Biology subjects

Paul, M.

Publications and source records attributed to Paul, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Characterisation of RNA guanine-7 methyltransferase (RNMT) using a small molecule approach

The maturation of the RNA cap involving guanosine N-7 methylation, catalyzed by the HsRNMT (RNA guanine-7 methyltransferase)-RAM (RNA guanine-N7 methyltransferase activating subunit) complex, is currently under investigation as a novel strategy to combat PIK3CA mutant breast cancer. However, the development of effective drugs is hindered by a limited understanding of the enzymes mechanism and a lack of small molecule inhibitors. Following the elucidation of the HsRNMT-RAM molecular mechanism, we report the biophysical characterization of two small molecule hits. Biophysics, biochemistry and structural biology confirm that both compounds bind competitively with cap and bind effectively to HsRNMT-RAM in the presence of the co-product SAM, with a binding affinity (KD) of approximately 1 M. This stabilisation of the enzyme-product complex results in uncompetitive inhibition. Finally, we describe the properties of the cap pocket and provided suggestions for further development of the tool compounds.

biochemistry↗

bioRxiv2024

Assessing the risk of highly pathogenic avian influenza H5 viruses spread within French broiler and layer production networks

Since 2015, French poultry production is threatened almost every year by a reintroduction of highly pathogenic avian influenza H5 viruses. The duck sector was the most concerned by this crisis but other sectors such as broiler, layer and turkey were also affected by outbreaks. The objective of this work was to assess the risk of highly pathogenic avian influenza H5 virus transmission from one farm to another within the French broiler and layer production network. This study used the WOAH risk assessment framework. After drawing up a scenario tree of virus transmission from one farm to another, data were collected through a literature review or through experts elicitation. Three questionnaires were developed according to the experts field of expertise: avian influenza, broiler and layer sectors. The experts estimates were combined using a beta distribution weighted by their confidence level. A Monte Carlo iteration process was used to combine the different probabilities of the scenario tree and to assess the transmission risk. In the broiler sector, the highest transmission probabilities were observed if the exposed farm was an indoor broiler farm and the source a broiler farm (indoor or free-range). The high transmission probability between broiler farms integrated within the same association suggests that integration is an important risk factor. Person movement, transport of feed and manure management were the pathways with the highest transmission probabilities between two integrated indoor broiler farms with good biosecurity levels. In the layer sector, the highest transmission probabilities were observed if the source farm was a free-range farm and the exposed farm a production farm (indoor or free-range). The pathways with the highest transmission probabilities were egg transport and person movement. The sensitivity analysis showed that the exposed farms biosecurity had a significant impact on the transmission probability. Our results provide an insight on the role of each type of farms in the virus spread within the French broiler and layer production sectors and will be useful for the implementation of control measures such as movement restriction or vaccination.

ecology↗

bioRxiv2024

New loci and candidate genes in spring two-rowed barley detected through meta-analysis of a field trial European network

This study contributes new knowledge on quantitative trait loci (QTLs) and candidate genes for adaptive traits and yield in two-rowed spring barley. A meta-analysis of a network of field trials, varying in latitude and sowing date, with 151 cultivars across several European countries, increased QTL detection power compared to single-trial analyses. The traits analysed were heading date (HD), plant height (PH), thousand-grain weight (TGW), and grain yield (GY). Breaking down the analysis by the main genotype-by-environment trends revealed QTLs and candidate genes specific to conditions like sowing date and latitude. A historical look on the evolution of QTL frequencies revealed that early selection focused on PH and TGW, likely due to their high heritability. GY selection occurred later, facilitated by reduced variance in other traits. The study observed that favourable alleles for plant height were often fixed before those for grain yield and TGW. Some regions showed linkage in repulsion, suggesting targets for future breeding. Several candidate genes were identified, including known genes and new candidates based on orthology with rice. Remarkably, the deficiens allele of gene Vrs1, appears associated to higher GY. These findings provide valuable insights for barley breeders aiming to improve yield, and other agronomic traits. HighlightA dense genome-wide meta-analysis provides new QTLs, reveals breeding history trends and identifies new candidate genes for yield, plant height, grain weight and heading time of spring barley.

genetics↗

bioRxiv2024

Paradoxical Activation of GCN2 by ATP-competitive inhibitors via allosteric activation and autophosphorylation

