Selected Grantee Publications
MARCKS Protein Is a Potential Target in a Naturally Occurring Equine Model of Neutrophilic Asthma
Conley et al., Respiratory Research. 2025.
https://pubmed.ncbi.nlm.nih.gov/40176021
Asthma is a chronic inflammatory airway disease that affects millions of people worldwide. Horses spontaneously develop asthma similar to humans, making the equine model ideal for studying airway inflammation. This study revealed that Myristoylated Alanine Rich C Kinase Substrate (MARCKS) protein levels were elevated in immune cells (macrophages and neutrophils) of male and female horses. Blocking this protein reduced inflammatory responses in these cells, suggesting that MARCKS may play a key role in driving asthma symptoms. These findings suggest that the MARCKS protein could potentially be a therapeutic target to reduce inflammation in severe neutrophilic asthma cases. Supported by ORIP (T32OD011130).
Whole-Genome Sequences of Six Borrelia recurrentis Strains Obtained via PacBio Sequencing
Gaber et al., Microbiology Resource Announcements. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11895452
The spirochetal bacterium Borrelia recurrentis causes louse-borne relapsing fever (LBRF), which leads to significant morbidity and mortality in several African countries. Previous sequencing studies of B. recurrentis demonstrated discrepancies and did not accurately define the antigenic variation system. In this study, researchers used long-read PacBio technology to conduct whole-genome sequencing of six B. recurrentis strains that had been isolated from LBRF patients earlier. The resulting sequences of each genome included one linear chromosome and five linear plasmids, whose average size was 1,284,895 bp, with the mean GC content being 27.5%. Supported by ORIP (T32OD011083) and NIAID.
Antimicrobial Resistance of Vibrio spp. from the Coastal California System: Discordance Between Genotypic and Phenotypic Patterns
Sebastian et al., Applied and Environmental Microbiology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39898660
Vibriosis, infection with non-cholera Vibrio spp., is the most common seafood-borne illness globally, with major impacts on public health, food security, and wildlife health. Potential treatments for antimicrobial-resistant Vibrio spp. in humans, aquaculture, and marine wildlife are complicated by current diagnostic challenges regarding bacterial species identification and interpretation of antimicrobial resistance patterns. Researchers sequenced 489 Vibrio spp. isolates, and antibiotic susceptibility testing was performed to compare the presence of resistance genes with phenotypes. Results determined that the presence of ß-lactamase genes alone in sea otter isolates does not necessarily correlate with an ampicillin-resistant phenotype, likely due to deleterious amino acid substitutions in certain blaCARB alleles. Unexpected detection of previously misidentified Vibrio diabolicus in sea otters suggests that a broader taxonomic group of Vibrio infect sea otters than previously described. Continued monitoring of Vibrio spp. phenotypes and genotypes in sea otters is warranted to observe biologically relevant changes in antimicrobial resistance. Supported by ORIP (T32OD011147).
Quorum Sensing LuxR Proteins VjbR and BabR Jointly Regulate Brucella abortus Survival During Infection
Caudill et al., Journal of Bacteriology. 2025.
https://pubmed.ncbi.nlm.nih.gov/40013834
Brucella abortus is a zoonotic bacterial pathogen that causes brucellosis, a persistent chronic infection that is globally endemic. B. abortus uses quorum sensing to escape immune clearance attempts, regulate virulence, and cause persistent infection within hosts. B. abortus quorum sensing system comprises two LuxR proteins, VjbR and BabR, as well as two signals, dodecanoyl (C12 AHL) and 3-oxododecanoyl (3-OXO-C12 AHL) homoserine lactone. Using chronic infection 6- to 7-week-old C57Bl/6 and BALB/c male and female mouse models, researchers found that the ΔvjbRΔbabR double-deletion strain was attenuated compared with single mutants. These results demonstrate that both quorum sensing proteins, VjbR and BabR, coordinate to maintain survival. This study helps further characterize the Brucella quorum sensing systems and indicates that further attention should be given to the joint interactions between VjbR and BabR in controlling virulence. Supported by ORIP (T32OD028239) and NIAID.
Enhanced RNA-Targeting CRISPR-Cas Technology in Zebrafish
Moreno-Sánchez et al., Nature Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/40091120
CRISPR-Cas13 RNA-targeting systems, widely used in basic and applied sciences, have generated controversy because of collateral activity in mammalian cells and mouse models. In this study, researchers optimized transient formulations as ribonucleoprotein complexes or mRNA-gRNA combinations to enhance the CRISPR-RfxCas13d system in zebrafish. Researchers used chemically modified gRNAs to allow more penetrant loss-of-function phenotypes, improve nuclear RNA targeting, and compare different computational models to determine the most accurate prediction of gRNA activity in vivo. Results demonstrate that transient CRISPR-RfxCas13d can effectively deplete endogenous mRNAs in zebrafish embryos without inducing collateral effects, except when targeting extremely abundant and ectopic RNAs. Their findings contribute to CRISPR-Cas technology optimization for RNA targeting in zebrafish through transient approaches and advance in vivo applications. Supported by ORIP (R21OD034161), NICHD, and NIGMS.
