Biology subjects

Li, C.

Publications and source records attributed to Li, C..

At least 739 records · Page 41Linked to original sources

bioRxiv2022

Spurious intragenic transcription is a hallmark of mammalian cellular senescence and tissue aging

Mammalian aging is characterized by the progressive loss of tissue integrity and function manifesting in ill health and increased risk for developing multiple chronic conditions. Accumulation of senescent cells in aging tissues partly contributes to this decline and targeted depletion of senescent cells in vivo ameliorates many age-related phenotypes. However, the fundamental molecular mechanisms responsible for the decline of cellular health and fitness during senescence and aging are largely unknown. In this study, we investigated whether chromatin-mediated loss of transcriptional fidelity, known to contribute to fitness and survival in yeast and worms, also occurs during human cellular senescence and mouse aging. Our findings reveal that aberrant transcription initiation inside genes is widespread in senescence and aging. It co-occurs with changes in the chromatin landscape and formation of non-canonical transcription start sites. Interventions that alter spurious transcripts have dramatic consequences on cellular health primarily affecting intracellular signal transduction pathways. We propose that spurious transcription is a conserved hallmark of aging that promotes a noisy transcriptome and degradation of coherent transcriptional networks.

genomics↗

bioRxiv2022

Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy.

There are no pharmacological disease-modifying treatments that can mitigate the seizures and comorbidities associated with established chronic temporal lobe epilepsy (TLE). This study evaluated the effect of sodium selenate in the post-status epilepticus (SE) rat model of chronic drug resistant TLE. Wistar rats underwent kainic acid-induced SE or sham. Ten-weeks post-SE, rats were randomly assigned to receive either sodium selenate, levetiracetam, or vehicle treatments continuously for 4 weeks. To evaluate the effects of the treatments, 1 week of continuous video-EEG was acquired before, during, and 4, 8 weeks post-treatment, followed by behavioral tests. Targeted and untargeted proteomics and metabolomics were performed on post-mortem brain tissue to identify potential pathways associated with modified disease outcomes. Telomere length was investigated as a novel surrogate marker of disease severity. Sodium selenate treatment was able to mitigate disease severity, reducing the number of spontaneous seizures (p< 0.05), cognitive dysfunction (p< 0.05 in both novel object placement and recognition tasks), and sensorimotor deficits (p< 0.01) 8 weeks post-treatment cessation. Moreover, increased protein phosphatase 2A (PP2A) expression, reduced hyperphosphorylated tau, and reversed telomere length shortening caused by SE (p< 0.05). Network medicine integration of multi-omics/ pre-clinical outcomes identified protein-metabolite modules positively correlated with the TLE phenotype. Our results provide evidence that treatment with sodium selenate results in a sustained disease modifying effect in chronically epileptic rats in the post-KA SE model of TLE, including improved comorbid learning and memory deficits.

neuroscience↗

bioRxiv2022

Adaptive Immune Landscape of T-Cell Mediated Rejection of Human Kidney Allografts

The frequently occurring T cell mediated rejection (TCMR) is a risk factor for allograft failure. Immunosuppressive therapy fails to reverse almost 40% of TCMRs occurring in human kidney allografts. A better understanding of the molecular mechanisms of TCMR and precision therapeutics may improve allograft longevity. We investigated adaptive immune landscape of TCMR by genome wide RNA sequencing of 34 prototypic kidney allograft biopsies from 34 adult recipients of human kidney allografts. Sixteen of the 34 biopsies were categorized as Banff TCMR and the remaining 18 as Banff Normal biopsies. Computational analysis identified higher intragraft abundance of the gene sets for key players of adaptive immune system in TCMR. TCMR allografts were characterized by, i) increased antigen processing and presentation and T cell receptor signaling, ii) increased memory T cells, Tregs, Th1, Th2 and Th17 subsets, iii) increased aerobic glycolysis of lymphocytes and reduced metabolic activity of graft parenchymal cells, iv) increased T cell inhibitory receptors and exhaustion markers, v) increased apoptosis and necroptosis, and vi) increased extracellular matrix remodeling, all in comparison to Normal biopsies. Our genome-wide transcriptomics provides an atlas of adaptive immune landscape of TCMR in human kidney allografts, help deduce molecular mechanisms and prioritization of therapeutic targets.

immunology↗

bioRxiv2022

Single-cell profiling coupled with lineage analysis reveals distinct sacral neural crest contributions to the developing enteric nervous