Recently it has been found that General Control Non-derepressible 2 (GCN2) can be activated by an array of small molecule ATP-competitive inhibitors, including clinically relevant compounds such as Ponatinib, and compounds specifically designed to be GCN2 inhibitors, such as GCN2iB. Furthermore, we recently showed that GCN2 can be activated in cells by clinically approved small molecule RAF inhibitors. GCN2 is a drug target, specifically in cancers such as mesothelioma, and a better understanding of this paradoxical activation is required to develop drugs which truly inhibit the enzyme. Using biochemical assays and structural mass spectrometry, we present a model for how GCN2 is activated by these compounds by promoting an active conformation in the HisRS domain while competitively inhibiting the kinase domain. This conformation promotes activating phosphorylation of GCN2, potentially through phosphorylation of other activated GCN2 molecules which are not bound to compound. Together this model suggests that efforts to inhibit GCN2 would benefit from exploring allosteric routes rather than targeting the ATP-binding pocket of the kinase domain.

biochemistry↗

bioRxiv2024

Chemoresistance of TP53 mutant AML requires the mevalonate byproduct, GGPP, for regulation of ROS and induction of a mitochondria stress response

Acute myeloid leukemia (AML) with mutations in the tumor suppressor gene, TP53 (TP53mut AML), is fatal with a median survival of only 6 months. RNA sequencing on purified AML patient samples show TP53mut AML has higher expression of mevalonate pathway genes. We retrospectively identified a survival benefit in TP53mut AML patients who received chemotherapy concurrently with a statin, which inhibits the mevalonate pathway. Mechanistically, TP53mut AML resistance to standard AML chemotherapy, cytarabine (AraC), correlates with increased mevalonate pathway activity and a mitochondria stress response with increased mitochondria mass and oxidative phosphorylation. Pretreatment with a statin reverses these effects and chemosensitizes TP53mut AML cell lines and primary samples in vitro and in vivo. Mitochondria-dependent chemoresistance requires the geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway and novel GGPP-dependent synthesis of glutathione to manage AraC-induced reactive oxygen species (ROS). Overall, we show that the mevalonate pathway is a novel therapeutic target in TP53mut AML. SignificanceChemotherapy-persisting TP53mut AML cells induce a mitochondria stress response that requires mevalonate byproduct, GGPP, through its novel role in glutathione synthesis and regulation of mitochondria metabolism. We provide insight into prior failures of the statin family of mevalonate pathway inhibitors in AML. We identify clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need of TP53mut AML.

cancer biology↗

bioRxiv2024

Most axonal mitochondria in cortical pyramidal neuronslack mitochondrial DNA and consume ATP

In neurons of the mammalian central nervous system (CNS), axonal mitochondria are thought to be indispensable for supplying ATP during energy-consuming processes such as neurotransmitter release. We have previously shown that glutamatergic excitatory cortical pyramidal neurons (CPNs) are characterized by a striking compartmentalization of mitochondrial structure. Axonal mitochondria are maintained at a small uniform size ([~]1 microns length) by high levels of MFF-dependent fission, whereas dendritic mitochondria form a highly fused network of mitochondria throughout the entire dendritic arbor(1, 2). Here, we tested whether these striking structural differences reflect functional and molecular compartmentalization. Using four independent techniques, we reveal that in CPNs as well as in two subtypes of GABAergic inhibitory cortical interneurons and neuromodulatory dopaminergic neurons of the substantia nigra, the majority of axonal, but not dendritic, mitochondria lack mitochondrial DNA (mtDNA) in vivo. We also show that axonal mitochondria are depleted in both mtDNA-encoded mRNAs and proteins compared to dendritic mitochondria. Timelapse imaging establishes that most mitochondria entering nascent dendritic and axonal processes from the soma are small and lack mtDNA. Using dynamic, optical imaging of genetically encoded sensors for ATP and pH targeted to the mitochondrial matrix, we demonstrate that in axons of CPNs, but not in their dendrites, mitochondrial F1F0-ATP synthase (Complex V) functions in a reverse way, hydrolyzing ATP and extruding H+ out of the matrix to maintain mitochondrial membrane potential. Our results indicate that in neurons of the mammalian CNS, the majority of axonal mitochondria lack mtDNA and likely do not play a major role in ATP generation, despite playing other functions such as regulation of neurotransmission via presynaptic Ca2+ buffering(1, 3-5).

neuroscience↗

bioRxiv2024

Precision phenotyping of a barley diversity set reveals distinct drought response strategies