Suppressing APOE4-Induced Neural Pathologies by Targeting the VHL-HIF Axis
Jiang et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39874294
The ε4 variant of human apolipoprotein E (APOE4) is a major genetic risk factor for Alzheimer’s disease and increases mortality and neurodegeneration. Using Caenorhabditis elegans and male APOE-expressing mice, researchers determined that the Von Hippel-Lindau 1 (VHL-1) protein is a key modulator of APOE4-induced neural pathologies. This study demonstrated protective effects of the VHL-1 protein; the loss of this protein reduced APOE4-associated neuronal and behavioral damage by stabilizing hypoxia-inducible factor 1 (HIF-1), a transcription factor that protects against cellular stress and injury. Genetic VHL-1 inhibition also mitigated cerebral vascular injury and synaptic damage in APOE4-expressing mice. These findings suggest that targeting the VHL–HIF axis in nonproliferative tissues could reduce APOE4-driven mortality and neurodegeneration. Supported by ORIP (R24OD010943, R21OD032463, P40OD010440), NHGRI, NIA, and NIGMS.
A Defining Member of the New Cysteine-Cradle Family Is an aECM Protein Signalling Skin Damage in C. elegans
Sonntag et al., PLoS Genetics. 2025.
https://pubmed.ncbi.nlm.nih.gov/40112269
The rigid yet flexible apical extracellular matrix (aECM), known as the cuticle, works with the underlying epidermal layer to create a protective physical barrier against injury or infection in the roundworm Caenorhabditis elegans. The aECM communicates crucial signals to the epidermis based on environmental insults, allowing it to trigger immune activation and combat potential threats. This study investigated the molecular link between aECM and immune response in C. elegans. Investigators found that a secreted protein called SPIA-1 acts as an extracellular signal activator of cuticle damage and mediates immune response. This study sheds light on how epithelial cells detect and respond to damage. Supported by ORIP (R21OD033663, P40OD010440) and NIGMS.
Local Tissue Response to a C-X-C Motif Chemokine Ligand 12 Therapy for Fecal Incontinence in a Rabbit Model
Ruetten et al., American Journal of Physiology—Gastrointestinal and Liver Physiology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39745592
Obstetric anal sphincter injury (OASI) occurs in 2–7% of vaginal childbirths. Surgical interventions for OASI are suboptimal, with 30% of women reporting continued reduction in quality of life due to long-term fecal incontinence. Researchers used a 4- to 5-month-old female New Zealand white rabbit model for OASI to determine whether local C-X-C motif chemokine ligand 12 (CXCL12) injection reduces postinjury pathologies. Treatment with CXCL12 significantly reduced fibrosis. Untreated rabbits demonstrated reduced distinction of anal sphincter skeletal muscle layering and significantly increased the amount of fibrosis. Treatment with CXCL12 did not affect recruitment of CD34+ cells, the number of PAX7+ satellite cells, or innervation and vascularization of skeletal muscle. This pilot study demonstrates the potential of a novel therapeutic for OASI. Supported by ORIP (T32OD010957).
Prostatic Escherichia coli Infection Drives CCR2-Dependent Recruitment of Fibrocytes and Collagen Production
Scharpf et al., Disease Models & Mechanisms. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11789281
In men, lower urinary tract dysfunction (LUTD) is commonly linked to prostatic collagen accumulation through inflammation-mediated mechanisms. Researchers used 8- to 10-week-old male reporter mice, exposed to either sterile phosphate buffered saline (PBS) or Escherichia coli, to identify that circulating Lyz2+S100a4+Gli1+ myeloid-derived cells are recruited to the prostate to drive inflammation and collagen synthesis. Researchers also used 8- to 10-week-old male Ccr2‑/ - null and Ccr2+/- control mice, exposed to either sterile PBS or E. coli, to determine if Ccr2 is necessary for the fibrotic response to prostatic uropathogen infection. Results demonstrated that CCR2+ cells mediate the collagen abundance and fibrotic response to prostate inflammation. This study elucidates the cell types underlying prostate fibrosis and can be utilized to develop targeted therapies. Supported by ORIP (T32OD010957), NCI, NIDDK, and NIEHS.
A Murine Model of Trypanosoma brucei-Induced Myocarditis and Cardiac Dysfunction
Crilly et al., Microbiology Spectrum. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11792545
Trypanosoma brucei is a protozoan parasite that causes human and animal African trypanosomiases, HAT and AAT, respectively. Cardiac symptoms are commonly reported in HAT patients, and intracardiac parasites with accompanying myocarditis have been observed in both natural hosts and animal models for T. brucei infection. A clinically relevant, reproducible murine model for T. brucei–associated cardiomyopathy is currently unavailable. The researchers developed a 7- to 10-week-old C57Bl/6J male and female mouse model for T. brucei infection that demonstrates myocarditis, elevated serum levels of NT-proBNP, and electrocardiographic abnormalities, recapitulating the clinical features of infection. The results demonstrate the importance of interstitial space in T. brucei colonization and provide a relevant, reproducible murine model to investigate the pathogenesis and potential therapeutics of T. brucei-mediated heart damage. Supported by ORIP (T32OD011089, S10OD026859), NCI, and NIA.