Selected Grantee Publications
A Defect in Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism and Causes Elevated Ceramide Levels
Dutta et al., Nature Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37653044/
Human mitochondrial enoyl coenzyme A reductase (Mecr), required for the last step of mitochondrial fatty acid synthesis (mtFAS), is linked to pediatric-onset neurodegeneration, but with unknown mechanisms. Researchers investigated phenotypes of mecr mutants in Drosophila and human-derived fibroblasts. They found that loss of function of Mecr in the whole body resulted in a defect in Fe-S cluster biogenesis and increased iron levels, leading to elevated ceramide levels and lethality in flies. Similar elevated ceramide levels and impaired iron homeostasis were observed human-derived fibroblasts with Mecr deficiency. Neuronal loss of Mecr led to progressive neurodegeneration in flies. This study pointed out a mechanistic link between mtFAS and neurodegeneration through Mecr. Supported by ORIP (R24OD022005, R24OD031447), NICHD, and NINDS.
Intestinal Microbiota Controls Graft-Versus-Host Disease Independent of Donor–Host Genetic Disparity
Koyama et al., Immunity. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480848/
Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematopoietic malignancies and non-malignant diseases, but acute graft-versus-host disease (GVHD) remains a serious complication. Specifically, severe gut GVHD is the major cause of transplant-related mortality. Here, the authors show that genetically identical mice, sourced from different vendors, had distinct commensal bacterial compositions, which resulted in significantly discordant severity in GVHD. These studies highlight the importance of pre-transplant microbiota composition for the initiation and suppression of immune-mediated pathology in the gastrointestinal tract, demonstrating the impact of non-genetic environmental determinants to transplant outcome. Supported by ORIP (S10OD028685), NIA, NCI, and NHLBI.
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
Proteomic Profiling of Extracellular Vesicles Isolated From Plasma and Peritoneal Exudate in Mice Induced by Crotalus scutulatus scutulatus Crude Venom and Its Purified Cysteine-Rich Secretory Protein (Css-CRiSP)
Reyes et al., Toxins (Basel). 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10467150/
Toxins in viperid snakes can induce clinically heterogeneous effects, but most viper venoms are composed of only 10 main protein families. Researchers investigated the proteome expression profile of extracellular vesicles isolated from biofluid samples from male and female mice after injection with crude venom and cysteine-rich secretory proteins. They reported changes in the expression of proteins involved in cell adhesion, cytoskeleton rearrangement, signal transduction, immune responses, and vesicle-mediated transports. This work could be applied in future efforts for early detection and assessment of local effects. Supported by ORIP (P40OD010960), NIGMS, and NHLBI.
Osteopontin Is an Integral Mediator of Cardiac Interstitial Fibrosis in Models of Human Immunodeficiency Virus Infection
Robinson et al., The Journal of Infectious Diseases. 2023.
https://www.doi.org/10.1093/infdis/jiad149
HIV infection is associated with increased risk of cardiovascular disease. Plasma osteopontin (Opn) is correlated with cardiac pathology, but more work is needed to understand the underlying mechanisms driving cardiac fibrosis. Researchers explored this topic using mouse embryonic fibroblasts, male macaques, and humanized mice of both sexes. They reported the accumulation of Opn in the heart with simian immunodeficiency virus infection. Systemic inhibition of Opn can prevent HIV-associated interstitial fibrosis in the left ventricle. These findings suggest that Opn could be a potential target for adjunctive therapies to reduce cardiac fibrosis in people with HIV. Supported by ORIP (P51OD011104), NIAID, NHLBI, NIMH, and NINDS.