Plants exhibit a wide array of responses and adaptive mechanisms to drought. During drought, the trade-off between water loss and CO2 uptake for growth is mediated by the regulation of stomatal aperture in response to soil water content (SWC), among other factors. We earlier identified, in a few reference varieties of barley that differed by the SWC at which transpiration was curtailed, two divergent water use strategies: water-saving ("isohydric") and water-spending ("anisohydric"). We proposed that an isohydric strategy may reduce risk from early droughts in climates where the probability of precipitation increases during the growing season, whereas an anisohydric strategy is consistent with environments having terminal droughts, or with those where dry periods are short and show little seasonal variation. Here, we have examined drought response in an 81-line barley diversity set that spans 20th century European barley breeding and identified a several lines with a third, dynamic transpirational response to drought. We found a strong positive correlation between vigor and transpiration, the dynamic group being highest for both. However, these lines curtailed daily transpiration at a higher SWC than the isohydric group. While the dynamic lines, particularly cv Hydrogen and Baronesse, were not the most resilient in terms of restoring initial growth rates, their strong initial vigor and high return to initial transpiration rates meant that their growth nevertheless surpassed more resilient lines during recovery from drought. The results will be of use for defining barley physiological ideotypes suited to future climate scenarios.

plant biology↗

bioRxiv2023

Gestures Of Hunger: Uncovering Intentional Gestural Communication In Free-Ranging Hanuman Langurs

Contrary to previous beliefs, intentional gestural communication (IGC) is not exclusive to the hominoid lineage but is also present in other non-human primates. Here, we report the presence of IGC among free-ranging Hanuman langur troop in Dakshineswar, West Bengal, India. These langurs exhibit a food-requesting behaviour wherein they use several gestures to communicate with the humans nearby. Moreover, they can also assess the recipients mental state and persistently check if the signal (food request) has been received, waiting until they receive the desired food item. We have identified eight begging gestures used by langurs of all ages, except infants. The most common gesture is by holding cloth (BGc), but provocation-initiated begging (BGpi) and begging by embracing legs (BGe) efficiently direct these events to its success. The frequency of successful begging events is higher in the evening due to increased human interactions. Our findings suggest that ontogenetic ritualization might be at play here among these troop members as this gestural communication has been learned through imitation and reinforced by the reward of receiving food. Moreover, these successful begging events serve as an effective foraging strategy for urban-adapted langurs, allowing them to acquire high-calorie processed food items within a human-modified urban ecosystem.

animal behavior and cognition↗

bioRxiv2023

SEPALLATA-driven MADS transcription factor tetramerization is required for inner whorl floral organ development

MADS genes encode transcription factors that act as master regulators of plant reproduction and flower development. The SEPALLATA (SEP) subfamily is required for the development of floral organs and plays roles in inflorescence architecture and development of the floral meristem. The SEPALLTAs act as organizers of MADS complexes, forming both heterodimers and heterotetramers in vitro. To date, the MADS complexes characterized in angiosperm floral organ development contain at least one SEPALLATA protein. Whether DNA-binding by SEPALLATA-containing dimeric MADS complexes are sufficient for launching floral organ identity programs, however, is not clear as only defects in floral meristem determinacy were observed in tetramerization impaired SEPALLATA mutants. Here, we used a combination of genome-wide binding studies, high resolution structural studies of the SEP3/AGAMOUS tetramerization domain, structure-based mutagenesis and complementation experiments in sep1 sep2 sep3 and sep1 sep2 sep3 ag-4 plants transformed with versions of SEP3 encoding tetramerization mutants. We demonstrate that while SEP3 heterodimers are able to bind DNA both in vitro and in vivo and recognize the majority of SEP3 wild type binding sites genome-wide, tetramerization is not only required for floral meristem determinacy, but also absolutely required for floral organ identity in the second, third and fourth whorls.

plant biology↗

bioRxiv2023

Aryl Hydrocarbon Receptor Suppresses Eosinophilic Esophagitis Responses through OVOL1 and SPINK7

