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PubMed2025

Health-associated key gut microbiota drives the variation in community metabolic interactions in non-human primates.

Gut microbiota often undergo metabolic cross-feeding and resource competition. However, our understanding of global variations in these interactions and their implications for host health remain elusive. By analyzing a microbial genome catalog from 841 fecal metagenomes across 53 primate species worldwide, we identified key microbiota assigned to two taxa, i.e., Bacillota_A and Pseudomonadota, which well predicted the trade-off of community-level interaction types between metabolic competition and cooperation. Specifically, Bacillota_A species were inherently competitive and amino acid auxotrophic and typically found in anaerobic habitats. In contrast, members of Pseudomonadota were inherently cooperative, siderophore producers, and more abundant in aerobic conditions. Random forest models successfully distinguished unhealthy gut samples from healthy samples through the key competitive and cooperative microbiota, suggesting potential links between community metabolic interactions and host health. Together, this study enhances our mechanistic understanding of microbial interaction dynamism within complex gut ecosystems, offering new targets for understanding host health.

Animals↗
PubMed2022

FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit.

Excessive alcohol consumption is a major health and social issue in our society. Pharmacologic administration of the endocrine hormone fibroblast growth factor 21 (FGF21) suppresses alcohol consumption through actions in the brain in rodents, and genome-wide association studies have identified single nucleotide polymorphisms in genes involved with FGF21 signaling as being associated with increased alcohol consumption in humans. However, the neural circuit(s) through which FGF21 signals to suppress alcohol consumption are unknown, as are its effects on alcohol consumption in higher organisms. Here, we demonstrate that administration of an FGF21 analog to alcohol-preferring non-human primates reduces alcohol intake by 50%. Further, we reveal that FGF21 suppresses alcohol consumption through a projection-specific subpopulation of KLB-expressing neurons in the basolateral amygdala. Our results illustrate how FGF21 suppresses alcohol consumption through a specific population of neurons in the brain and demonstrate its therapeutic potential in non-human primate models of excessive alcohol consumption.

Alcohol Drinking↗
PubMed2026

Establishment of a Common Marmoset Lineage Carrying a Frameshift Mutation in SETD1A, a Schizophrenia Risk Gene.

Appropriate histone modifications are essential for maintaining functional chromatin structure and gene expression, and dysfunction of their regulators has been linked to a variety of diseases. Among these modifications, trimethylation of lysine 4 on histone H3 (H3K4me3) is a well-characterized epigenetic mark enriched at transcription start sites of actively transcribed genes. H3K4me3 regulates gene transcription by recruiting transcription factors, facilitating chromatin accessibility, and preventing DNA methylation. In mammals, methylation of H3K4 is catalyzed by a family of histone methyltransferases including SET domain containing 1A (SETD1A), which is primarily responsible for genome-wide deposition of H3K4me2/3. Loss-of-function variants in SETD1A, highlighting its critical role in brain development and cognitive function, are strongly associated with schizophrenia (SCZ) and other neurodevelopmental disorders, but the underlying mechanisms remain largely unclear. To better understand the epigenetic and neurobiological consequences of SETD1A dysfunction, non-human primate models can serve as a useful tool because of their close evolutionary relationship to humans and highly developed cognitive abilities. In this study, we established a genetically engineered common marmoset (Callithrix jacchus) lineage carrying a frameshift mutation in SETD1A, which is, to the best of our knowledge, the first non-human primate lineage carrying a mutation in an epigenetic regulatory gene associated with SCZ, and confirmed germline transmission of the mutant allele. In a comparison between fibroblasts derived from one SETD1A mutant and one wild-type marmoset, the mutant showed a lower SETD1A protein level, modest differences in H3K4me3 deposition, and broader differences in gene expression profiles. Although these molecular observations require validation using additional biological replicates, the establishment of this SETD1A mutant marmoset lineage provides a valuable platform for bridging molecular mechanisms with primate neurobiology and for investigating the role of epigenetic regulation in the pathophysiology of neuropsychiatric and neurodevelopmental disorders.

