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Orally delivered toxin–binding protein protects against diarrhoea in a murine cholera model
Oral vaccines against Vibrio cholera have been critical for cholera management, but the production of more efficacious and cost-effective approaches is still needed. Here the authors deliver a bivalent VHH construct that binds to cholera toxin and show protection in a murine cholera model.
- Marcus Petersson
- , Franz G. Zingl
- & Sandra Wingaard Thrane
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Nf2-FAK signaling axis is critical for cranial bone ossification and regeneration
Nf2 physically engages with focal adhesion kinase (FAK) to preferentially mediate Erk1/2 and PI3K catalytic p110 subunit/Akt signaling, regulating osteogenic lineage development, cranial bone ossification and regeneration.
- Junguang Liao
- , Yuping Huang
- & Guiqian Chen
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Age-associated differences in mucosal and systemic host responses to SARS-CoV-2 infection
The likelihood of severe COVID-19 increases with age upon SARS-CoV-2 infection and even milder disease manifestations might differ among age groups. Here authors show, by immune transcriptome analysis of samples from the upper respiratory tract and peripheral blood of participants from different age groups, that interferon responses are more typical for the young, while activation of myeloid, inflammatory, and coagulation pathways is exclusive to adults.
- Jillian H. Hurst
- , Aditya A. Mohan
- & Matthew S. Kelly
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Tracking HIV persistence across T cell lineages during early ART-treated HIV-1-infection using a reservoir-marking humanized mouse model
Characterization of HIV infection at the cellular level is important to understand the molecular forces maintaining the latent reservoir and productive infection in T cells. Here authors describe the pathways that are governing these T cell states across the T lineage via a humanized mouse model allowing precise labeling of the HIV-infected cells coupled to single cell RNA sequencing.
- Namita Satija
- , Foramben Patel
- & Benjamin K. Chen
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Dissecting apicoplast functions through continuous cultivation of Toxoplasma gondii devoid of the organelle
Here, Chen et al. bypass the critical metabolic pathways of the remnant plastid organelle of Toxoplasma gondii. A subsequent detailed characterization of parasites devoid of the apicoplast organelle provides unprecedented insights into its constituents, evolution and functions, uncovering new vulnerabilities.
- Min Chen
- , Szilamér Gyula Koszti
- & Joachim Kloehn
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Transcriptional diversification in a human-adapting zoonotic pathogen drives niche-specific evolution
Ghosh et al study transcriptional diversification in the human-adapting zoonotic pathogen, Bordetella hinzii, as it evolved during the course of a chronic infection, revealing plasticity and niche-specific functional adaptation to the blood and gastrointestinal compartments.
- Soma Ghosh
- , Chao-Jung Wu
- & John P. Dekker
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Early Alzheimer’s Disease with frequent neuritic plaques harbors neocortical tau seeds distinct from primary age-related tauopathy
Abnormal, misfolded tau proteins are found in cognitively normal individuals and Tauopathies, suggesting not all tau species are pathogenic. Here, the authors show tau seeding and post-translational modification profiles were associated with Aβ neuritic plaque density and differentiated two tauopathies.
- Danielle F. Browne
- , Denis S. Smirnov
- & Allison Kraus
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Axin formation inhibitor 1 aggravates hepatic ischemia‒reperfusion injury by promoting the ubiquitination and degradation of PPARβ
Hepatic ischemia reperfusion injury (HIRI) is a common complication after hepatectomy and liver transplantation. Here, the authors show that Axin1 exacerbates HIRI by promoting PPARβ ubiquitination and degradation via E3 ubiquitin ligase RBBP6, activating the NF-κB pathway, and may be a potential therapeutic target.
- Baolin Qian
- , Bing Yin
- & Yong Ma
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Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK
Adipose tissue macrophage (ATM) has been implicated in inflammation and obesity, but the underlying mechanisms are still unclear. Here the authors show that AMPK is suppressed in ATMs from mice fed with high fat diet, leading to subsequent activation of SUCLA2, over-production of succinate and IL-1β, and ultimately inflammation and obesity.
- Chang Peng
- , Haowen Jiang
- & Jia Li
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Structural insights into transcription regulation of the global OmpR/PhoB family regulator PhoP from Mycobacterium tuberculosis
The global regulator PhoP plays crucial roles in bacterial pathogenicity. Shi et al. report four cryo-EM structures of PhoP-dependent transcription activation and repression complexes, revealing dual transcription regulation mechanisms of PhoP.
