Selected Grantee Publications
Baseline Tumor Gene Expression Signatures Correlate With Chemoimmunotherapy Treatment Responsiveness in Canine B Cell Lymphoma
Dittrich et al., PLOS ONE. 2023.
https://pubmed.ncbi.nlm.nih.gov/37624862/
Pet dogs develop spontaneous diffuse large B cell lymphoma (DLBCL), and veterinary clinical trials have been employed to treat canine DLBCL and to inform clinical trials for their human companions. Investigators evaluated gene expression in lymph node aspirates from 18 trial dogs and defined good responders as those who relapsed after 90 days, and poor responders as those who relapsed prior to 90 days. They found increased CCND3 correlated with poor prognosis and increased CD36 correlated with good prognosis, as is observed in humans. These findings identify biomarkers that may help guide the choice of chemoimmunotherapy treatment in dogs. Supported by ORIP (K01OD028268) and NCI.
Intestinal Microbiota Controls Graft-Versus-Host Disease Independent of Donor–Host Genetic Disparity
Koyama et al., Immunity. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480848/
Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematopoietic malignancies and non-malignant diseases, but acute graft-versus-host disease (GVHD) remains a serious complication. Specifically, severe gut GVHD is the major cause of transplant-related mortality. Here, the authors show that genetically identical mice, sourced from different vendors, had distinct commensal bacterial compositions, which resulted in significantly discordant severity in GVHD. These studies highlight the importance of pre-transplant microbiota composition for the initiation and suppression of immune-mediated pathology in the gastrointestinal tract, demonstrating the impact of non-genetic environmental determinants to transplant outcome. Supported by ORIP (S10OD028685), NIA, NCI, and NHLBI.
Assessment of Various Standard Fish Diets on Gut Microbiome of Platyfish Xiphophorus maculatus
Soria et al., Journal of Experimental Zoology Part B. 2023.
https://onlinelibrary.wiley.com/doi/10.1002/jez.b.23218
Diet is an important factor affecting experimental reproducibility and data integration across studies. Reference diets for nontraditional animal models are needed to control diet-induced variation. In a study of the dietary impacts on the gut microbiome, researchers found that switching from a custom diet to a zebrafish diet altered the Xiphophorus gut microbiome. Their findings suggest that diets developed specifically for zebrafish can affect gut microbiome composition and might not be optimal for Xiphophorus. Supported by ORIP (R24OD011120, R24OD031467, P40OD011021) and NCI.
A Gut-Restricted Glutamate Carboxypeptidase II Inhibitor Reduces Monocytic Inflammation and Improves Preclinical Colitis
Peters et al., Science Translational Medicine. 2023.
https://www.science.org/doi/10.1126/scitranslmed.abn7491
Many patients with moderate-to-severe inflammatory bowel disease (IBD) do not have adequate disease control, and glutamate carboxypeptidase II (GCPII) offers a promising target for therapeutic development. Researchers generated a class of GCPII inhibitors. They demonstrated that the inhibitor reduced monocytic inflammation in mice and protected against the loss of barrier integrity in primary human colon epithelial air–liquid interface monolayers. Their findings suggest that local inhibition of GCPII could be applied for the development of IBD therapeutics. Supported by ORIP (K01OD030517, T32OD011089), NIGMS, and NCCIH.
Identification of an Anergic BND Cell–Derived Activated B Cell Population (BND2) in Young-Onset Type 1 Diabetes Patients
Stensland et al., The Journal of Experimental Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/37184563/
B cells have been shown to play a role in the pathogenesis of type 1 diabetes (T1D), but the specificity, phenotype, and function of B cells in young-onset T1D is not understood fully. The investigators performed a cross-sectional analysis comparing insulin-reactive to tetanus-reactive B cells in the blood of male and female T1D patients and control participants using mass cytometry. They found elevated insulin-reactive BND2 cells in the blood and pancreatic lymph nodes of young-onset T1D donors. This work suggests that an antigen-specific B cell subset could contribute to the rapid progression of young-onset T1D. Supported by ORIP (K01OD028759) and NIDDK.
