Selected Grantee Publications
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- 77 results found
- Cardiovascular
- COVID-19/Coronavirus
Cytomegalovirus Infection Facilitates the Costimulation of CD57+CD28- CD8 T Cells in HIV Infection and Atherosclerosis via the CD2–LFA-3 Axis
Winchester et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38047900/
People with HIV are at increased risk of developing atherosclerosis and other cardiovascular diseases, and HIV coinfection with cytomegalovirus (CMV) is associated with immune activation and inflammation. In this study, researchers explored the role of the CD2–LFA-3 axis in driving activation and proliferation of CD57+CD28- CD8 T cells using clinical samples from patients with or without HIV. They propose a model in which CMV infection is linked to enhanced CD2 expression on the T cells, enabling the activation via LFA-3 signals and potentially leading to cardiopathogenic interactions with vascular endothelial cells that express LFA-3. This work provides a potential therapeutic target in atherosclerosis development and progression, especially for people with HIV. Supported by ORIP (P51OD011132, U24OD011023) and NIAID.
Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population
Cruz Cisneros et al., Vaccines. 2024.
https://pubmed.ncbi.nlm.nih.gov/38276675/
The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. Although host genetic factors are known to affect vaccine efficacy for such respiratory pathogens as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. Investigators used the diversity outbred mouse model to study the effects of genetic variation on vaccine efficiency. Data indicate that variations in vaccine response in mice are heritable, similar to that in human populations. Supported by ORIP (U42OD010924), NIAID, and NIGMS.
The Impact of SIV-Induced Immunodeficiency on Clinical Manifestation, Immune Response, and Viral Dynamics in SARS-CoV-2 Coinfection
Melton et al., bioRxiv. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680717/
The effects of immunodeficiency caused by chronic HIV infection on COVID-19 have not been directly addressed in a controlled setting. Investigators conducted a pilot study in which two pigtail macaques (PTMs) chronically infected with SIVmac239 were exposed to SARS-CoV-2 and compared with SIV-naive PTMs infected with SARS-CoV-2. Despite the marked decrease in CD4+ T cells in the SIV-positive animals prior to exposure to SARS-CoV-2, investigators found that disease progression, viral persistence, and evolution of SARS-CoV-2 were comparable to the control group. These findings suggest that SIV-induced immunodeficiency alters the immune response to SARS-CoV-2 infection, leading to impaired cellular and humoral immunity. However, this impairment does not significantly alter the course of infection. Supported by ORIP (P51OD011104, U42OD013117, S10OD026800, S10OD030347) and NIAID.
Broad Receptor Tropism and Immunogenicity of a Clade 3 Sarbecovirus
Lee et al., Cell Host and Microbe. 2023.
https://www.sciencedirect.com/science/article/pii/S1931312823004225
Investigators showed that the S glycoprotein of the clade 3 sarbecovirus PRD-0038 in the African Rhinolophus bat has a broad angiotensin-converting enzyme 2 (ACE2) usage and that receptor-binding domain (RBD) mutations further expand receptor promiscuity and enable human ACE2 utilization. They generated a cryogenic electron microscopy structure of the RBD bound to ACE2, explaining receptor tropism and highlighting differences between SARS-CoV-1 and SARS-CoV-2. PRD‑0038 S vaccination elicits greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses, compared with SARS-CoV-2. These findings underline a potential molecular pathway for zoonotic spillover of a clade 3 sarbecovirus, as well as the need to develop pan-sarbecovirus vaccines and countermeasures. Supported by ORIP (S10OD032290, S10OD026959, S10OD021644), NIAID, NCI, and NIGMS.
The Power of the Heterogeneous Stock Rat Founder Strains in Modeling Metabolic Disease
Wagner et al., Endocrinology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37882530/
Metabolic diseases are a host of complex conditions, including obesity, diabetes mellitus, and metabolic syndrome. Endocrine control systems (e.g., adrenals, thyroid, gonads) are causally linked to metabolic health outcomes. In this study, investigators determined novel metabolic and endocrine health characteristics in both sexes of six available substrains similar to the N/NIH Heterogeneous Stock (HS) rat founders. This deep-phenotyping protocol provides new insight into the exceptional potential of the HS rat population to model complex metabolic health states. The following hypothesis was tested: The genetic diversity in the HS rat founder strains represents a range of endocrine health conditions contributing to the diversity of cardiometabolic disease risks exhibited in the HS rat population. Supported by ORIP (R24OD024617), NHLBI, NIGMS and NIDDK.
First-in-Human ImmunoPET Imaging of COVID-19 Convalescent Patients Using Dynamic Total-Body PET and a CD8-Targeted Minibody
Omidvari et al., Science Advances. 2023.
https://pubmed.ncbi.nlm.nih.gov/36993568/
Developing noninvasive methods for in vivo quantification of T cell distribution and kinetics is important because most T cells reside in the tissue. Investigators presented the first use of dynamic positron emission tomography (PET) and kinetic modeling for in vivo measurement of CD8+ T cell distribution in healthy individuals and COVID-19 patients. Kinetic modeling results aligned with the expected T cell trafficking effects. Tissue-to-blood ratios were consistent with modeled net influx rates and flow cytometry analysis. These results provide a promising platform for using dynamic PET to study the total-body immune response and memory. Supported by ORIP (S10OD018223) and NCI.
Zebrafish as a High Throughput Model for Organ Preservation and Transplantation Research
Da Silveira Cavalcante et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300076R
Organ transplantation increases the quality of life and life expectancy of patients with chronic end-stage diseases, but the preservation of organs for transplantation remains a significant barrier. In the current study, researchers demonstrate the value of zebrafish as a high-throughput model organism in the fields of solid-organ preservation and transplantation, with a focus on heart preservation via partial freezing. Their techniques have the potential to advance research in the fields of cryobiology and solid-organ transplantation. Supported by ORIP (R24OD031955) 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.
Sequential Intrahost Evolution and Onward Transmission of SARS-CoV-2 Variants
Gonzalez-Reiche et al., Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239218/
Most patients with COVID-19 clear the virus upon resolution of acute infection, but a subset of immunocompromised individuals develop persistent SARS-CoV-2 infections. In this study, investigators describe sequential persistent SARS-CoV-2 infections in three individuals that led to the emergence, forward transmission, and continued evolution of the Omicron BA.1 variant Omicron BA.1.23. The study demonstrated that in the presence of suboptimal immune responses, persistent viral replication is an important driver of SARS-CoV-2 diversification. This and other studies also highlight that strategies to prevent virus persistence and shedding and more effective therapies are needed to limit the spread of newly emerging, neutralization-resistant variants in vulnerable patients. Supported by ORIP (S10OD026880, S10OD030463), NIAID, and NCATS.
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.