- Jing Shi
- , Zhenzhen Feng
- & Wei Lin
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FTO-associated osteoclastogenesis promotes alveolar bone resorption in apical periodontitis male rat via the HK1/USP14/RANK pathway
Alveolar bone resorption (ABR) is a key pathological manifestation in the development of apical periodontitis (AP) that contributes to the AP-associated tooth loss, and whose underlying mechanism is largely unknown. Here, the authors show a molecular mechanism on osteoclastogenesis-related ABR and provides a therapeutic target of AP via modulating the FTO/HK1/USP14/RANK axis.
- Yajie Qian
- , Jing Wu
- & Deyan Chen
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Article
| Open Access
Deep mutational scanning of the Trypanosoma brucei developmental regulator RBP6 reveals an essential disordered region influenced by positive residues
Little is known about the presence and role of intrinsically disordered regions in RNA-binding proteins in trypanosomes. Here, the authors provide evidence for an intrinsically disordered domain in the essential N-terminal segment of RBP6.
- Saúl Rojas-Sánchez
- , Nikolay G. Kolev
- & Christian Tschudi
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Tunable control of Cas12 activity promotes universal and fast one-pot nucleic acid detection
CRISPR-based detection has long been challenged by the separation of amplification and detection steps. In this study, Cheng et al., show that heparin sodium modulates Cas12 cleavage activity and apply a one pot system to detect clinical influenza A virus and SARS-CoV-2 in wastewater.
- Zhou-Hua Cheng
- , Xi-Yan Luo
- & Han-Qing Yu
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MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma
The tumour immune microenvironment is known to be suppressive to immune cells, but the causal functional and metabolic cues are not fully known. Here authors show that tumour cells skew the metabolism of multiple types of intra-tumour dendritic cells via their own altered carbohydrate pattern, which could be mitigated by the inhibition of lactate transport.
- Camille Niveau
- , Mélanie Cettour-Cave
- & Caroline Aspord
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Lymphatic platelet thrombosis limits bone repair by precluding lymphatic transporting DAMPs
Lymphatic vessels are vital in the musculoskeletal system, but their role in bone repair is unclear. Here the authors found early lymphatic drainage insufficiency in fractures impacts osteoblast survival and stem cell proliferation by modulating the hematoma niche via DAMP transport.
- Yangkang Zheng
- , Lin Cong
- & YongJun Wang
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α-Synuclein fibrils enhance HIV-1 infection of human T cells, macrophages and microglia
Here, Olari et al show that alpha-synuclein enhances HIV-1 entry and replication in human T cells, macrophages and microglia which may contribute to the development of neurodegenerative disease.
- Lia-Raluca Olari
- , Sichen Liu
- & Frank Kirchhoff
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The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis
Therapy of tuberculosis is challenging, mainly due to complex structures of necrotic granulomas that often impair drug delivery. In this work, the authors show that the drug BTZ-043 fully penetrates necrotic granulomas and has potent lesional antibacterial activity.
- Andreas Römpp
- , Axel Treu
- & Kerstin Walter
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Patterns of Klebsiella pneumoniae bacteremic dissemination from the lung
Tracing barcoded clones of Klebsiella pneumoniae during pneumonia with bacteremia, Holmes and colleagues identify two modes of dissemination, with high or low bacterial burdens, and define the host and bacterial factors that influence this process.
- Caitlyn L. Holmes
- , Katherine G. Dailey
- & Michael A. Bachman
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Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease
Long Fung Chau and colleagues report the generation of transgenic pigs expressing human ACE2, and show that they exhibit clinical signs and immunopathology consistent with COVID-19 following infection with SARS-CoV-2, suggesting that human ACE2 transgenic pigs are a viable large animal model for COVID-19.
- Long Fung Chau
- , Simon Lillico
- & Finn Grey
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Neutrophil adhesion to vessel walls impairs pulmonary circulation in COVID-19 pathology
COVID-19 severity is linked to microthrombus formation. Here, using an in vivo two-photon imaging technique in mice and human scRNA-Seq data, the authors show increased adhesion molecules on vascular neutrophils leading to platelet aggregation and reduced lung perfusion.
