KAT5 as a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states. KAT5 activity suppresses the emergence of non-dividing subpopulations with oligodendrocyte progenitor and radial glial cell characteristics both in vitro and in a human GSC brain tumor model. In primary gliomas, KAT5 activity is dynamic with KAT5low tumor cells displaying quiescent properties, while KAT5 activity overall increases from low to high grade tumors and is associated with worse patient outcomes.

cancer biology↗

bioRxiv2021

Ancient genomes from the last three millennia support multiple human dispersals into Wallacea

Previous research indicates that the human genetic diversity found in Wallacea - islands in present-day Eastern Indonesia and Timor-Leste that were never part of the Sunda or Sahul continental shelves - has been shaped by complex interactions between migrating Austronesian farmers and indigenous hunter-gatherer communities. Here, we provide new insights into this regions demographic history based on genome-wide data from 16 ancient individuals (2600-250 yrs BP) from islands of the North Moluccas, Sulawesi, and East Nusa Tenggara. While the ancestry of individuals from the northern islands fit earlier views of contact between groups related to the Austronesian expansion and the first colonization of Sahul, the ancestry of individuals from the southern islands revealed additional contributions from Mainland Southeast Asia, which seems to predate the Austronesian admixture in the region. Admixture time estimates for the oldest individuals of Wallacea are closer to archaeological estimates for the Austronesian arrival into the region than are admixture time estimates for present-day groups. The decreasing trend in admixture times exhibited by younger individuals supports a scenario of multiple or continuous admixture involving Papuan- and Asian-related groups. Our results clarify previously debated times of admixture and suggest that the Neolithic dispersals into Island Southeast Asia are associated with the spread of multiple genetic ancestries.

genomics↗

bioRxiv2020

AGO HITS-CLIP in Adipose Tissue Reveals miR-29 as a Post-Transcriptional Regulator of Leptin

MicroRNAs (miRNAs) are short, non-coding RNAs that associate with Argonaute (AGO) to regulate mRNA stability and translation. While individual miRNAs have been shown to play important roles in white and brown adipose tissue in normal physiology and disease1,2,3, a comprehensive analysis of miRNA activity in these tissues has not been performed. We used high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) to comprehensively characterize the network of high-confidence, in vivo mRNA:miRNA interactions across white and brown fat, revealing over 100,000 unique miRNA binding sites. Targets for each miRNA were ranked to generate a catalog of miRNA binding activity, and the miR-29 family emerged as a top regulator of adipose tissue gene expression. Among the top targets of miR-29 was leptin, an adipocyte-derived hormone that acts on the brain to regulate food intake and energy expenditure4. Two independent miR-29 binding sites in the leptin 3-UTR were validated using luciferase assays, and miR-29 gain and loss-of-function modulated leptin mRNA and protein secretion in primary adipocytes. In mice, miR-29 abundance inversely correlated with leptin levels in two independent models of obesity. This work represents the only experimentally generated miRNA targetome in adipose tissue and identifies the first known post-transcriptional regulator of leptin. Future work aimed at manipulating miR-29:leptin binding may provide a therapeutic opportunity to treat obesity and its sequelae.

cell biology↗

bioRxiv2018

Uncoupled activation and cyclisation in catmint reductive terpenoid biosynthesis

Terpene synthases typically form complex molecular scaffolds by concerted activation and cyclization of linear starting materials in a single enzyme active site. Here we show that iridoid synthase, an atypical reductive terpene synthase, catalyses the activation of its substrate 8-oxogeranial into a reactive enol intermediate but does not catalyse the subsequent cyclisation into nepetalactol. This discovery led us to identify a class of nepetalactol-related short-chain dehydrogenase enzymes (NEPS) from catmint (Nepeta mussinii) which catalyse the stereoselective cyclisation of the enol intermediate into nepetalactol isomers. Subsequent oxidation of nepetalactols by NEPS1 provides nepetalactones, metabolites that are well known for both insect-repellent activity and euphoric effect in cats. Structural characterisation of the NEPS3 cyclase reveals it binds to NAD+ yet does not utilise it chemically for a non-oxidoreductive formal [4+2] cyclisation. These discoveries will complement metabolic reconstructions of iridoid and monoterpene indole alkaloid biosynthesis.

biochemistry↗

bioRxiv2018

Zika viruses of both African and Asian lineages cause fetal harm in a vertical transmission model