Animals↗
PubMed2026

MADCAP: isolation of novel nAb-naïve AAV capsids from metagenomic data.

UNLABELLED: Gene therapy using adeno-associated virus (AAV) vectors offers promising treatment for genetic disorders, but significant limitations restrict clinical application. Current AAV serotypes exhibit strong liver tropism and require high doses for extra-hepatic targeting, and pre-existing antibodies (NAbs) exclude up to 50% of potential patients. Evolutionarily distant isolates can evade neutralization but typically transduce human tissues poorly and require extensive engineering. We developed MADCAP (Metagenomic AAV Discovery and Capsid Annotation Pipeline) to systematically mine metagenomic data for functional, clinically relevant AAV capsids. We hypothesized that these sources might contain capsids that do not circulate widely in humans, can transduce human cells, and avoid neutralization. We screened 4.2 million metagenomic samples and identified 139 novel AAV capsid isolates which were tested for viral capsid assembly, viability, neutralization evasion, and tissue transduction in non-human primates. While natural serotypes (AAV1, AAV2, AAV9) were neutralized at low dilutions of pooled human immunoglobulin (IVIG), 68% of tested MADCAP capsids exhibited minimal to undetectable neutralization even at supra-physiological IVIG concentrations. Systemically delivered MADCAP capsids effectively transduced multiple clinically relevant tissues in non-human primates. Two capsids, MC46 and MC55, demonstrated improved CNS tropism compared to AAV9 while maintaining comparable production yields. In passive transfer studies, MC46 retained full transduction efficiency in the presence of human antibodies, while AAV9 transduction was completely lost. This work establishes metagenomic mining as a powerful tool for accelerating AAV capsid discovery, identifying isolates with favorable tissue tropisms and resistance to broadly neutralizing antibodies. IMPORTANCE: This work provides proof of concept that potentially clinically relevant AAVs can be isolated from metagenomic data. Our findings lay the groundwork for accelerated discovery of AAV capsids which could potentially increase the accessibility and effectiveness of AAV gene therapy.

AAV↗
PubMed2026

Long-term functional synaptic integration of genome-edited retinal organoids in a primate model of macular degeneration.

Retinal organoids represent a promising regenerative strategy for restoring vision in retinal degenerative diseases, but the capacity of host cone bipolar cells in the primate macula to rewire with transplanted photoreceptors has not been established. In this study, we transplanted genome-edited ISL1-/- human retinal organoids lacking ON-bipolar cells into an acute laser-induced macular photoreceptor ablation non-human primate model. Using immunohistochemistry, ultrastructural imaging, and focal macular electroretinography, we demonstrate that host rod and cone bipolar cells actively extend dendrites toward grafted photoreceptors and form synaptic contacts, with evidence of functional signal transmission in a subset of transplanted eyes. Longitudinal, per-eye analyses revealed that host ON-bipolar responses improved in two of four eyes with ISL1-/- graft by up to 21.6% and remained stable for up to 2 years post transplantation. Moreover, OFF-pathway connectivity showed potential progressive maturation, with delayed increase in d-wave after 13 months in one of those eyes. These findings provide the first demonstration of long-term anatomical host-graft synaptic integration in the primate macula, establishing that central cone bipolar circuits retain the capacity for durable rewiring with human stem-cell-derived grafts. Our results highlight ISL1-/- retinal organoids as a promising approach for central vision restoration in macular degeneration.

Animals↗
PubMed2025

Phylogenetics and genomic variation of Hepatocystis isolated from shotgun sequencing of wild primate hosts.