- Hiroshi Ueki
- , I-Hsuan Wang
- & Yoshihiro Kawaoka
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Proteomic signature of HIV-associated subclinical left atrial remodeling and incident heart failure
Mechanisms underlying excess risk of heart failure among people with HIV are unclear. Here, the authors identify a proteomic signature enriched in immune activation and extracellular matrix remodeling that may reflect shared pathways in HIV and aging that contribute to risk of heart failure.
- Tess E. Peterson
- , Virginia S. Hahn
- & Wendy S. Post
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Two-component system GrpP/GrpQ promotes pathogenicity of uropathogenic Escherichia coli CFT073 by upregulating type 1 fimbria
Here, Li et al. report a two-component system, GrpP/GrpQ, which promotes UPEC pathogenicity. Mechanistically, GrpP/GrpQ directly activates type 1 fimbria expression to promote UPEC invasion in response to D-serine in the host urine.
- Xueping Li
- , Yu Pang
- & Lei Wang
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ITGB4/CD104 mediates zika virus attachment and infection
Here, the authors identify integrin beta 4 (ITGB4) as a key entry factor for Zika virus infection. An antibody targeting ITGB4 protects against viral infection and prevents fetal damage in mice, offering a potential therapeutic strategy.
- Haolong Cong
- , Jiuqiang Wang
- & Xiaodong Han
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Dynamics of the blood plasma proteome during hyperacute HIV-1 infection
How the human plasma proteome is altered during hyperacute HIV-1 infection remains elusive. Here, the authors profile plasma proteins in participants from sub-Saharan African countries before, during and after hyperacute infection and report differentially expressed proteins that define early host response and might serve as biomarkers.
- Jamirah Nazziwa
- , Eva Freyhult
- & Joakim Esbjörnsson
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The capicua-ataxin-1-like complex regulates Notch-driven marginal zone B cell development and sepsis progression
Follicular and marginal zone B cells differ in their development and in their role in subverting pathogens with marginal zone B cells bearing more innate-like properties, such as production of proinflammatory cytokines. Here authors show via B-cell specific genomic deletion mouse models that the transcriptional repressor capicua (CIC) and its binding partner, ataxin-1-like (ATXN1L), differentially regulate the development and function of these two main mature B cell populations, while playing a shared role in sepsis mediated by marginal zone B cells.
- Jong Seok Park
- , Minjung Kang
- & Yoontae Lee
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Granzyme K+CD8+ T cells interact with fibroblasts to promote neutrophilic inflammation in nasal polyps
Chronic rhinosinusitis with nasal polyps generally has a type 2 inflammatory eosinophilic profile but can have a treatment resistant neutrophilic phenotype. Here the authors characterise nasal polyps using single cell sequencing and spatial transcriptomics and show granzyme K+CD8+ T cells associated with neutrophilic inflammation which promote release of neutrophilic chemoattractants from fibroblasts.
- Cui-Lian Guo
- , Chong-Shu Wang
- & Zheng Liu
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Defective germinal center selection results in persistence of self-reactive B cells from the primary to the secondary repertoire in Primary Antiphospholipid Syndrome
Primary antiphospholipid syndrome (PAPS) is a clotting disorder attributed to autoreactive antibodies produced by B cells. Here the authors show, using single cell omics and B cell repertoire data, that autoreactive B cells originate from the natural B cell repertoire and escape germinal center selection to persist in PAPS patient via potential dysregulation of mTORC1 and MYC pathways.
- Yannick Dieudonné
- , Raquel Lorenzetti
- & Vincent Gies
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Mechanics-activated fibroblasts promote pulmonary group 2 innate lymphoid cell plasticity propelling silicosis progression
Crystalline silica particle exposure in the airways can lead to lung silicosis and progressive fibrosis. Here the authors use mouse silicosis models to show mechanics activated fibroblasts promote conversion of ILC2 to ILC1-like cells pulmonary fibrosis and that this is associated with a Notch3-IL-18 signalling pathway.
- Yangyang He
- , Fan Yang
- & Chao Li
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Altered genomic methylation promotes Staphylococcus aureus persistence in hospital environment
In this study, authors examine Staphylococcus aureus adaptability in hospitals, highlighting how a lineage evolved to reversibly suppress Agr, enhancing antibiotic resistance and colonization.
- Yuriko Yamazaki
- , Tomoka Ito
- & Yuumi Nakamura
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Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade
Macrophages are pleiotropic and can have different functions and phenotypes. Here the authors show that a population of macrophages, previously described as pro-fibrotic, can be induced through Notch2 blockade and that in a mouse lung injury and fibrosis model this macrophage population does not promote inflammation or fibrosis.
