Selected Grantee Publications
A Multidimensional Metabolomics Workflow to Image Biodistribution and Evaluate Pharmacodynamics in Adult Zebrafish
Jackstadt et al., Disease Models & Mechanisms. 2022.
https://www.doi.org/10.1242/dmm.049550
The evaluation of tissue distribution and pharmacodynamic properties of a drug is essential but often expensive in clinical research. The investigators developed a multidimensional metabolomics platform to evaluate drug activity that integrates mass spectrometry–based imaging, absolute drug quantitation, in vivo isotope tracing, and global metabolome analysis in zebrafish. They validated this platform by evaluating whole-body distribution of the anti-rheumatic agent hydroxychloroquine sulfate and its impact on the systemic metabolism of adult zebrafish. This work suggests that the multidimensional metabolomics platform is a cost-effective method for evaluating on- and off-target effects of drugs. Supported by ORIP (R24OD024624) and NIEHS.
Large Comparative Analyses of Primate Body Site Microbiomes Indicate That the Oral Microbiome Is Unique Among All Body Sites and Conserved Among Nonhuman Primates
Asangba et al., Microbiology Spectrum. 2022.
https://www.doi.org/10.1128/spectrum.01643-21
Microbiomes are critical to host health and disease, but large gaps remain in the understanding of the determinants, coevolution, and variation of microbiomes across body sites and host species. Thus, researchers conducted the largest comparative study of primate microbiomes to date by investigating microbiome community composition at eight distinct body sites in 17 host species. They found that the oral microbiome is unique in exhibiting notable similarity across primate species while being distinct from the microbiomes of all other body sites and host species. This finding suggests conserved oral microbial niche specialization, despite substantial dietary and phylogenetic differences among primates. Supported by ORIP (P51OD010425, P51OD011107, P40OD010965, R01OD010980), NIA, NIAID, and NICHD.
Adverse Biobehavioral Effects in Infants Resulting from Pregnant Rhesus Macaques’ Exposure to Wildfire Smoke
Capitanio et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-29436-9
Exposure to wildfire smoke (WFS) is a growing health concern as wildfires increase in number and size due to climate change. Researchers found that developing rhesus monkeys exposed to WFS from the Camp Fire in California (November 2018) during the first third of gestation exhibited greater inflammation, blunted cortisol, more passive behavior, and memory impairment compared to animals conceived after smoke had dissipated. Analysis of a historical control cohort did not support the alternative hypothesis that conception timing alone explained the results. These findings suggest that WFS may have a teratogenic effect on neural development in the primate fetus. Supported by ORIP (P51OD011107, R24OD010962) and NIEHS.
A Potent Myeloid Response Is Rapidly Activated in the Lungs of Premature Rhesus Macaques Exposed to Intra-Uterine Inflammation
Jackson et al., Mucosal Immunology. 2022.
https://www.doi.org/10.1038/s41385-022-00495-x
Up to 40% of preterm births are associated with histological chorioamnionitis (HCA), which can lead to neonatal mortality, sepsis, respiratory disease, and neurodevelopmental problem. Researchers used rhesus macaques to comprehensively describe HCA-induced fetal mucosal immune responses and delineate the individual roles of IL-1β and TNFα in HCA-induced fetal pathology. Their data indicate that the fetal innate immune system can mount a rapid, multifaceted pulmonary immune response to in utero exposure to inflammation. Taken together, this work provides mechanistic insights into the association between HCA and the postnatal lung morbidities of the premature infant and highlights the therapeutic potential of inflammatory blockade in the fetus. Supported by ORIP (P51OD011107), NIEHS, NIDDK, NHLBI, and NICHD.
Inflammatory Blockade Prevents Injury to the Developing Pulmonary Gas Exchange Surface in Preterm Primates
Toth et al., Science Translational Medicine. 2022.
https://www.doi.org/10.1126/scitranslmed.abl8574
Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25% to 40% of preterm births. Investigators used a prenatal rhesus macaque model to assess how fetal inflammation could affect lung development. They found that inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure. Blockade of the inflammatory cytokines IL-1β and TNFα ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells. These data provide new insight into key mechanisms of developmental lung injury and highlight targeted inflammatory blockade as a potential therapeutic approach to ameliorate lung injury in the neonatal population. Supported by ORIP (P51OD011107), NIAID, NHLBI, NICHD, and NIEHS.
