Selected Grantee Publications
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- Microbiome
- CRISPR
- Genetics
The Mutant Mouse Resource and Research Center (MMRRC) Consortium: The U.S.-Based Public Mouse Repository System
Agca et al., Mammalian Genome. 2024.
https://link.springer.com/article/10.1007/s00335-024-10070-3
The MMRRC has been the nation’s preeminent public repository and distribution archive of mutant mouse models for 25 years. The Consortium, with support from NIH, facilitates biomedical research by identifying, acquiring, evaluating, characterizing, preserving, and distributing a variety of mutant mouse strains to investigators around the world. Since its inception, the MMRRC has fulfilled more than 20,000 orders from 13,651 scientists at 8,441 institutions worldwide. Today, the MMRRC maintains an archive of mice, cryopreserved embryos and sperm, embryonic stem-cell lines, and murine monoclonal antibodies for nearly 65,000 alleles. The Consortium also provides scientific consultation, technical assistance, genetic assays, microbiome analysis, analytical phenotyping, pathology, husbandry, breeding and colony management, and more. Supported by ORIP (U42OD010918, U42OD010924, U42OD010983).
Time of Sample Collection Is Critical for the Replicability of Microbiome Analyses
Allaband et al., Nature Metabolism. 2024.
https://pubmed.ncbi.nlm.nih.gov/38951660/
Lack of replicability remains a challenge in microbiome studies. As the microbiome field moves from descriptive and associative research to mechanistic and interventional studies, being able to account for all confounding variables in the experimental design will be critical. Researchers conducted a retrospective analysis of 16S amplicon sequencing studies in male mice. They report that sample collection time affects the conclusions drawn from microbiome studies. The lack of consistency in the time of sample collection could help explain poor cross-study replicability in microbiome research. The effect of diurnal rhythms on the outcomes and study designs of other fields is unknown but is likely significant. Supported by ORIP (T32OD017863), NCATS, NCI, NHLBI, NIAAA, NIAID, NIBIB, NIDDK, and NIGMS.
Natural Killer–Like B Cells Are a Distinct but Infrequent Innate Immune Cell Subset Modulated by SIV Infection of Rhesus Macaques
Manickam et al., PLOS Pathogens. 2024.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012223
Natural killer–like B (NKB) cells express both natural killer (NK) and B cell receptors. Intracellular signaling proteins and trafficking markers were expressed differentially on naive NKB cells. CD20+ NKG2A/C+ NKB cells were identified in organs and lymph nodes of naive rhesus macaques (RMs). Single-cell RNA sequencing (scRNAseq) of sorted NKB cells confirmed that NKB cells are unique, and transcriptomic analysis of naive splenic NKB cells by scRNAseq showed that NKB cells undergo somatic hypermutation and express Ig receptors, similar to B cells. Expanded NKB frequencies were observed in RM gut and buccal mucosa after simian immunodeficiency virus (SIV) infection, and mucosal and peripheral NKB cells were associated with colorectal cytokine milieu and oral microbiome changes. NKB cells gated on CD3-CD14-CD20+NKG2A/C+ cells were inclusive of transcriptomically conventional B and NK cells in addition to true NKB cells, confounding accurate phenotyping and frequency recordings. Supported by ORIP (P51OD011132, S10OD026799) and NIAID.
Intestinal Epithelial Adaptations to Vertical Sleeve Gastrectomy Defined at Single-Cell Resolution
Koch-Laskowski et al., Genomics. 2024.
https://pubmed.ncbi.nlm.nih.gov/38309446/
Perturbations in the intestinal epithelium have been linked to the pathogenesis of metabolic disease. Bariatric procedures, such as vertical sleeve gastrectomy (VSG), cause gut adaptations that induce robust metabolic improvements. Using a male mouse model, the authors assessed the effects of VSG on different cell lineages of the small intestinal epithelium. They show that Paneth cells display increased expression of the gut peptide Reg3g after VSG. Additionally, VSG restores pathways pertaining to mitochondrial respiration and cellular metabolism, especially within crypt-based cells. Overall, this work demonstrates how adaptations among specific cell types can affect gut epithelial homeostasis; these findings can help researchers develop targeted, less invasive treatment strategies for metabolic disease. Supported by ORIP (F30OD031914), NCI, and NIDDK.
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.
IL-21 and IFNα Therapy Rescues Terminally Differentiated NK Cells and Limits SIV Reservoir in ART-Treated Macaques
Harper et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-23189-7
Nonpathogenic simian immunodeficiency virus (SIV) infections in natural hosts, such as vervet monkeys, are characterized by a lack of gut microbial translocation, robust secondary lymphoid natural killer cell responses, and limited SIV dissemination in lymph node B-cell follicles. Using antiretroviral therapy-treated, SIV-infected rhesus monkeys—a pathogenic model—researchers showed that interleukin-21 and interferon alpha therapy generate terminally differentiated blood natural killer cells with potent human leukocyte antigen-E-restricted activity in response to SIV envelope peptides. The correlated reduction of replication-competent SIV in lymph node demonstrates that vervet-like natural killer cell differentiation can be rescued in rhesus monkeys to promote viral clearance. Supported by ORIP (P51OD011132, R24OD010947), NIAID, and NCI.