Hepatocystis are apicomplexan parasites nested within the Plasmodium genus that infect primates and other vertebrates, yet few isolates have been genetically characterized. Using taxonomic classification and mapping characteristics, we searched for Hepatocystis infections within publicly available, blood-derived whole genome sequence (WGS) data from 326 wild non-human primates (NHPs) in 17 genera. We identified 37 Hepatocystis infections in Papio cynocephalus (yellow baboons) and four species of Chlorocebus monkeys (grivets, green monkeys, vervet monkeys, and malbroucks) sampled from locations in west, east, and south Africa. Hepatocystis cytb sequences from Papio and Chlorocebus hosts each clustered within host species among previously reported isolates from other NHP taxa. Utilizing the low-coverage sequence data (0.11-0.76X per sample) recovered across the nuclear Hepatocystis genome, we identified 349,893 polymorphic sites. Principle components analysis based on genotype likelihoods across all samples showed evidence for population structure by primate host species. Across the genome, windows of high SNP density revealed candidate hypervariable loci including Hepatocystis-specific gene families possibly involved in immune evasion and genes that may be involved in adaptation to their insect vector and hepatocyte invasion. Overall, this work demonstrates how WGS data from wild NHPs can be leveraged to study the evolution of apicomplexan parasites and potentially test for association between host genetic variation and parasite infection.

Animals↗
PubMed2026

Discovery and evolution of endogenous retroviruses in the genome of crab-eating macaque (Macaca fascicularis).

Endogenous retroviruses (ERVs) are a dynamic and biologically significant component of vertebrate genomes, with integration events spanning deep evolutionary time. The crab-eating macaque (Macaca fascicularis) is an important non-human primate model for biomedical research because of its close phylogenetic relationship to humans and its conservation status as an endangered species. However, the ERV complement of its genome has not been systematically characterized. Using the current highest-quality chromosome-level genome assembly for this species, we performed a genome-wide, homology-based survey of relatively intact ERV proviruses in M. fascicularis. We identified 106 proviral loci distributed across all chromosomes. Phylogenetic reconstruction based on conserved reverse transcriptase domains classified these elements into β-, γ-, and unclassified lineages, with β- and γ-retroviral lineages predominating. LTR divergence-based dating indicated that these proviruses represent multiple waves of historical retroviral activity and span a broad range of integration ages. This curated dataset provides a high-confidence reference set for investigating the evolutionary history and genomic impact of preserved ERV proviruses in an endangered primate model; however, it does not include degraded ERV fragments or solo LTRs.

Animals↗
PubMed2026

Genomic Analysis of CTX-M-15-Producing E. coli Colonizing a Rescued Capuchin Monkey.

Illegal wild animal trade and possession represents a threat to One Health due to the pathogens exchange between wild animals and humans. We report the detection and genomic characterization of a multidrug-resistant (MDR) Escherichia coli strain (MP02) colonizing a capuchin monkey (Sapajus sp.) rescued from illegal possession. MP02 exhibited ExPEC-related genes, harbored an IncHI2-ST1 plasmid composed of quinolones, aminoglycosides, and sulfonamides resistance genes, besides the extended-spectrum β-lactamase (ESBL)-encoding gene blaCTX-M-15 located in a conserved Tn3-like transposon. To the author's knowledge, this is the first report and genomic analysis of a MDR bacterium isolated from an illegally traded non-human primate.

antibiotic resistance↗
PubMed2026

Pre-clinical immunogenicity and safety evaluation of H2 strain Hepatitis A Inactivated Vaccine in rhesus macaques.

BACKGROUND: Hepatitis A is a viral infection of the liver that can cause mild to severe illness. Currently, two types of HAV vaccines are used worldwide, inactivated hepatitis A vaccines, which are used in most countries, and live attenuated vaccines (H2 and L-A-1 strain), which are mainly used in China. The major disadvantage of live attenuated virus to cause secondary infections among contacts and mutation shifts of the live vaccine strain. The H2 strain was selected for the development of an inactivated hepatitis A vaccine to further reduce biosafety risks. Rhesus macaques high genomic homology with humans and the incubation period after hepatitis A vaccination and human natural infections are similar. We use rhesus macaques to assess immunogenicity and safety of the H2 strain Hepatitis A Inactivated Vaccine. METHODS: The vaccine was assessed in rhesus macaques, divided into four groups (n = 10 per group): the control group (adjuvant buffer; aluminum content 0.35 mg/mL; 2 mL per dose), the low-dose group (320EU, 0.5 mL of 640EU/mL with aluminum content 0.35 mg/mL), the medium-dose group (640EU, 1 mL of 640EU/mL with aluminum content 0.35 mg/mL), and the high-dose group (1280EU, 2 mL of 640EU/mL with aluminum content 0.35 mg/mL). Animals were injected intramuscularly at multiple sites in the hind limbs and received four inoculations at 4-week intervals. Test items including Clinical indicators, immunogenicity indicators and Histopathological examination. RESULTS: No abnormalities were observed in any group in terms of general clinical condition throughout the study period except for slight decreases in body temperature after immunization. Hematological parameters, serum biochemistry indices, and histopathological findings showed fluctuated to different degrees of fluctuation after immunization across all groups. Immunogenicity assessments showed that the inactivated hepatitis A vaccine (H2) induced both humoral and cellular immune responses effectively, and the levels of antibodies increased with certain dose- and time-response trends. CONCLUSION: The inactivated hepatitis A vaccine (H2 strain, human diploid cell) was safe and immunogenic in non-human primates. The results provide strong preclinical support for the further clinical development of this vaccine candidate.