- Mayra Cruz Tleugabulova
- , Sandra P. Melo
- & Maximilian Nitschké
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Classification of distinct tendinopathy subtypes for precision therapeutics
This study classifies rotator cuff tendinopathy into three distinct subtypes that include a hypoxic atrophic, an inflammatory proliferative with white appearance and an inflammatory proliferative with red appearance subtype. Using both clinical data and animal models, the research reveals that glucocorticoid is only effective in treating the latter inflammatory proliferative subtype that has the highest level of neovascularization.
- Chenqi Tang
- , Zetao Wang
- & Weiliang Shen
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Humans without a sense of smell breathe differently
Humans use their nose to both smell and to breath, and respiratory patterns are known to be impacted by odors. Here, the authors applied a wearable respiratory logger to people without a sense of smell, and found that they breath differently. They suggest that this altered breathing may affect health, emotion and cognition.
- Lior Gorodisky
- , Danielle Honigstein
- & Noam Sobel
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HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status
It’s poorly understood how renal manifestations develop in HEV infection in patients. Here, the authors observe glomerular accumulation of the viral protein ORF2 in complex with host IgG in immunocompromised patients with chronic or acute HEV infection who developed glomerulonephritis.
- Anne-Laure Leblond
- , Birgit Helmchen
- & Achim Weber
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Annexin A2 promotes proliferative vitreoretinopathy in response to a macrophage inflammatory signal in mice
Proliferative vitreoretinopathy (PVR) is a vision-threatening response to ocular injury, in which retinal cells secrete tractional, scar-forming proteins. Here, the authors show that antibody blockade of either Annexin A2 or its inducer, macrophage inflammatory protein-1, prevents PVR in mice.
- Min Luo
- , Dena Almeida
- & Katherine A. Hajjar
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Single-cell transcriptomics reveals aberrant skin-resident cell populations and identifies fibroblasts as a determinant in rosacea
Rosacea is a common chronic inflammatory skin disorder mainly affecting the central face. Here, a single-cell atlas of facial skin from rosacea patients and healthy individuals reveals the molecular and cellular changes in skin-resident cell populations and identifies fibroblasts as a determinant in rosacea development.
- Mengting Chen
- , Li Yang
- & Ji Li
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Single-cell RNA sequencing reveals the pro-inflammatory roles of liver-resident Th1-like cells in primary biliary cholangitis
Primary biliary cholangitis is a chronic autoimmune disease critically linked to immunological dysregulation but the local immune-pathogenesis is poorly understood. Here the authors present single cell transcriptomic characterisation of primary biliary cholangitis and implicates Th1 like cells in a murine model.
- Ciliang Jin
- , Penglei Jiang
- & Yida Yang
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| Open Access
Nur77 protects the bladder urothelium from intracellular bacterial infection
Recent research has found that a protein, Nur77, helps detect the bacterial product lipopolysaccharide inside cells. In this study, authors show that Nur77 helps protect the bladder from infections caused by a common bacterium, Escherichia coli, which leads to urinary tract infections.
- Christina A. Collins
- , Chevaughn Waller
- & Nicole M. Gilbert
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Shared neutrophil and T cell dysfunction is accompanied by a distinct interferon signature during severe febrile illnesses in children
Severe febrile illnesses in children may be various in presentation and aetiology but involve immune dysfunction amenable to immunomodulation. Here, the authors identify shared neutrophil and T cell dysfunction and a distinct interferon signature in critically ill children with severe febrile illness.
- Harsita Patel
- , Michael J. Carter
- & Leire Estamiana Elorieta
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| Open Access
Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis
Antineutrophil cytoplasmic antibody (ANCA) is currently treated with broad-spectrum immune suppressive drugs. Here the authors decipher inflammatory niches in the kidney of patients with ANCA-GN by combining spatial and single-cell transcriptomics to identify ustekinumab as a promising treatment option and successfully treat four ANCA-GN patients.
- Jonas Engesser
- , Robin Khatri
- & Ulf Panzer
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| Open Access
A mouse protozoan boosts antigen-specific mucosal IgA responses in a specific lipid metabolism- and signaling-dependent manner
Immunoglobulin A (IgA) is an important part of the mucosal immune response. Here, the authors show that an intestinal commensal protist can enhance mucosal IgA production upon vaccination and that this involves the accumulation of free arachidonic acid in the intestinal lumen.
