Selected Grantee Publications
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- Immunology
- 2022
Reduced Alcohol Preference and Intake after Fecal Transplant in Patients with Alcohol Use Disorder Is Transmissible to Germ-Free Mice
Wolstenholme et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-34054-6
Alcohol use disorder is a major cause of reduced life expectancy worldwide, and this misuse has increased exponentially during the COVID-19 pandemic. Fecal microbiota transplant has been shown previously to reduce alcohol craving in humans with cirrhosis. Here, the investigators report that the reduction in craving and alcohol preference is transmissible to male germ-free mice only when live bacteria—and not germ-free supernatants—are used for colonization. This differential colonization was associated with alterations in the gut immune–inflammatory response through short-chain fatty acids. Supported by ORIP (P40OD010995), NIAAA, NIDDK, and NIMH.
Neuroinflammatory Transcriptional Programs Induced in Rhesus Pre‑Frontal Cortex White Matter During Acute SHIV Infection
Hawes et al., Journal of Neuroinflammation. 2022.
https://www.doi.org/10.1186/s12974-022-02610-y
Neuroinflammation has evolved as a protective immune response within the central nervous system (CNS), but chronic neuroinflammation leads to oxidative stress, cellular damage, and neurodegeneration. People living with HIV are at increased risk for age-related neurodegenerative diseases. Using rhesus macaques of both sexes, the researchers characterized the molecular underpinnings of acute neuroinflammation following simian–human immunodeficiency virus (SHIV) infection. Viral entry and integration within the CNS demonstrated vulnerabilities of key cognitive and motor function brain regions during the acute phase of infection. SHIV-induced transcriptional alterations also were observed. These findings indicate the presence of pervasive immune surveillance at homeostasis and reveal key perturbations during infection. Supported by ORIP (S10OD010786, K01OD023034) and NIAID.
Distinct Sensitivities to SARS-CoV-2 Variants in Vaccinated Humans and Mice
Walls et al., Cell Reports. 2022.
https://www.doi.org/10.1016/j.celrep.2022.111299
Emergence of SARS-CoV-2 variants necessitates real-time evaluation of their impact on serum neutralizing activity, as a proxy for vaccine efficacy, to inform public health policies and guide vaccine development. The investigators report that vaccinated female BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses toward the SARS-CoV-2 Beta and Gamma variants of concern, compared with humans of both sexes and male nonhuman primates (i.e., rhesus and pigtail macaques). This finding was consistent across several vaccine modalities, doses, antigens, and assays, suggesting caution should be exercised when interpreting serum neutralizing data obtained from mice. Supported by ORIP (P51OD010425, U42OD011123) and NIAID.
Maternal Western-Style Diet Reduces Social Engagement and Increases Idiosyncratic Behavior in Japanese Macaque Offspring
Mitchell et al., Brain, Behavior, and Immunity. 2022.
https://www.doi.org/10.1016/j.bbi.2022.07.004
Evidence points to an association between maternal obesity and risk of early-emerging neurodevelopmental disorders in offspring, yet few preclinical studies have tested for associations between maternal Western-style diet (mWSD) and offspring behavior. Using Japanese macaques, researchers found that mWSD offspring exhibited less proximity to peers and initiated fewer affiliative social behaviors. These outcomes appear to be mediated by increased maternal interleukin-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin. These findings suggest specific prevention and intervention targets for early-emerging neurodevelopmental disorder in humans. Supported by ORIP (P51OD011092), NIMH, and NICHD.
Molecular Insights Into Antibody-Mediated Protection Against the Prototypic Simian Immunodeficiency Virus
Zhao et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32783-2
Most simian immunodeficiency virus (SIV) vaccines have focused on inducing T cell responses alone or in combination with non-neutralizing antibody responses. To date, studies investigating neutralizing antibody (nAb) responses to protect against SIV have been limited. In this study, researchers isolated 12 potent monoclonal nAbs from chronically infected rhesus macaques of both sexes and mapped their binding specificities on the envelope trimer structure. They further characterized the structures using cryogenic electron microscopy, mass spectrometry, and computational modeling. Their findings indicate that, in the case of humoral immunity, nAb activity is necessary and sufficient for protection against SIV challenge. This work provides structural insights for future vaccine design. Supported by ORIP (P51OD011106), NIAID, and NCI.
