Selected Grantee Publications
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- 351 results found
- Immunology
- Vaccines/Therapeutics
Chronic TREM2 Activation Exacerbates Aβ-Associated Tau Seeding and Spreading
Jain et al., Journal of Experimental Medicine. 2023.
Using a mouse model for amyloidosis in which Alzheimer’s Disease (AD)–associated tau is injected into the brain to induce amyloid β (Aβ)–dependent tau seeding/spreading, investigators found that chronic administration of an activating triggering receptor expressed on myeloid cells 2 (TREM2) antibody increases microglial activation of dystrophic neurites surrounding Aβ plaques (NP) but increases NP-tau pathology and neuritic dystrophy without altering Aβ plaque burden. These data suggest that sustained microglial activation through TREM2 that does not result in strong myeloid removal might exacerbate Aβ-induced tau pathology, which could have important clinical implications. Supported by ORIP (S10OD021629) and NIA.
A Deep Learning Platform to Assess Drug Proarrhythmia Risk
Serrano et al., Cell Stem Cell. 2023.
https://www.sciencedirect.com/science/article/pii/S1934590922004866?via%3Dihub=
Investigators trained a convolutional neural network (CNN) classifier to learn and ultimately identify features of in vitro action potential recordings of human induced pluripotent stem cell (iPSC)–derived cardiomyocytes (hiPSC-CMs) that are associated with lethal Torsade de Pointes arrhythmia. The CNN classifier accurately predicted the risk of drug-induced arrhythmia. The risk profiles of the test drugs were similar across hiPSC-CMs derived from different healthy donors. In addition, pathogenic mutations that cause arrhythmogenic cardiomyopathies in patients significantly increased the proarrhythmic propensity to certain intermediate and high‑risk drugs in the hiPSC-CMs. These data indicate that deep learning can identify in vitro arrhythmic features that correlate with clinical arrhythmia and discern the influence of patient genetics on the risk of drug-induced arrhythmia. Supported by ORIP (S10OD030264) and NHLBI.
Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection
Abeynaike et al., Viruses. 2023.
https://www.mdpi.com/1999-4915/15/2/365
A major obstacle to human natural killer (NK) cell reconstitution is the lack of human interleukin‑15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Researchers show that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical cord blood–derived hematopoietic stem cells (HSCs). These mice demonstrate robust and long-term reconstitution with human immune cells but do not develop graft-versus-host disease, allowing long-term studies of human NK cells. The HSC-engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses. This work provides a robust novel model to study NK cell responses to HIV-1. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.
PGRN Deficiency Exacerbates, Whereas a Brain Penetrant PGRN Derivative Protects, GBA1 Mutation–Associated Pathologies and Diseases
Zhao et al., Proc Natl Acad Sci USA. 2023.
https://www.pnas.org/doi/10.1073/pnas.2210442120
Mutations in GBA1 are associated with Gaucher disease (GD) and are also genetic risks in developing Parkinson’s disease (PD). Investigators created a mouse model and demonstrated that progranulin (PGRN) deficiency in Gba1 mutant mice caused early onset and exacerbated GD phenotypes, leading to substantial increases in substrate accumulation and inflammation in visceral organs and the central nervous system. These in vivo and ex vivo data demonstrated that PGRN plays a crucial role in the initiation and progression. In addition, the mouse model provides a clinically relevant system for testing therapeutic approaches for GD and PD. Supported by ORIP (R21OD033660), NIAMS, and NINDS.
Elevated Transferrin Receptor Impairs T Cell Metabolism and Function in Systemic Lupus Erythematosus
Voss et al., Science Immunol. 2023.
https://www.science.org/doi/10.1126/sciimmunol.abq0178
Systemic lupus erythematosus (SLE) is an autoimmune disease in which dysfunctional T cells exhibit abnormalities in metabolism. Investigators performed a CRISPR screen to examine mechanisms associated with the role of excess iron in dysfunctional T cells. The transferrin receptor (CD71) was identified as differentially critical for Type 1 T helper cells and inhibitory for induced regulatory T cells. Activated T cells induced CD71 and iron uptake, which was exaggerated in SLE-prone T cells. Disease severity correlated with CD71 expression in cells from male and female patients with SLE, and blocking CD71 in vitro enhanced interleukin 10 secretion. These findings suggest that T cell iron uptake via CD71 contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology. Supported by ORIP (S10OD030264), NIAID, NCI, and NIDDK.