- Yanbo Kou
- , Shenghan Zhang
- & Yugang Wang
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Article
| Open Access
Prion protein alters viral control and enhances pathology after perinatal cytomegalovirus infection
The role of cellular prion protein (PrP) during CMV infection in newborns is not entirely clear. Here, the authors show that CMV-induced PrP release mediated by ADAM10 shedding impairs the neonatal antiviral response in mice by compromising CD8 T-cells leading to higher viral titers and more severe disease outcome.
- Dubravka Karner
- , Daria Kvestak
- & Tihana Lenac Rovis
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| Open Access
Mycobacterium tuberculosis cough aerosol culture status associates with host characteristics and inflammatory profiles
Using cough-generated aerosol cultures, authors probe the inflammatory markers and epidemiological characteristics of individuals with pulmonary tuberculosis, in association with infection state.
- Videlis Nduba
- , Lilian N. Njagi
- & David J. Horne
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| Open Access
The artemisinin-induced dormant stages of Plasmodium falciparum exhibit hallmarks of cellular quiescence/senescence and drug resilience
Artemisinin can induce dormant Plasmodium falciparum forms likely resulting in treatment failure. Here the authors characterize the transcriptome, viability, drug sensitivities, and cellular ultrastructure of dormant parasites after a ~ 5-day maturation process and demonstrate hallmarks of cellular quiescence and senescence.
- Jaishree Tripathi
- , Michal Stoklasa
- & Zbynek Bozdech
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| Open Access
Macrophage ILF3 promotes abdominal aortic aneurysm by inducing inflammatory imbalance in male mice
Here the authors investigate the involvement of the immune modulator ILF3 in abdominal aortic aneurysm, showing that macrophage ILF3 promotes aneurysm progression by increasing NF-kB activity and inhibiting Keap1-Nrf2 signaling.
- Zhao-yang Wang
- , Jie Cheng
- & Ming-xiang Zhang
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Rapid intra-host diversification and evolution of SARS-CoV-2 in advanced HIV infection
High-throughput, single-copy sequencing of SARS-CoV-2 spike in a longitudinal cohort of people with and without HIV infection demonstrates striking intra-host diversity and adaptive evolution of SARS-CoV-2 in people with advanced HIV infection.
- Sung Hee Ko
- , Pierce Radecki
- & Eli A. Boritz
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Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation
Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in type 2 alveolar epithelial (AT2) cells is thought to aggravate alveolar inflammation in acute lung injury. Here, the authors show that the mtLCFAO rate limiting enzyme CPT1a is decreased in AT2 cells in acute respiratory distress syndrome, highlighting the role of mtLCFAO in immunometabolism in this context.
- Kuei-Pin Chung
- , Chih-Ning Cheng
- & Chong-Jen Yu
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Molecular epidemiology and population immunity of SARS-CoV-2 in Guangdong (2022–2023) following a pivotal shift in the pandemic
Release of the zero-COVID policy in China in late 2022 led to two large Omicron-driven waves of infection in 2023. Here, the authors analyze virus genomes and serology data from before and after the two waves and describe changes in virus lineage distribution and age-specific antibody responses.
- Zhencui Li
- , Pei Hu
- & Jing Lu
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| Open Access
Dynamic PET reveals compartmentalized brain and lung tissue antibiotic exposures of tuberculosis drugs
Antibiotic treatments for tuberculous meningitis, the deadliest form of tuberculosis, are not optimized. Here, PET in human and animal studies is used to measure the biodistribution of several antibiotics to develop optimized regimens for drug-resistant tuberculous meningitis.
- Xueyi Chen
- , Bhavatharini Arun
- & Sanjay K. Jain
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| Open Access
RNA interactome of hypervirulent Klebsiella pneumoniae reveals a small RNA inhibitor of capsular mucoviscosity and virulence
By performing a global RNA-RNA interactome analysis in hypervirulent Klebsiella pneumoniae, the authors identify the small RNA ArcZ targets many capsule genes and a key virulence factor MlaA, inhibiting Klebsiella infection and pathogenesis in mice.
- Kejing Wu
- , Xingyu Lin
- & Yanjie Chao
Whole-body visualization of SARS-CoV-2 biodistribution in vivo by immunoPET imaging in non-human primates