Eosinophilic esophagitis (EoE) is a type 2 allergic disease characterized by esophageal inflammation and epithelial cell dysfunction. Acquired loss of the anti-serine protease of kazal type 7 (SPINK7) in the squamous epithelium of the esophagus has a causal role in EoE pathogenesis. Yet there is a limited understanding of the factors that regulate its expression and responsiveness to inflammatory stimuli. Herein, we identified the transcription factor, ovo like transcriptional repressor 1 (OVOL1) as an esophageal selective gene product that regulates SPINK7 promoter activity. Overexpression of OVOL1 increased SPINK7 expression, whereas, its depletion decreased SPINK7 expression, impaired epithelial barrier and increased production of the pro-atopy cytokine thymic stromal lymphopoietin (TSLP). Mechanistically, ligands of AHR induced nuclear translocation of OVOL1 which in turn promoted epithelial cell differentiation, barrier function and SPINK7 expression. Interleukin (IL)-4 and IL-13 abolished AHR ligand-induced OVOL1 nuclear translocation. Stimulation with IL-13 abrogated the nuclear translocation of OVOL1 and promoted enhanced degradation of OVOL1 protein. This effect of IL-13 was dependent on the esophageal specific cysteine protease calpain-14. Translational studies demonstrated loss of OVOL1 protein expression in patients with EoE. In summary, AHR mediates its action via OVOL1-induced SPINK7 transcription, and IL-4 and IL-13 repress this pathway in EoE. As such, activation of the AHR pathway is a potential intervention strategy for reversing EoE. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/541192v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1e946a1org.highwire.dtl.DTLVardef@1c087forg.highwire.dtl.DTLVardef@71ecc8org.highwire.dtl.DTLVardef@17044da_HPS_FORMAT_FIGEXP M_FIG C_FIG The influence of the exposome on regulatory networks in EoE pathogenesis. AHR is activated and influenced by diet nutrients, environmental toxicants, microbiome composition, tryptophan metabolites, and drugs. When AHR is activated, it promotes translocation of OVOL1 to the nucleus, which in turn promotes expression of epithelial genes including SPINK7. SPINK7 expression promotes epithelial differentiation, barrier function, decreased proteolytic activity, and decreased TSLP production. IL-4 and IL-13 inhibit OVOL1 nuclear translocation and therefore, repress SPINK7 expression. IL-13-stimulated CAPN14 expression decreases OVOL1 protein expression and SPINK7 transcription.

immunology↗

bioRxiv2023

Left or right: Handedness in free-ranging Hanuman langurs (Semnopithecus entellus) residing in an urban ecosystem.

Examining manual lateralization (handedness) in nonhuman primates might be an interesting approach to gaining insight into the evolution of asymmetry in humans. Moreover, handedness could also reflect the effect of environmental alterations on the free-ranging animals who are forced to live with anthropogenic interferences. Despite addressing the handedness among monkeys and apes, only a few studies have focused on these free-ranging urban-adapted nonhuman primates, which could challenge our perception of habitat loss and deforestation. Here, we conducted 193 field-based experimental trials with two experimental tasks, one unimanual (simple reaching) and one bimanual (tube task) to explore manual lateralization in a highly human-provisioned group of free-ranging Hanuman langur (Semnopithecus entellus). Experimental outcomes revealed an asymmetrical hand-use distribution, with a bias toward the left hand. As bimanual tasks evoked a higher degree of lateralization, these tasks seem to be more suited to study manual laterality, and our results also highlight the significance of experimental tasks in establishing hand preference in langurs. Furthermore, this study also reveals that such lateralization developed with age as adults distinctly displayed their preference toward left-hand usage in contrast to juveniles and subadults who used both hands comparably. Mostly considered to be arboreal, the langurs of our study group spend a considerable amount of time with humans on the ground, thereby portraying a terrestrial tendency. Postural Origin Theory states that terrestrial animals tend to use their right hand and arboreal their left. Therefore, here the presence of group-level left-hand biasness in the adult langurs of Dakshineswar creates a dilemma in the Postural Origin Theory.

animal behavior and cognition↗

bioRxiv2023

Drought and recovery in barley: key gene networks and retrotransposon response.

O_LIDuring drought, plants close their stomata at a critical soil water content (SWC), together with diverse physiological, developmental, and biochemical responses. C_LIO_LIUsing precision-phenotyping lysimeters, we imposed pre-flowering drought on four barley varieties (Arvo, Golden Promise, Hankkija 673 and Morex) and followed their physiological responses. For Golden Promise, we carried out RNA-seq on leaf transcripts before and during drought, and during recovery, also examining retrotransposon BARE1 expression. Transcriptional data were subjected to network analysis. C_LIO_LIThe varieties differed by their critical SWC, Hankkija 673 responding at the highest and Golden Promise at the lowest. Pathways connected to drought and salinity response were strongly upregulated during drought; pathways connected to growth and development were strongly downregulated. During recovery, growth and development pathways were upregulated; altogether 117 networked genes involved in ubiquitin-mediated autophagy were downregulated. The differential response to SWC suggests adaptation to distinct rainfall patterns. C_LIO_LIWe identified several strongly differentially expressed genes not earlier associated with drought response in barley. BARE1 transcription is strongly transcriptionally upregulated by drought and downregulated during recovery unequally between the investigated cultivars. The downregulation of networked autophagy genes suggests a role for autophagy in drought response; its importance to resilience should be further investigated. C_LI