Surrogate Biomarkers of Disease Progression in Human Pegivirus Seropositive Human Immunodeficiency Virus–Infected Individuals
Vimali et al., Viral Immunology. 2023.
Researchers have previously observed that human pegivirus (HPgV) infection is associated with reduced progression of HIV. Investigators examined markers of HIV progression in male and female individuals with HIV and HPgV infection. They reported that HIV plasma viral load was lower in HPgV-seropositive individuals with HIV than in HPgV‑seronegative individuals with HIV. They also found that clinical markers of hepatic damage were significantly lower in HPgV-seropositive individuals with HIV. Future work could examine pathways through which HPgV influences HIV control, which might inform the development of new therapeutics. Supported by ORIP (P51OD011132) and NIAID.
The Ras GTPase‐Activating‐Like Protein IQGAP1 Bridges Gasdermin D to the ESCRT System to Promote IL‐1β Release via Exosomes
Liao et al., The EMBO Journal. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9811620/
The investigators identified IQGAP1, a scaffold protein, as a gasdermin D (GSDMD)–interacting protein through a nonbiased proteomic analysis. Functional investigation indicated that the interaction is required for lipopolysaccharide (LPS)- and ATP-induced exosome release. Further analysis revealed that IQGAP1 serves as an adaptor that bridges GSDMD and the associated IL‐1β complex to Tsg101 and enables the packaging of GSDMD and IL‐1β into exosomes. This process is dependent on an LPS‐induced increase in GTP‐bound CDC42, a small GTPase known to activate IQGAP1. This study reveals IQGAP1 as a link between inflammasome activation and exosomal release of IL‐1β. Supported by ORIP (S10OD023436) and NIAID.
Duration of Antiretroviral Therapy Impacts the Degree of Residual SIV Infection in the Gut in Long‐Term Non‐Progressing Chinese Rhesus Macaques
Solis-Leal et al., Journal of Medical Virology. 2023.
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28185
HIV and simian immunodeficiency virus (SIV) reservoirs have been shown to persist with antiretroviral therapy (ART), particularly in the gut‐associated lymphoid tissues in the intestine. The effects of ART on the reservoir size, however, had not been explored fully. In this study, researchers used male Chinese‐origin rhesus macaques to assess the effects of long- and short-term ART on gut infection—across segments of the small and large intestines—in long‐term non‐progressors (LTNPs). They reported that although ART does not eliminate SIV in LTNPs, a longer ART period dramatically reduces SIV infection and diversity in the gut. Further studies are needed to better understand the reduction of HIV gut reservoirs in this context. Supported by ORIP (P51OD011133, P51OD011104), NIAID, NIMH, and NINDS.
Recombinant Simian Varicella Virus–Simian Immunodeficiency Virus Vaccine Induces T and B Cell Functions and Provides Partial Protection Against Repeated Mucosal SIV Challenges in Rhesus Macaques
Pahar et al., Viruses. 2022.
https://www.doi.org/10.3390/v14122819
An effective vaccine is needed urgently to control the global HIV epidemic completely by 2030. Recombinant simian varicella virus (rSVV) vaccines expressing SIV antigens offer a potential new approach in the evaluation of HIV vaccine candidates. Building on their previous findings, the investigators induced systemic and mucosal immune responses with live, attenuated rSVV vaccinations followed by SIV group–specific antigen and SIV envelope protein boosts in female rhesus macaques treated with repeated intravaginal SIV challenges. Their findings demonstrate that the vaccination with protein boosts induces a 37.5% efficacy rate against pathogenic SIV challenge by generating mucosal memory, virus‑specific neutralizing antibodies, binding antibodies, and polyfunctional T cell responses. Supported by ORIP (P51OD011104) and NIAID.
Gut Microbiome Dysbiosis in Antibiotic-Treated COVID-19 Patients Is Associated with Microbial Translocation and Bacteremia
Bernard-Raichon et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-33395-6
The investigators demonstrated that SARS-CoV-2 infection induced gut microbiome dysbiosis in male mice. Samples collected from human COVID-19 patients of both sexes also revealed substantial gut microbiome dysbiosis. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicated that bacteria might translocate from the gut into the systemic circulation of COVID-19 patients. These results were consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19. Supported by ORIP (S10OD021747), NCI, NHLBI, NIAID, and NIDDK.