Animals↗
PubMed2026

Long-term (>7-year) parental consumption of genetically modified maize (Cry1Ab/Cry2Aj and EPSPS) induces no adverse sperm DNA methylation alterations across two generations of cynomolgus monkeys.

This study assessed the long-term safety of genetically modified (GM) maize from a male reproductive perspective, using a non-human primate model. We analyzed the sperm DNA methylation profiles in cynomolgus monkeys fed GM maize, non-GM parental maize, or a conventional diet over two generations (F0/F1). Whole-genome bisulfite sequencing (WGBS) revealed no significant differences in global methylation levels among groups. The identified differentially methylated regions (DMRs) were short, enriched in non-regulatory genomic areas, and did not cluster after treatment. Functional enrichment analysis showed that DMR-associated genes were consistently involved in the same core biological pathways (e.g., mTOR and Wnt signaling) across all dietary comparisons. These findings indicate that GM maize consumption did not induce specific adverse epigenetic alterations in sperm, with the observed changes reflecting common physiological adaptations to dietary variations rather than GM-related effects.

Animals↗
PubMed2026

289th ENMC international workshop: assessing and managing emerging AAV related toxicities after gene therapy for neuromuscular disorders, 26 - 28 September 2025, Hoofddorp, The Netherlands.

Adeno-associated virus (AAV) mediated gene therapies has emerged as a potentially transformative treatment approaches for neuromuscular disorders, with two FDA-approved products now in widespread clinical use: onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy and delandistrogene moxeparvovec-rokl (Elevidys) for Duchenne Muscular Dystrophy. However, severe and occasionally fatal adverse events affecting vital organs, including the blood, liver, muscle, and heart, have emerged in both clinical trials and real-world post marketing settings. The 289th European NeuroMuscular Centre (ENMC) workshop convened 38 participants from patient advocacy groups, industry, and preclinical and clinical research groups to collaboratively review these toxicities, their underlying mechanisms, and potential mitigation and monitoring strategies. Discussions addressed the clinical spectrum and biological drivers of these events, the respective roles of innate and adaptive immunity, the contribution of specific vector characteristics as well as of the specific disease and recipient. The application of risk stratification and immunosuppressive regimens for prevention, monitoring, and management were considered. Emerging toxicities, including capillary leak syndrome, endothelial and dorsal root ganglia injuries, were reviewed alongside corresponding preclinical data from non-human primates. Participants agreed on the need to harmonize standard operating procedures, clinical guidelines, and data-sharing practices, and endorsed collaborative initiatives to proactively address critical gaps and unresolved key questions through a patient-centered framework.

Adaptive immune response↗
PubMed2026

Glucocorticoids and placental 11βHSD2 - A systematic review of human studies and animal models.