plant biology↗

bioRxiv2022

Endogenous tagging of Unc-13 reveals nanocluster reorganization at active zones during presynaptic homeostatic potentiation

Neurotransmitter release at presynaptic active zones (AZs) requires concerted protein interactions within a dense 3D nano-hemisphere. Among the complex protein mesh-work the (M)unc-13 family member Unc-13 of Drosophila melanogaster is essential for docking of synaptic vesicles and transmitter release. We employ MiMIC-based gene editing using GFSTF (EGFP-FlAsH-StrepII-TEV-3xFlag) to endogenously tag all annotated Drosophila Unc-13 isoforms enabling visualization of endogenous Unc-13 expression within the central and peripheral nervous system. Electrophysiological characterization using two-electrode voltage clamp (TEVC) reveals that evoked and spontaneous synaptic transmission remain unaffected in unc-13GFSTF 3rd instar larvae and acute presynaptic homeostatic potentiation (PHP) can be induced at control levels. Furthermore, multi-color structured-illumination shows precise co-localization of Unc-13GFSTF, Bruchpilot and GluRIIA-receptor subunits within the synaptic mesoscale. Localization microscopy in combination with HDBSCAN algorithms detect Unc-13GFSTF nanoclusters that move towards the AZ center during PHP with unaltered Unc-13GFSTF protein levels.

neuroscience↗

bioRxiv2022

Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs

The Hippo signaling pathway acts as a brake on regeneration in many tissues. This cascade of kinases culminates in the phosphorylation of the transcriptional cofactors Yap and Taz, whose concentration in the nucleus consequently remains low. Various types of cellular stress can reduce phosphorylation, however, resulting in the accumulation of Yap and Taz in the nucleus and subsequently in mitosis. We earlier identified a small molecule, TRULI, that blocks the final kinases in the pathway, Lats1 and Lats2, and thus elicits proliferation of several cell types that are ordinarily post-mitotic and aids regeneration in mammals. In the present study we present the results of chemical modification of the original compound and demonstrate that a derivative, TDI-011536, is an effective blocker of Lats kinases in vitro at nanomolar concentrations. The compound fosters extensive proliferation in retinal organoids derived from human induced pluripotent stem cells. Intraperitoneal administration of the substance to mice suppresses Yap phosphorylation for several hours and induces transcriptional activation of its target genes in the heart, liver, and skin. Moreover, the compound initiates the proliferation of cardiomyocytes in adult mice following cardiac cryolesions. After further chemical refinement, related compounds might prove useful in protective and regenerative therapies. Significance StatementIn humans and other mammals, many organs regenerate through the proliferation of cells that replace those that have succumbed to aging or injury. However, proliferation is largely absent in certain critical organs, including the heart, the central nervous system, and sensory organs such as the inner ear and retina. The Hippo-Yap biochemical signaling pathway, a cascade of proteins that--when active--inhibits cell division, constitutes one impediment to proliferation. We earlier identified a small molecule that interrupts Hippo-Yap signaling and thus relieves this block for some non-proliferating cells in vitro. In the present investigation, we have chemically modified the original substance to yield a more potent analog that is effective for several hours in mammalian tissues in vivo and initiates the proliferation of heart-muscle cells after cryolesioning. After further refinements, compounds of this family might prove useful in regenerative therapies.

cell biology↗

bioRxiv2022

CD169+ macrophages orchestrate plasmacytoid dendritic cell arrest and retention for optimal priming in the bone marrow of malaria-infected mice