During development, the enteric nervous system (ENS) arises from neural crest cells that emerge from the neural tube, migrate to and along the gut, and colonize the entire intestinal tract. While much of the ENS arises from vagal neural crest cells that originate from the caudal hindbrain, there is a second contribution from the sacral neural crest that migrates from the caudal end of the spinal cord to populate the post-umbilical gut. By coupling single cell transcriptomics with axial-level specific lineage tracing in avian embryos, we compared the contributions between embryonic vagal and sacral neural crest cells to the ENS. The results show that the two neural crest populations form partially overlapping but also complementary subsets of neurons and glia in distinct ganglionic units. In particular, the sacral neural crest cells appear to be the major source of adrenergic/dopaminergic and serotonergic neurons, melanocytes and Schwann cells in the post-umbilical gut. In addition to neurons and glia, the results also reveal sacral neural crest contributions to connective tissue and mesenchymal cells of the gut. These findings highlight the specific properties of the sacral neural crest population in the hindgut and have potential implications for understanding development of the complex nervous system in the hindgut environment that may influence congenital neuropathies.

developmental biology↗

bioRxiv2022

An endolysosome membrane transformation process for engulfment of autophagosomes independently of ESCRT

Endolysosome, usually regarded as the cellular recycling bin, digests materials from multiple origins. The materials from different origins are delivered to endolysosome through the vesicle fusion, kiss-and-run mechanisms, CMA or microautophagy. However, it remains unknown whether endolysosome can receive cargo via other ways. Here, we reported another endolysosomal process for receiving materials. In this, endolysosome receives materials by extending two arms which embraces autophagosomes and engulfs the autophagosomes ultimately, but not via the conventional fusion of autophagosomes with endolysosomes. We named this process as LEA (lysosome eats autophagosome) and the endolysosome arms as LF (endolysosome filopodia) provisionally. The endolysosomes with engulfed autophagosomes (LEA endolysosomes) get more autophagosomes via the fusion with other LEA endolysosomes. The engulfed autophagosomes are labelled by F-actin on their membranes and have ER protein Sec61{beta} and peroxisome protein Pex14 inside their lumens, but mitochondria are excluded outside endolysosome. Our discovery of LEA and LF reveal an unidentified endolysosome transformation process which is responsible for receiving cargoes.

cell biology↗

bioRxiv2022

ISG15 Monomer Promotes IFNα-mediated Antiviral Activity against Pseudorabies Virus by Facilitating phosphorylation of STAT1/STAT2

Pseudorabies virus (PRV), which presently lacks both an antiviral drug and a viable therapeutic option, is a major viral pathogen that poses a danger to the pig industry worldwide. Interferon-stimulated gene 15 (ISG15) is strongly upregulated during viral infections and has been reported to have proviral or antiviral properties, depending on the virus and host species. Our previous studies demonstrated ISG15 was remarkably upregulated during PRV infection, and the overexpression of ISG15 inhibited PRV replication. Nevertheless, the exact mechanism through which ISG15 influences PRV replication poorly understood unclear. Here, we demonstrate that ISG15 accumulation induced by PRV infection requires viral gene expression and viral growth. Conjugation inhibition assays showed that ISG15 imposes its antiviral effects via unconjugated (free) ISG15 and affects the viral release. In addition, we found ISG15 promoted IFN-mediated antiviral activity against PRV by facilitating the phosphorylation of STAT1 and STAT2, along with an increase of ISGF3-induced ISRE promoter activity. Furthermore, we evaluated the role of ISG15 in host defense to control PRV infection by using ISG15-/- mice model. When challenged with PRV, ISG15-/- mice exhibited increased morbidity and mortality, as well as viral load compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the brains of ISG15-/- mice, along with the upregulation of the cytokines. Our findings establish the importance of ISG15 in IFN-induced antiviral response and in the control of PRV infection.

molecular biology↗

bioRxiv2022

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility over BA.21. The new variants receptor binding and immune evasion capability require immediate investigation. Here, coupled with Spike structural comparisons, we show that BA.2.12.1 and BA.4/BA.5 exhibit comparable ACE2-binding affinities to BA.2. Importantly, BA.2.12.1 and BA.4/BA.5 display stronger neutralization evasion than BA.2 against the plasma from 3-dose vaccination and, most strikingly, from post-vaccination BA.1 infections. To delineate the underlying antibody evasion mechanism, we determined the escaping mutation profiles2, epitope distribution3 and Omicron neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory. The resulting elicited antibodies could neutralize both wildtype and BA.1 and are enriched on non-ACE2-competing epitopes. However, most of these cross-reactive NAbs are heavily escaped by L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1; nevertheless, these NAbs are largely escaped by BA.2/BA.4/BA.5 due to D405N and F486V, and react weakly to pre-Omicron variants, exhibiting poor neutralization breadths. As for therapeutic NAbs, Bebtelovimab4 and Cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

immunology↗

bioRxiv2022

Metformin decreases Cyp26a1 to prevent hepatocarcinogenesis through down- regulating CD8+ T cells

Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, which limits the selectivity of prevention and treatment. Preclinical and clinical studies suggested that in patients with diabetes, prolonged use of metformin, the AMPK activator, was associated with a reduction of HCC incidence. This association promotes us to investigate the possible functions and mechanisms of metformin in HCC without diabetes backgrounds. Here, we found that several unique pathways that changed during chronic liver injury of Fah-/- mice, including glucose metabolic process and retinol metabolism. Further, metformin suppressed the tumor formation in chronic liver injury of Fah-/- mice. RNA sequencing, in vivo and in vitro experiments showed that metformin suppressed Cyp26a1 gene expression of hepatocyte. Moreover, the down-regulation of Cyp26a1 leads to the increased level of all-trans-retinoic acid (atRA), which could suppress the tumor formation in our model. On the other hand, flow multicolor analysis showed that the cell number and proportion of cancer promoting (pro-tumor) CD8+ T cells increased significantly during chronic liver injury in Fah-/- mice, and both metformin and atRA treatment could reduce the number and proportion of pro-tumor CD8+ T cells. We also found metformin decreased the Cyp26a1 expression through the AMPK/JNK/c-Jun pathway. In short, the association between the metformin and atRA may explain the commonness of their anti-tumor activities. Our findings highlight the importance of targeting the precancerous microenvironment for the prognosis, prevention and treatment of HCC.

cancer biology↗

bioRxiv2022

Ancestral Body Plan and Adaptive Radiation of Sauropterygian Marine Reptiles

Mesozoic was the age of reptiles that not only occupied the land and sky but also adapted to the sea. Sauropterygia, from turtle-like placodonts, lizard-like pachypleurosaurs, and predatory nothosaurs to long-necked pistosaurs including plesiosaurs, is one of the most predominant lineages among secondarily aquatic reptiles. However, we know little about the early evolution of sauropterygians involving the morphological gaps among aforementioned sub-groups and their ancestral body-plan, because the Early Triassic fossil remains are scarce shortly after their origin. Here we report a skeleton from the Early Triassic in South China, representing the oldest known complete specimen related to Sauropterygia. It can be referred to Hanosaurus hupehensis and shows a mosaic morphology combining the characters of multiple sauropterygian sub-lineages. We constructed an updated character matrix obtaining the hitherto most comprehensive phylogeny of Triassic sauropterygians, and Hanosaurus hupehensis is stably resolved as the basal-most member of the Sauropterygiformes (clade nov.). Sauropterygians were previously considered using limb propulsion for the movement that is distinguishable from ichthyosaurs and other marine reptiles, but this skeleton reflects an ancestral body plan of sauropterygians unexpectedly developing an elongate trunk and four short limbs, being different from most sauropterygians but more convergently similar to the basal members of other marine reptilian lineages in body shape. After this convergence, we confirm the rapid adaptive radiation of sauropterygiform reptiles following the end-Permian mass extinction. Our results provide an evolutionary framework of sauropterygian marine reptiles and highlight the integrations of both convergences and divergences when an emerging animal lineage arises.

paleontology↗

bioRxiv2022

CircEML1 facilitates the steroid synthesis in follicular granulosa cells of chicken through sponging gga-miR-449a to release IGF2BP3 expression

