Selected Grantee Publications
SALL1 Enforces Microglia-Specific DNA Binding and Function of SMADs to Establish Microglia Identity
Fixsen et al., Nature Immunology. 2023.
https://doi.org/10.1038/s41590-023-01528-8
Microglia function is thought to play a role in neurodevelopmental, psychiatric, and neurodegenerative diseases. Using knockout mice, investigators explored functional interactions between spalt-like transcription factor 1 (SALL1) and SMAD4, which demonstrated that interactions are mediated by a conserved microglia-specific SALL1 super-enhancer and result in direct activation of regulatory elements. The concerted interactions induce a microglia lineage determining program of gene expression. These findings indicate that expression of SALL1 and associated genes could contribute to phenotypes of aging and neurodegenerative diseases. Supported by ORIP (S10OD026929), NIA, NIMH, and NINDS.
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.
Allogeneic Immunity Clears Latent Virus Following Allogeneic Stem Cell Transplantation in SIV-Infected ART-Suppressed Macaques
Wu et al., Immunity. 2023.
https://doi.org/10.1016/j.immuni.2023.04.019
Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been documented as curative for HIV, but the mechanisms are not yet known. Using Mauritian cynomolgus macaques of both sexes, researchers performed reduced-intensity alloHSCT experiments to define the individual contributions of allogeneic immunity and CCR5 deficiency to an alloHSCT-mediated HIV cure. They reported that allogeneic immunity was the major driver of reservoir clearance, mediating graft-versus-reservoir effects in HIV infection. Their results also point to a protective mechanism for CCR5 deficiency early during engraftment. Future efforts could focus on harnessing the beneficial effects of allogeneic immunity while avoiding graft-versus-host disease. Supported by ORIP (P51OD011092) and NIAID.
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.
Phytochemical Compound PB125 Attenuates Skeletal Muscle Mitochondrial Dysfunction and Impaired Proteostasis in a Model of Musculoskeletal Decline
Musci et al., Journal of Physiology. 2023.
https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP282273
Age-related musculoskeletal decline contributes to disability and cardiometabolic diseases and is linked to impaired mitochondrial function and disrupted proteostasis. Using male and female Hartley guinea pigs, investigators tested a purported phytochemical activator of nuclear factor erythroid 2-related factor 2, which helps promote redox homeostasis, proteome maintenance, and mitochondrial energetics. They reported that the activator, PB125, improved mitochondrial respiration and attenuated disease- and age-related declines in skeletal muscle protein synthesis. This study provides insights for the development of interventions in humans. Supported by ORIP (T32OD010437) and NIA.
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.
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.
Simultaneous Evaluation of Treatment Efficacy and Toxicity for Bispecific T-Cell Engager Therapeutics in a Humanized Mouse Model
Yang et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300040R
Immuno-oncology–based therapies are an evolving powerful treatment strategy that targets the immune system and harnesses it to kill tumor cells directly. Investigators describe the novel application of a humanized mouse model that can simultaneously evaluate the efficacy of bispecific T cell engagers to control tumor burden and the development of cytokine release syndrome. The model also captures variability in responses for individual patients. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.
Brain Microglia Serve as a Persistent HIV Reservoir Despite Durable Antiretroviral Therapy
Tang et al., The Journal of Clinical Investigation. 2023.
https://www.doi.org/10.1172/JCI167417
Brain microglia are likely to play a role in rebound viremia following the cessation of antiretroviral therapy, but more work is needed to fully understand HIV persistence in the central nervous system (CNS). The investigators developed a protocol to isolate highly pure populations of brain myeloid cells and microglia from the tissues of male rhesus macaques, as well as from rapid autopsies of men and women with HIV. Their observations support the concept that brain microglia are a stable reservoir of quiescent infection. Thus, this work provides a physiologically relevant platform for studies of the biology of CNS reservoirs. Supported by ORIP (P51OD011132), NIAID, and NIMH.
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.