Isoniazid and Rifapentine Treatment Effectively Reduces Persistent M. tuberculosis Infection in Macaque Lungs
Sharan et al., Journal of Clinical Investigation. 2022.
https://www.doi.org/10.1172/JCI161564
People with HIV and asymptomatic latent tuberculosis (TB) coinfection are at risk of developing active TB symptoms. The Centers for Disease Control and Prevention recommends a weekly dose of isoniazid and rifapentine for 3 months (3HP) for treatment of latent TB infection, but the sterilizing efficacy of the regimen has not been demonstrated previously. Using rhesus macaques of both sexes, researchers evaluated the efficacy of the 3HP regimen in eradicating persistent Mycobacterium tuberculosis infection. They found that treatment reduced the risk of developing active TB but did not establish complete sterilization. This work establishes a new animal model for evaluating the efficacy of different drug regimens. Supported by ORIP (P51OD011133, S10OD028732).
Wastewater Sequencing Reveals Early Cryptic SARS-CoV-2 Variant Transmission
Karthikeyan et al., Nature. 2022.
https://www.doi.org/10.1038/s41586-022-05049-6
The investigators explored the use of SARS-CoV-2 RNA concentration in wastewater as a practical approach to estimate community prevalence of COVID-19, detect emerging variants, and track regional infection dynamics. Two obstacles must be overcome to leverage wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. The investigators developed and deployed improved virus concentration protocols and deconvolution software to fully resolve multiple virus strains from wastewater. Results indicate that emerging variants of concern were detected up to 14 days earlier in wastewater samples, and multiple instances of virus spread that were not captured by clinical genomic surveillance were identified by wastewater-based genomic surveillance. The study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission. The work suggests a critical, urgently needed methodology for early detection of emerging variants and early public health interventions. Supported by ORIP (S10OD026929), and NIAID.
Evolution of the Nitric Oxide Synthase Family in Vertebrates and Novel Insights in Gill Development
Annona et al., Proceedings of the Royal Society B. 2022.
https://www.doi.org/10.1098/rspb.2022.0667
Nitric oxide (NO) plays essential roles in biological systems, including cardiovascular homeostasis, neurotransmission, and immunity. Knowledge of NO synthases (NOS) is substantial, but the origin of nos gene orthologues in fishes, with respect to tetrapods, remains largely unknown. The recent identification of nos3 in the spotted gar, considered lost in this lineage, prompted the authors to explore nos gene evolution. Here, they report that nos2 experienced several lineage-specific gene duplications and losses. Additionally, nos3 was found to be lost independently in two teleost lineages, Elopomorpha and Clupeocephala. Further, the expression of at least one nos paralogue in gills of developing shark, bichir, sturgeon, and gar, but not in gills of lamprey, suggests nos expression in the gill might have arisen in the last common ancestor of gnathostomes. These results provide a framework for further research on the role of nos genes. Supported by ORIP (P40OD019794, R01OD011116).
Early Treatment Regimens Achieve Sustained Virologic Remission in Infant Macaques Infected with SIV at Birth
Wang et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32554-z
About 150,000 children are infected postnatally with HIV each year. Early antiretroviral therapy (ART) in infants with HIV can reduce viral reservoir size, but ART-free virologic remission has not been achieved. The researchers hypothesized that proviral reservoir seeding in infants exposed to HIV might differ from that in adults. They characterized viral reservoirs in neonatal rhesus macaques of both sexes inoculated with simian immunodeficiency virus (SIV) at birth and given combination ART. The researchers reported that 9 months of treatment initiated at day 3 resulted in a sustained virologic remission, suggesting that early intervention with proper treatment regimens could be an effective strategy. Supported by ORIP (P51OD011104), NIAID, NICHD, and NIDCR.
Distinct Metabolic States Guide Maturation of Inflammatory and Tolerogenic Dendritic Cells
Adamik et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32849-1
The investigators mapped single-cell metabolic states and immune profiles of inflammatory and tolerogenic monocytic dendritic cells using recently developed multiparametric approaches. Activation scores revealed simultaneous engagement of multiple metabolic pathways in distinct monocytic dendritic cell differentiation stages (e.g., rapid reprogramming of glycolytic monocytes and transient co-activation of mitochondrial pathways followed by maturation of dendritic cells). This data set provides insights into metabolic pathways that affect the immune profiles of human dendritic cells. Supported by ORIP (S10OD026940) and NIDDK.