Non-coding RNAs (ncRNAs) induced competing endogenous RNAs (ceRNA) play crucial roles in various biological process by regulating target gene expression. However, the studies of ceRNA networks in the regulation of ovarian ovulation process of chicken remains deficient compared to that in mammals. In the present study, it was revealed that circEML1 was differential expressed in hens ovarian tissue at different ages (15W, 20W, 30W and 68W) and identified as a loop structure from EML1 pre-mRNA, which promoted the expressions of CYP19A1 and StAR and the production of E2 and P4 in follicular granulosa cells (GCs) using qRT-PCR and ELISA. Furthermore, circEML1 was proved to serve as a sponge of gga-miR-449a to participate in the steroidogenesis using the dual luciferase reporter, RNA FISH assays, qRT-PCR and ELISA assays. In addition, we evaluated several potential target genes of gga-miR-449a and found that IGF2BP3 was targeted by gga-miR-449a and promoted steroidogenesis and E2/P4 secretions in GCs, which may act the regulatory role via mTOR/p38MAPK pathways. Meanwhile, we implemented a rescue experiment and demonstrated that gga-miR-449a reversed the promoting role of circEML1 on IGF2BP3 expression and steroidogenesis. Eventually, this study suggested that circEML1/gga-miR-449a/IGF2BP3 axis exerted an important role in the regulation of steroidogenesis and steroid hormones production possibly through mTOR/p38MAPK pathways in follicular GCs of chicken and may contribute a better understanding of ceRNA network in the modulatory mechanism of hens ovarian development and ovulation cycle.

molecular biology↗

bioRxiv2022

A robust and transformation-free joint model with matching and regularization for metagenomic trajectory and disease onset

BackgroundTo identify operational taxonomy units (OTUs) signaling disease onset in an observational study, a powerful strategy was selecting participants by matched sets and profiling temporal metagenomes, followed by trajectory analysis. Existing trajectory analyses modeled individual OTU or microbial community without adjusting for the within-community correlation and matched-set-specific latent factors. ResultsWe proposed a joint model with matching and regularization (JMR) to detect OTU-specific compositional trajectory predictive of host disease status, using nested random effects and covariate taxa pre-selected by Bray-Curtis distance and elastic net regression. The inherent negative correlation in microbiota composition was adjusted by incorporating the top-correlated taxa as covariate. We designed a simulation pipeline to generate true biomarkers for disease onset and the pseudo biomarkers caused by compositionality or latent noises. We demonstrated that JMR effectively controlled the false discovery and pseudo biomarkers in a simulation study that generated temporal high-dimensional metagenomic counts with random intercept or slope. Application of the competing methods in the simulated data and the TEDDY cohort showed that JMR outperformed the other methods and identified important taxa in infants fecal samples with dynamics preceding host disease status. ConclusionOur method JMR is a robust framework that models taxon-specific compositional trajectory and host disease status in the matched participants, improving the power of detecting disease-predictive microbial features in certain scenarios.

bioinformatics↗

bioRxiv2022

Crystal structure of the Rubella virus protease reveals a unique papain-like protease fold

Rubella is well-controlled due to an effective vaccine, but outbreaks are still occurring without any available antiviral treatments. There is still much to learn about the rubella virus (RUBV) papain-like protease (RubPro) that could be a potential drug target. This protease is crucial to RUBV replication, cleaving the non-structural polyprotein p200 into 2 multi-functional proteins, p150 and p90. Here we report a novel crystal structure of RubPro at 1.64 [A] resolution. It has a similar catalytic core structure to that of SARS-CoV-2 and foot-mouth-disease virus (FMDV) proteases. RubPro has well-conserved sequence motifs that are also found in its newly discovered Rubivirus relatives. The RubPro construct was shown to have protease activity in trans against a construct of RUBV protease-helicase and fluorogenic peptide. A protease-helicase construct was also cleaved in E. coli expression. RubPro was demonstrated to possess deubiquitylation activity, suggesting a potential role of RubPro in modulating the hosts innate immune responses. The structural and functional insights of the RubPro will advance our current understanding of its function and point to more structure-based research into the RUBV replication machinery, in hopes of developing antiviral therapeutics in the future.

microbiology↗

bioRxiv2022

Quantitative landscapes reveal trajectories of cell-state transitions associated with drug resistance in melanoma

Drug resistance and tumor relapse in melanoma patients is attributed to a combination of genetic and non-genetic mechanisms. Non-genetic mechanisms of drug resistance commonly involve reversible changes in the cell-state or phenotype, i.e., alterations in molecular profiles that can help cells escape being killed by targeted therapeutics. In melanoma, one of the most common mechanisms of non-genetic resistance is dedifferentiation, which is characterized by loss of melanocytic markers. While various molecular attributes of de-differentiation have been identified, the transition dynamics remains poorly understood. Here, we construct cell-state transition landscapes, to quantify the stochastic dynamics driving phenotypic switch in melanoma based on its underlying regulatory network. These landscapes reveal the existence of multiple alternative paths to resistance - de-differentiation and transition to a hyper-pigmented phenotype. Finally, by visualizing the changes in the landscape during in silico molecular perturbations, we identify combinatorial strategies that can lead to the most optimal outcome - a landscape with the minimal occupancy of the two drug-resistant states. Therefore, we present these landscapes as platforms to screen possible therapeutic interventions in terms of their ability to lead to most favourable patient outcomes.