Congenital Zika virus (ZIKV) infection was first linked to birth defects during the American outbreak 1-3. It has been proposed that mutations unique to the Asian/American-genotype explain, at least in part, the ability of Asian/American ZIKV to cause congenital Zika syndrome (CZS) 4,5. Recent studies identified mutations in ZIKV infecting humans that arose coincident with the outbreak in French Polynesia and were stably maintained during subsequent spread to the Americas 5. Here we show that African ZIKV can infect and harm fetuses and that the S139N mutation that has been associated with the American outbreak is not essential for fetal harm. Our findings, in a vertical transmission mouse model, suggest that ZIKV will remain a threat to pregnant women for the foreseeable future, including in Africa, southeast Asia, and the Americas. Additional research is needed to better understand the risks associated with ZIKV infection during pregnancy, both in areas where the virus is newly endemic and where it has been circulating for decades.

microbiology↗

bioRxiv2018

Pre-existing SIV Infection Increases Susceptibility to Tuberculosis in Mauritian Cynomolgus Macaques

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is the leading cause of death among HIV positive patients. The precise mechanisms by which HIV impairs host resistance to a subsequent M.tb infection are unknown. We modeled this co-infection in Mauritian cynomolgus macaques (MCM) using SIV as an HIV surrogate. We infected seven MCM with SIVmac239 intrarectally and six months later co-infected them via bronchoscope with ~10 CFU M.tb. Another eight MCM were infected with M.tb alone. TB progression was monitored by clinical parameters, by culturing bacilli in gastric and bronchoalveolar lavages, and by serial 18F-FDG PET/CT imaging. The eight MCM infected with M.tb alone displayed dichotomous susceptibility to TB, with four animals reaching humane endpoint within 13 weeks and four animals surviving >19 weeks post M.tb infection. In stark contrast, all seven SIV+ animals exhibited rapidly progressive TB following co-infection and all reached humane endpoint by 13 weeks. Serial PET/CT imaging confirmed dichotomous outcomes in MCM infected with M.tb alone and marked susceptibility to TB in all SIV+ MCM. Notably, imaging revealed a significant increase in TB granulomas between four and eight weeks post M.tb infection in SIV+, but not in SIV-naive MCM and implies that SIV impairs the ability of animals to contain M.tb dissemination. At necropsy, animals with pre-existing SIV infection had more extrapulmonary TB disease, more overall pathology, and increased bacterial loads than animals infected with M.tb alone. We thus developed a tractable MCM model in which to study SIV-M.tb co-infection and demonstrate that pre-existing SIV dramatically diminishes the ability to control M.tb co-infection.\n\nAuthor summaryMycobacterium tuberculosis (M.tb) is the etiologic agent of tuberculosis (TB) and infects a tremendous number of individuals. TB causes millions of deaths each year and is the leading cause of death in human immunodeficiency virus (HIV)-positive individuals. Currently, the mechanisms by which pre-existing HIV infection increases susceptibility to subsequent M.tb infection and predisposes an individual to TB disease are poorly understood. We developed a simian immunodeficiency virus (SIV) - M.tb co-infection model in Mauritian cynomolgus macaques (MCM) to investigate how SIV impairs the immune response to a subsequent M.tb infection. We show that naive MCM display variable resistance to TB while all SIV-infected MCM failed to control M.tb infection. Using quantitative measures of disease and serial PET/CT imaging, we show that SIV+ co-infected animals uniformly exhibit rapid TB progression, more tuberculosis disease dissemination, and increased mortality. This coinfection model will facilitate studies, provide unique insights into the defects underlying TB susceptibility in HIV+ individuals and will help us develop approaches to overcome these defects.

immunology↗

bioRxiv2017

Infection via mosquito bite alters Zika virus replication kinetics in rhesus macaques

For more than three decades it has been recognized that small amounts of vector saliva can significantly alter the infectivity of vector-borne pathogens and subsequent in vivo dynamics. Mouse and nonhuman primate models now serve as useful platforms to study Zika virus (ZIKV) pathogenesis, candidate therapies, and vaccines, but they rely on needle inoculation of virus: the effects of mosquito-borne infection on disease outcome have not been explored in these models. To model vector-borne transmission of ZIKV in nonhuman primates, we infected Aedes aegypti mosquitoes with ZIKV and allowed them to feed on four ZIKV-naive rhesus macaques. We compared ZIKV replication kinetics and tissue distribution between animals that were subcutaneously inoculated with 104 plaque-forming units of ZIKV and those that were exposed via mosquito bite. Here, we show that infection via mosquito bite delays ZIKV replication to peak viral loads in rhesus macaques. Importantly, in mosquito-infected animals ZIKV tissue distribution was limited to hemolymphatic tissues, female reproductive tract tissues, kidney, and liver, potentially emulating key features of human ZIKV infections, most of which are characterized by mild or asymptomatic disease. This newly developed system will be valuable for studying ZIKV disease because it more closely mimics human infection by mosquito bite than needle-based inoculations.

microbiology↗