CONTEXT: Elevated prenatal glucocorticoid (GC) exposure is linked to adverse offspring outcomes. The placental enzyme 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2) protects the fetus by converting maternal derived cortisol to inactive cortisone. Although in vitro studies suggest GC mediated upregulation of 11βHSD2, in vivo evidence remains inconclusive. METHODS: PubMed, Embase, and PsycInfo were searched in October 2024 for human and mammalian animal studies on endogenous or exogenous GCs during pregnancy and associations with placental 11βHSD2 (mRNA, protein, activity, gene methylation). Narrative synthesis was conducted due to heterogeneity precluding meta-analysis. RESULTS: Eighteen studies (eight human, ten animal populations) met inclusion criteria. Exogenous GC exposure was associated with modifications in placental 11βHSD2 expression in animal models, with effects varying by substance, timing, and species. Dexamethasone trended towards increased expression in rodents, whereas betamethasone increased expression in non-human primates but not rodents. Human studies on endogenous GCs showed inconsistent associations with 11βHSD2 changes. In asthmatic pregnancies, moderate inhaled GC-use maintained enzyme activity compared to untreated patients. No convincing sex-specific trend emerged. CONCLUSIONS: GC exposure alters placental 11βHSD2 in a substance- and species-specific way; translational relevance remains limited based on current literature. Future studies should employ technological advances and include GC-sensitive biomarkers to clarify mechanisms of maternal-fetal stress transmission.

Female↗
PubMed2016

Activin A programs the differentiation of human TFH cells.

Follicular helper T cells (TFH cells) are CD4(+) T cells specialized in helping B cells and are associated both with protective antibody responses and autoimmune diseases. The promise of targeting TFH cells therapeutically has been limited by fragmentary understanding of extrinsic signals that regulate the differentiation of human TFH cells. A screen of a human protein library identified activin A as a potent regulator of TFH cell differentiation. Activin A orchestrated the expression of multiple genes associated with the TFH program, independently or in concert with additional signals. TFH cell programming by activin A was antagonized by the cytokine IL-2. Activin A's ability to drive TFH cell differentiation in vitro was conserved in non-human primates but not in mice. Finally, activin-A-induced TFH programming was dependent on signaling via SMAD2 and SMAD3 and was blocked by pharmacological inhibitors.

Activins↗
PubMed2021

Comparative cellular analysis of motor cortex in human, marmoset and mouse.

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

Animals↗
PubMed2021

AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset.

Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system. The safety and efficacy of gene therapies rely upon expressing a transgene in affected cells while minimizing off-target expression. Here we show organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery, which we achieved by employing a Cre-transgenic-based screening platform and sequential engineering of AAV-PHP.eB between the surface-exposed AA452 and AA460 of VP3. From this selection, we identified capsid variants that were enriched in the brain and targeted away from the liver in C57BL/6J mice. This tropism extends to marmoset (Callithrix jacchus), enabling robust, non-invasive gene delivery to the marmoset brain after intravenous administration. Notably, the capsids identified result in distinct transgene expression profiles within the brain, with one exhibiting high specificity to neurons. The ability to cross the blood-brain barrier with neuronal specificity in rodents and non-human primates enables new avenues for basic research and therapeutic possibilities unattainable with naturally occurring serotypes.

Administration, Intravenous↗
PubMed2026

Mapping ovarian cellular and molecular landscape across the lifespan of women: a scoping review.