Lymph-Node-Based CD3+ CD20+ Cells Emerge From Membrane Exchange Between T Follicular Helper Cells and B Cells and Increase Their Frequency Following Simian Immunodeficiency Virus Infection
Samer et al., Journal of Virology. 2023.
https://www.doi.org/10.1128/jvi.01760-22
CD4+ T follicular helper cells are known to persist during antiretroviral therapy (ART) and have been identified as key targets for viral replication and persistence. Researchers identified a lymphocyte population that expresses CD3 (i.e., T cell lineage marker) and CD20 (i.e., B cell lineage marker) on the cellular surface in lymphoid tissues from rhesus macaques of both sexes and humans of male and female sexes. In macaques, the cells increased following simian immunodeficiency virus infection, were reduced with ART, and increased in frequency after ART interruption. These cells represent a potential area for future therapeutic strategies. Supported by ORIP (P51OD011132, U42OD011023), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography
Coughlan et al., JAMA Neurology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37010830/
To understand the predominance (70%) of women among individuals with Alzheimer’s disease, the investigators studied regional tau and β-amyloid (Aβ) in relation to age at menopause and hormone therapy (HT) in postmenopausal women and age-matched men using positron emission tomography. The study demonstrated that females exhibited higher tau deposition compared with age-matched males, particularly in the setting of elevated Aβ; earlier age at menopause and late initiation of HT were associated with increased tau vulnerability. This study suggests female individuals with these conditions may be at higher risk of pathological burden. Supported by ORIP (S10OD025245), NIA, and NICHD.
HIV, Asymptomatic STI, and the Rectal Mucosal Immune Environment Among Young Men Who Have Sex With Men
Van Doren et al., PLOS Pathogens. 2023.
https://www.doi.org/10.1371/journal.ppat.1011219
Young men who have sex with men (YMSM) are affected disproportionately by HIV and bacterial sexually transmitted infections (STIs) and therefore are likely to face an increased burden of associated chronic inflammation. Researchers studied the immunologic effects and interactions of HIV and bacterial STIs, as well as their effects on the rectal mucosal immune environment, among various populations of YMSM. Their findings suggest that asymptomatic bacterial STIs could contribute to inflammation, particularly among YMSM with HIV. This study provides insights into the immunopathogenesis of asymptomatic bacterial STIs and identifies a syndemic interaction between HIV and bacterial STIs in YMSM. Supported by ORIP (P51OD011132), NIAID, and NICHD.
CD8+ T Cells Promote HIV Latency by Remodeling CD4+ T Cell Metabolism to Enhance Their Survival, Quiescence, and Stemness
Mutascio et al., Immunity. 2023.
https://www.doi.org/10.1016/j.immuni.2023.03.010
An HIV reservoir persists following antiretroviral therapy, representing the main barrier to an HIV cure. Using a validated in vitro model, investigators explored the mechanism by which CD8+ T cells promote HIV latency and inhibit latency reversal in HIV-infected CD4+ T cells. They reported that CD8+ T cells favor the establishment of HIV latency by modulating metabolic, stemness, and survival pathways that correlate with the downregulation of HIV expression and promote HIV latency. In future studies, comparative analyses may provide insight into common molecular mechanisms in the silencing of HIV expression by CD8+ T cells and macrophages, which can be applied to new intervention strategies that target the HIV reservoir. Supported by ORIP (P51OD011132, S10OD026799), NIAID, NIDDK, NIDA, NHLBI, and NINDS.
Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates
Maity et al., Molecular & Cellular Proteomics. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981268/
In this study, researchers examined the proteins expressed in cerebrospinal fluid (CSF) in nonhuman primates (NHPs) to better understand how COVID-19 infection can result in brain pathology, a common outcome. The study found that even in NHPs with minimal or mild COVID‑19, CSF proteins were significantly dysregulated compared with uninfected NHPs. Furthermore, the most affected proteins were enriched in the same brain regions that show lesions after COVID-19 infection, including the cerebral cortex, basal ganglia, and brain stem. Collectively, these regions have wide-ranging control over such crucial functions as cognition, motor control, and breathing, showing how even mild COVID-19 infection can result in significant neurological impairment. Supported by ORIP (P51OD011104, S10OD032453), NIGMS, NCI, and NICHD.