Selected Grantee Publications
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- 7 results found
- Rodent Models
- Infectious Diseases
- Imaging
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.
Characterization of Collaborative Cross Mouse Founder Strain CAST/EiJ as a Novel Model for Lethal COVID-19
Baker et al., Scientific Reports. 2024.
https://www.nature.com/articles/s41598-024-77087-1
Researchers characterized the Collaborative Cross (CC) mouse model founder strain CAST/EiJ as a novel model for severe COVID-19, exhibiting high viral loads and mortality. By leveraging genetically diverse CC strains, this study identified variations in susceptibility and survival against SARS-CoV-2 variants. CAST/EiJ mice developed lung pathology and mortality despite antiviral defenses, making them a valuable tool for understanding host–pathogen interactions. The findings emphasize the utility of diverse animal models in uncovering genetic and immunological factors that influence disease outcomes, facilitating the development of targeted therapies against COVID-19 to mitigate future pandemics. Supported by ORIP (P40OD011102).
Comparison of the Immunogenicity of mRNA-Encoded and Protein HIV-1 Env-ferritin Nanoparticle Designs
Mu et al., Journal of Virology. 2024.
https://journals.asm.org/doi/10.1128/jvi.00137-24
Inducing broadly neutralizing antibodies (bNAbs) against HIV-1 remains a challenge because of immune system limitations. This study compared the immunogenicity of mRNA-encoded membrane-bound envelope (Env) gp160 to HIV-1 Env-ferritin nanoparticle (NP) technology in inducing anti-HIV-1 bNAbs. Membrane-bound mRNA encoding gp160 was more immunogenic than the Env-ferritin NP design in DH270 UCA KI mice, but at lower doses. These results suggest further analysis of mRNA design expression and low-dose immunogenicity studies are necessary for anti-HIV-1 bNAbs. Supported by ORIP (P40OD012217, U42OD021458) and NIAID.
Loss of Lymphatic IKKα Disrupts Lung Immune Homeostasis, Drives BALT Formation, and Protects Against Influenza
Cully et al., Immunohorizons. 2024.
https://pubmed.ncbi.nlm.nih.gov/39007717/
Tertiary lymphoid structures (TLS) have context-specific roles, and more work is needed to understand how they function in separate diseases to drive or reduce pathology. Researchers showed previously that lymph node formation is ablated in mice constitutively lacking IκB kinase alpha (IKKα) in lymphatic endothelial cells (LECs). In this study, they demonstrated that loss of IKKα in lymphatic endothelial cells leads to the formation of bronchus-associated lymphoid tissue in the lung. Additionally, they showed that male and female mice challenged with influenza A virus (IAV) exhibited markedly improved survival rates and reduced weight loss, compared with littermate controls. They concluded that ablating IKKα in this tissue reduces the susceptibility of the mice to IAV infection through a decrease in proinflammatory stimuli. This work provides a new model to explore the mechanisms of TLS formation and the immunoregulatory function of lung lymphatics. Supported by ORIP (T35OD010919), NHLBI, NIAID, and NIAMS.
Proof-of-Concept Studies With a Computationally Designed Mpro Inhibitor as a Synergistic Combination Regimen Alternative to Paxlovid
Papini et al., PNAS. 2024.
As the spread and evolution of SARS-CoV-2 continues, it is important to continue to not only work to prevent transmission but to develop improved antiviral treatments as well. The SARS-CoV-2 main protease (Mpro) has been established as a prominent druggable target. In the current study, investigators evaluate Mpro61 as a lead compound, utilizing structural studies, in vitro pharmacological profiling to examine possible off-target effects and toxicity, cellular studies, and testing in a male and female mouse model for SARS-CoV-2 infection. Results indicate favorable pharmacological properties, efficacy, and drug synergy, as well as complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate. Supported by ORIP (R24OD026440, S10OD021527), NIAID, and NIGMS.
In Vitro and In Vivo Functions of SARS-CoV-2 Infection-Enhancing and Neutralizing Antibodies
Li et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.06.021
Antibody-dependent enhancement of infection is a concern for clinical use of antibodies. Researchers isolated neutralizing antibodies against the receptor-binding domain (RBD) or N-terminal domain (NTD) of SARS-CoV-2 spike from COVID-19 patients. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific binding modes. RBD and NTD antibodies mediated both neutralization and infection enhancement in vitro. However, infusion of these antibodies into mice or macaques resulted in suppression of virus replication, demonstrating that antibody-enhanced infection in vitro does not necessarily predict enhanced infection in vivo. RBD-neutralizing antibodies having cross-reactivity against coronaviruses were protective against SARS-CoV-2, the most potent of which was DH1047. Supported by ORIP (P40OD012217, U42OD021458, S10OD018164), NIAID, NCI, NIGMS, and NIH Common Fund.