BACKGROUND: With growing interest in ART, fertility preservation, and postmenopausal health of women, reproductive medicine is increasingly focused on characterizing oocytes and ovarian tissue composition, as well as understanding the molecular mechanisms that guide ovarian function throughout its lifecycle. High-throughput omics technologies have enabled the characterization of different molecular layers, leading to substantial advances in our understanding of their complex dynamics. However, not all molecular aspects are studied equally, and studies examining the same modalities often show inconsistencies, underscoring the need for data standardization and highlighting the potential for using transformative artificial intelligence and machine-learning (AI/ML) methods for ovary studies. OBJECTIVE AND RATIONALE: This study aims to evaluate how multi-omic studies have advanced our understanding of the ovarian lifecycle from fetal development to postmenopause. We systematically reviewed published studies that have investigated molecular/omic layers, including the genome, methylome, transcriptome, and proteome throughout ovarian development and aging. Our analysis identified key molecular and cellular patterns, highlighted inconsistencies across studies and addressed gaps in data analysis, interpretation, and reproducibility to guide future research. SEARCH METHODS: We conducted a systematic literature search of Medline (PubMed), Embase (Ovid), and Web of Science Core Collection (Clarivate) using a combination of controlled and free text terms for human ovary, oogenesis, folliculogenesis, ovary development and (epi)genome, transcriptome, proteome, and multi-omic mechanisms to find relevant articles published before August 2025. To focus the scope of the current review, studies of domesticated and farm animals, rodents and other model organisms, non-human primates, as well as those examining various human ovarian pathologies were excluded. OUTCOMES: The search identified 23 546 studies for screening, of which 637 full-text studies were assessed for eligibility. Subsequently, we extracted data from 121 studies. Most studies analyzed the transcriptome of oocytes, granulosa cells, and ovarian tissue from reproductive-age individuals (n = 91), with fewer studies examining samples from individuals of advanced reproductive age (n = 45) and fetal (n = 16) samples. Transcriptome analyses were most common (n = 103, 85%), followed by proteome (n = 19, 16%) and epigenome (n = 14, 12%) studies. We found substantial variation in how studies defined and reported participants' groups as well as in their sequencing technologies and data analysis methods, with a lack of standardized reporting of background clinical information, data analysis methods, and pipeline details. The key findings underscore the prevailing consensus on genes defining major ovarian cell types and their roles throughout the ovarian lifespan, from prenatal development to postmenopausal transformation. This review highlighted the underrepresentation of certain patient groups, particularly prepubertal and peri-/postmenopausal individuals, among researched populations, due to obvious clinical and ethical reasons. WIDER IMPLICATIONS: This scoping review offers a comprehensive overview and benchmark of the current state of high-throughput omics-based research on ovarian cellular composition and molecular dynamics. To address these shortcomings, we propose general recommendations for multi-omics ovary studies and emphasize the necessity for more thorough multi-omic data integration by effectively applying novel AI/ML approaches. They can potentially improve the quality of multi-omics analyses at both single-cell and tissue levels despite limited sample sizes and enable integration of molecular profiling data with clinical and radiology datasets, enabling a more comprehensive understanding of ovarian biology. Such advancements can enhance reproducibility of research findings and guide future research to deepen our understanding of ovarian biology and ultimately support the development of medical technologies for better preserving fertility and alleviating infertility. REGISTRATION NUMBER: A protocol was published a priori on the Open Science Framework (https://osf.io/z38gb/).

Female↗
PubMed2025

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques.

The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses (β-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other β-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather than the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n = 6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-β-CoV vaccines.

Animals↗
PubMed2025

A genome-wide screen in ex vivo gallbladders identifies Listeria monocytogenes factors required for virulence in vivo.

Listeria monocytogenes is a Gram-positive pathogen that causes the severe foodborne disease listeriosis. Following oral infection of the host, L. monocytogenes disseminates from the gastrointestinal tract to peripheral organs, including the gallbladder, where it replicates to high densities, establishing the gallbladder as the primary bacterial reservoir. Despite its importance in pathogenesis, little is known about how L. monocytogenes survives and replicates in the gallbladder. In this study, we assessed the L. monocytogenes genes required for growth and survival in ex vivo non-human primate gallbladders using a transposon sequencing approach. The screen identified 43 genes required for replication in the gallbladder, some of which were known to be important for virulence, and others had not been previously studied in the context of infection. We evaluated the roles of 19 genes identified in our screen both in vitro and in vivo, and demonstrate that most were required for replication in bile in vitro, for intracellular infection of murine cells in tissue culture, and for virulence in an oral murine model of listeriosis. Interestingly, strains lacking the mannose and glucose phosphoenolpyruvate-dependent phosphotransferase system (PTS) permeases Mpt and Mpo exhibited no defects in intracellular growth or intercellular spread, but were significantly attenuated during murine infection. While the roles of PTS systems in vivo were not previously appreciated, these results suggest that PTS permeases are necessary for extracellular replication during infection. Overall, this study demonstrates that L. monocytogenes genes required for replication in the gallbladder also play broader roles in disease.

Listeria monocytogenes↗