systems biology↗

bioRxiv2022

Knowledge-graph-based cell-cell communication inference for spatially resolved transcriptomic data with SpaTalk

Spatially resolved transcriptomics (ST) provides genetic information in space toward elucidation of the spatial architecture in intact organs and the spatially resolved cell-cell communications mediating tissue homeostasis, development, and disease. To facilitate inference of spatially resolved cell-cell communications from ST data, we here present SpaTalk, which relies on a graph network and knowledge graph to model and score the ligand-receptor-target signaling network between spatially proximal cells, decomposed from ST data through a non-negative linear model and spatial mapping between single-cell RNA-sequencing and ST data. The performance of SpaTalk benchmarked on public single-cell ST datasets was superior to that of existing cell-cell communication inference methods. SpaTalk was then applied to STARmap, Slide-seq, and 10X Visium data, revealing the in-depth communicative mechanisms underlying normal and disease tissues with spatial structure. SpaTalk can uncover spatially resolved cell-cell communications for single-cell and spot-based ST data universally, providing new insights into spatial inter-cellular dynamics.

bioinformatics↗

bioRxiv2022

Genome-wide analysis reveals PhoP regulates pathogenicity in Riemerella anatipestifer

Duck infectious serositis, also known as the Riemerella anatipestifer disease infects domestic ducks, geese, turkeys, and wild birds. However, the regulatory mechanism of its pathogenicity remains unclear. The phoP/phoR two-component system was first reported in gram-negative bacteria in our previous research and was demonstrated to be involved in virulence and gene expression. Here, the DNA-affinity-purified sequencing (DAP-seq) was applied to further explore the regulation of phoP/phoR to pathogenicity in R. anatipestifer. A conserved motif was identified in the upstream of 583 candidate target genes which were directly regulated by phoP. To further confirm the genes which are regulated by phoP/phoR, phoR and phoP, the single-gene deletion strains were constructed. The results of transcriptome analysis using next-generation RNA sequencing showed 136 differential expression genes (DEGs) between {Delta}phoP and RA-YM, and 183 DEGs between {Delta}phoR and WT. The candidate target genes of PhoP were further identified by combining transcriptome analysis and DAP-seq. The results of DAP-seq and RNA-seq of {Delta}phoP in combination revealed that the main direct regulons of PhoP are located on the membrane and PhoP is involved in regulating aerotolerance. Using the in vivo duck model, the pathogenicity of {Delta}phoP or {Delta}phoR was significantly lower than that of the WT. Together, our findings provided a perception about the direct regulation of PhoP and suggested that phoP/phoR is essential for the pathogenicity of R. anatipestifer, and phoP/phoR is related to the aerotolerance of R. anatipestifer. The gene deletion strains are expected to be the candidate live vaccine strains of R. anatipestifer which can be used as ideal genetic engineering vector strains for the expression of foreign antigens. Author summaryRiemerella anatipestifer is a severe pathogen in the poultry industry with high mortality in ducks and geese mainly due to acute septicemia and infectious polyserositis. A two-component system phoP/phoR was previously characterized in R. anatipestifer, and the phoP/phoR TCS was reported for the first time in Gram-negative bacteria. A deleted phoP/phoR in R. anatipestifer has been reported to almost lose its pathogenicity in ducklings. However, the mechanism of phoP/phoR regulating the virulence of R. anatipestifer had not been explored in detail. This study has utilized DAP-seq to explore the DNA-binding sites of PhoP as a response regulator in the global genome. Furthermore, the phoP and phoR were deleted separately and the transcriptomics of the corresponding gene-deleted strains was analyzed. A series of directly regulated genes of phoP/phoR TCS were determined in combination. The duckling model revealed both PhoP and PhoR as essential virulence-related factors of R. anatipestifer.