Plasmacytoid dendritic cells (pDC) are the most potent producer of type I interferon (IFN), but how pDC are primed in vivo is poorly defined. Using a mouse model of severe malaria, we have previously established that upon priming by CD169+ macrophages (MP), pDC initiate type I IFN-I secretion in the bone marrow (BM) of infected mice via cell-intrinsic TLR7 sensing and cell-extrinsic STING sensing. Herein we show that CD169+ MP and TLR7-sensing are both required for pDC arrest during priming, suggesting CD169+ MP are the source of TLR7 ligands. We establish that TLR7 sensing in pDC and chemotaxis are both required for pDC arrest and functional clustering with CD169+ MP in the BM. Lastly, we demonstrate that STING-sensing in CD169+ MP control pDC initiation of type I IFN production while also regulating pDC clustering and egress from the BM. Collectively, these results link pDC acquisition of type I IFN secreting capacity with changes in their motility, homing and interactions with CD169+ MP during infection. Thus, targeting this cellular interaction may help modulate type I IFN to improve outcomes of microbial infections and autoimmune diseases.

immunology↗

bioRxiv2022

Ultrastructural analysis of wildtype and RIM1α knock-out active zones in a large cortical synapse

Rab3A-interacting molecule (RIM) is crucial for fast Ca2+-triggered synaptic vesicle (SV) release in presynaptic active zones (AZ). While loss of RIM1 impairs long-term plasticity at hippocampal giant mossy fiber boutons (MFB), it remains unclear how AZ ultrastructure is altered. We investigated MFB AZ architecture in 3D using electron tomography of rapid cryo-immobilized acute brain slices in RIM1-/- and wild-type mice. In RIM1-/-, AZs are larger with increased synaptic cleft heights and with a three-fold reduced number of tightly docked SVs (0-2nm). The distance of tightly docked SVs to the AZ center is increased from 110 to 195 nm, and the width of their electron dense material between outer SV membrane and AZ membrane is reduced. Furthermore, the SV pool in RIM1-/- is more heterogeneous. Thus, RIM1, beside its role in tight SV docking, is crucial for synaptic architecture and vesicle pool organization in MFBs.

neuroscience↗

bioRxiv2021

Direct quantification of ligand-induced lipid and protein microdomains with distinctive signaling properties

Lipid rafts are known as highly ordered lipid domains that are enriched in saturated lipids such as the ganglioside GM1. While lipid rafts are believed to exist in cells and to serve as signaling platforms through their enrichment in signaling components, they have never been directly observed in the plasma membrane without treatments that artificially cluster GM1 into large lattices. Here we report that microscopic GM1-enriched domains can form, without lipid cross-linking, in the plasma membrane of live mammalian cells expressing the EphA2 receptor tyrosine kinase in response to its ligand ephrinA1-Fc. The GM1-enriched microdomains form concomitantly with EphA2-enriched microdomains, but only partially co-localize with them. To gain insight into how plasma membrane heterogeneity controls signaling, we quantify the degree of EphA2 segregation and study initial EphA2 signaling steps in both EphA2-enriched and EphA2-depleted domains. By measuring dissociation constants, we demonstrate that EphA2 oligomerization is the same in EphA2-enriched and -depleted domains. However, EphA2 interacts preferentially with its downstream effector SRC in EphA2-depleted domains. The ability to induce microscopic GM1-enriched domains in live cells using a ligand for a transmembrane receptor will give us unprecedented opportunities to study the biology of lipid rafts.

biophysics↗

bioRxiv2020

Inferring within-flock transmission dynamics of highly pathogenic avian influenza (H5N8) in France, 2020

Following the emergence of highly pathogenic avian influenza (H5N8) in France in early December 2020, we used duck mortality data of the index case to investigate within-flock transmission dynamics. A stochastic epidemic model was adjusted to the daily mortality data and model parameters were estimated using an approximate Bayesian computation sequential Monte Carlo (ABC-SMC) algorithm. Results suggested that the virus was introduced 4 days (95% credible interval: 3 - 5) prior to the day suspicion was reported and that the transmission rate was 3.7 day-1 (95%CI: 2.6 - 5.3). On average, ducks started being infectious 3.1 hours (95%CI: 0.4 - 8.0) after infection and remained infectious for 4.4 days (95%CI: 3.1 - 5.6). Model outputs also suggested that the number of infectious ducks was already 3239 (95%CI: 26 - 3706) the day before suspicion, emphasising the substantial latent threat this virus could pose to other poultry farms and to neighbouring wildlife. These estimations can be applied to upcoming outbreaks and made available to veterinary services within few hours. This study illustrates how mechanistic models can provide rapid relevant insights to contribute to the management of infectious disease outbreaks of farmed animals.

ecology↗