Natural Disaster and Immunological Aging in a Nonhuman Primate
Watowich et al., PNAS. 2022.
https://www.pnas.org/content/119/8/e2121663119
Weather-related disasters can exacerbate existing morbidities and increase mortality risk. Researchers examined Hurricane Maria’s impact on immune cell gene expression in large, age-matched, cross-sectional samples from free-ranging rhesus macaques (Macaca mulatta) living on an isolated island. Hurricane Maria was significantly associated with differential expression of 4% of immune-cell-expressed genes and was correlated with age-associated alterations in gene expression, in addition to expression of key immune genes, dysregulated proteostasis networks, and greater expression of inflammatory immune cell-specific marker genes. These findings illuminate that natural disasters might become biologically embedded and contribute to earlier onset of disease and death. Supported by ORIP (P40OD012217), NIA, NIMH.
Monoclonal Antibodies Protect Aged Rhesus Macaques From SARS-CoV-2-Induced Immune Activation and Neuroinflammation
Verma et al., Cell Reports. 2021.
https://www.sciencedirect.com/science/article/pii/S2211124721014157?via%3Dihub%C2%A0=
In aged diabetic female rhesus macaques, prophylactic administration of neutralizing monoclonal antibodies (mAbs) effectively limits SARS-CoV-2 replication in both the upper and lower respiratory tract, and decreases immune activation, including reducing interferon-induced chemokines and limiting effector CD4 T cell influx into the cerebrospinal fluid. These protective mechanisms took place in the areas of the body targeted by the virus and may prevent adverse inflammatory consequences of SARS-CoV-2 infection in high-risk populations. Supported by ORIP (P51OD011107), NIAID, and NIA.
Advancing Human Disease Research with Fish Evolutionary Mutant Models
Beck et al., Trends in Genetics. 2021.
https://pubmed.ncbi.nlm.nih.gov/34334238/
Model organism research is essential to understand disease mechanisms. However, laboratory-induced genetic models can lack genetic variation and often fail to mimic disease severity. Evolutionary mutant models (EMMs) are species with evolved phenotypes that mimic human disease. They have improved our understanding of cancer, diabetes, and aging. Fish are the most diverse group of vertebrates, exhibiting a kaleidoscope of specialized phenotypes, many that would be pathogenic in humans but are adaptive in the species' specialized habitat. Evolved compensations can suggest avenues for novel disease therapies. This review summarizes current research using fish EMMs to advance our understanding of human disease. Supported by ORIP (R01OD011116), NIA, NIDA, and NIGMS.
Innate Immunity Stimulation via CpG Oligodeoxynucleotides Ameliorates Alzheimer’s Disease Pathology in Aged Squirrel Monkeys
Patel et al., Brain: A Journal of Neurology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34128045/
Alzheimer's disease is the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The authors have shown in transgenic Alzheimer's disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-β, tau pathology, and cerebral amyloid angiopathy (CAA). They used a nonhuman primate model for sporadic Alzheimer's disease pathology that develops extensive CAA-elderly squirrel monkeys. They demonstrate that long-term use of Class B CpG ODN 2006 induces a favorable degree of innate immunity stimulation. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. This evidence together with their earlier research validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach. Supported by ORIP (P40OD010938), NINDS, NIA, and NCI.
Rhesus Macaques Build New Social Connections After a Natural Disaster
Testard et al., Current Biology. 2021.
https://www.sciencedirect.com/science/article/pii/S0960982221003687
Climate change has increased the frequency and intensity of weather-related disasters such as hurricanes and floods. In 2017, Puerto Rico suffered its worst natural disaster, Hurricane Maria, leaving 3,000 dead and provoking a mental health crisis. Cayo Santiago Island, home to a population of rhesus macaques (Macaca mulatta), was devastated by this storm. Testard et al. compared social networks of two groups of macaques before and after the hurricane and found an increase in affiliative social connections, driven largely by monkeys most socially isolated before Hurricane Maria. Further analysis revealed monkeys invested in building new relationships rather than strengthening existing ones. Supported by ORIP (P40OD012217), NIA, and NIMH.