pathology↗

bioRxiv2022

A chemomechanical model of sperm locomotion reveals two modes of swimming

The propulsion of mammalian spermatozoa during reproduction relies on the spontaneous periodic oscillation of their flagella. These oscillations are driven internally by the coordinated action of ATP-powered dynein motors that exert active sliding forces between microtubule doublets, resulting in bending waves that propagate along the flagellum and enable locomotion of the cell through the viscous medium. In this work, we present a chemomechanical model of a freely swimming spermatozoon that uses a sliding-control model of the flagellar axoneme capturing the coupling of motor kinetics with elastic deformations and accounts for the effect of non-local hydrodynamic interactions between the sperm head and flagellum. Nonlinear simulations of the model equations are shown to produce realistic beating patterns and swimming trajectories, which we analyze as a function of sperm number and motor activity. Our results demonstrate that the swimming velocity does not vary monotonically with dynein activity, but instead displays two local maxima corresponding to distinct modes of swimming, each characterized by qualitatively different waveforms and trajectories.

biophysics↗

bioRxiv2022

Toxoplasma gondii Coq1 is a heptaprenyl diphosphate synthase and its inhibition by a lipophilic bisphosphonate protects mice against T. gondii infection

Prenyldiphosphate synthases catalyze the reaction of allylic diphosphates with one or more isopentenyl diphosphate molecules to form compounds such as farnesyl diphosphate, used in e.g. sterol biosynthesis and protein prenylation, as well as longer "polyprenyl" diphosphates, used in ubiquinone and menaquinone biosynthesis. Quinones play an essential role in electron transport and are associated with the inner mitochondrial membrane due to the presence of the polyprenyl group. In this work, we investigated the synthesis of the polyprenyl diphosphate that alkylates the ubiquinone ring precursor in Toxoplasma gondii, an opportunistic pathogen that causes serious disease in immunocompromised patients and the unborn fetus. The enzyme that catalyzes this early step of the ubiquinone synthesis is Coq1 (TgCoq1), and we show that it produces the C35 species, heptaprenyl diphosphate. TgCoq1 localizes to the mitochondrion, and is essential for in vitro T. gondii growth. We demonstrate that the growth defect of a T. gondii TgCoq1 mutant is rescued by complementation with a homologous TgCoq1 gene or with a (C45) solanesyl diphosphate synthase from Trypanosoma cruzi (TcSPPS). We find that a lipophilic bisphosphonate (BPH-1218) inhibits T. gondii growth at low nM concentrations, while overexpression of the TgCoq1 enzyme dramatically reduced growth inhibition by the bisphosphonate. Both the severe growth defect of the mutant and the inhibition by BPH-1218 were rescued by supplementation with a long chain (C30) ubiquinone (UQ6). Importantly, BPH-1218 also protected mice against a lethal T. gondii infection. TgCoq1 thus represents a potential drug target that could be exploited for improved chemotherapy of toxoplasmosis. ImportanceMillions of people are infected with Toxoplasma gondii and the available treatment for toxoplasmosis is not ideal. Most of the drugs currently used are only effective for the acute infection and treatment can trigger serious side-effects requiring changes in the therapeutic approach. There is, therefore, a compelling need for safe and effective treatments for toxoplasmosis. In this work, we characterize an enzyme of the mitochondrion of T. gondii that can be inhibited by an isoprenoid pathway inhibitor. We present evidence that demonstrate that inhibition of the enzyme is linked to parasite death. In addition, the drug is able to protect mice against a lethal dose of T. gondii. Our results thus reveal a promising chemotherapeutic target for the development of new medicines for toxoplasmosis.

microbiology↗

bioRxiv2022

Robustness of the ferret model for influenza risk assessment studies: a cross-laboratory exercise

Ferrets represent the preferred animal model for assessing the transmission potential of newly emerged zoonotic influenza viruses. However, heterogeneity among established experimental protocols and facilities across different laboratories may lead to variable results, complicating interpretation of transmission experimental data. Between 2018-2020, a global exercise was conducted by 11 participating laboratories to assess the range of variation in ferret transmission experiments using two common stock H1N1 influenza viruses that possess different transmission characteristics in ferrets. Inoculation route, dose, and volume were standardized, and all participating laboratories followed the same experimental conditions for respiratory droplet transmission, including a strict 1:1 donor:contact ratio. Additional host and environmental parameters likely to affect influenza transmission kinetics were monitored throughout. Overall transmission outcomes for both viruses across 11 laboratories were concordant, suggesting the robustness of the ferret model for zoonotic influenza risk assessment. To attain high confidence in identifying zoonotic influenza viruses with moderate-to-high or low transmissibility, our analyses support that as few as three but as many as five laboratories, respectively, would need to independently perform viral transmission experiments with concordant results. This exercise facilitates the development of a more homogenous protocol for ferret transmission experiments that are employed for the purposes of risk assessment.

microbiology↗