Downregulation of CCR5 on Brain Perivascular Macrophages in Simian Immunodeficiency Virus–Infected Rhesus Macaques
Bollimpelli et al., Nature Communications. 2023.
https://www.doi.org/10.1038/s41467-023-40430-7
Researchers have been exploring multiple strategies to develop an HIV vaccine. In this study, the investigators determined the immunogenicity and efficacy of intradermal and intramuscular routes of modified vaccinia Ankara (MVA) vaccination in female rhesus macaques. They found that both routes of MVA vaccination enabled control of viral replication, but only the intradermal vaccination was effective in protection against viral acquisition. Their findings suggest that the intradermal MVA vaccinations provide protection by modulating the innate and T helper responses. Taken together, this work underscores the importance of testing the influence of the route of immunization for HIV vaccines in humans. Supported by ORIP (P51OD011132, R24OD010976) and NIAID.
Antiretroviral Therapy Ameliorates Simian Immunodeficiency Virus–Associated Myocardial Inflammation by Dampening Interferon Signaling and Pathogen Response in the Heart
Robinson et al., The Journal of Infectious Diseases. 2023.
https://doi.org/10.1093/infdis/jiad105
HIV is associated with increased risk of cardiovascular disease, but the underlying mechanisms are not fully understood. Using RNA sequencing, investigators characterized the effects of simian immunodeficiency virus (SIV) infection on the hearts of male rhesus macaques. They demonstrated that SIV infection drives a canonical antiviral response in the heart, as well as dysregulation of genes involved in fatty acid shuttling and metabolism. Their findings suggest that antiretroviral therapy helps mitigate immune activation during viremic conditions and plays a cardioprotective role. Future studies are needed to assess the long-term effects of these dynamics. Supported by ORIP (P51OD011104), NIAID, NIMH, and NINDS.
The Contribution of Maternal Oral, Vaginal, and Gut Microbiota to the Developing Offspring Gut
Russell et al., Scientific Reports. 2023.
https://www.nature.com/articles/s41598-023-40703-7#Ack1
The maturation process of the gut microbiota (GM) is an essential process for life-long health that is defined by the acquisition and colonization of microorganisms in the gut and the subsequent immune system induction that occurs during early life. To address significant knowledge gaps in this area, investigators characterized the neonatal fecal and ileal microbiota of entire litters of mice at multiple pre-weaning time-points. Results indicated that specific-pathogen-free mouse microbiotas undergo a dynamic and somewhat characteristic maturation process, culminating by roughly two to three weeks of age. Prior to that, the neonatal GM is more similar in composition to the maternal oral microbiota, as opposed to the vaginal and fecal microbiotas. Further studies are needed to expand our knowledge regarding the effect of these developmental exposures on host development. Supported by ORIP (U42OD010918, R03OD028259).
Disentangling the Link Between Zebrafish Diet, Gut Microbiome Succession, and Mycobacterium chelonae Infection
Sieler et al., Animal Microbiome. 2023.
https://pubmed.ncbi.nlm.nih.gov/37563644/
Despite the long-established importance of zebrafish (Danio rerio) as a model organism and their increasing use in microbiome-targeted studies, relatively little is known about how husbandry practices involving diet impact the zebrafish gut microbiome. Given the microbiome's important role in mediating host physiology and the potential for diet to drive variation in microbiome composition, the authors sought to clarify how three different dietary formulations that are commonly used in zebrafish facilities impact the gut microbiome. They report that diet drives the successional development of the gut microbiome, as well as its sensitivity to exogenous exposure. Consequently, investigators should carefully consider the role of diet in their microbiome zebrafish investigations, especially when integrating results across studies that vary by diet. Supported by ORIP (R24OD010998) and NIEHS.
A Germ-Free Humanized Mouse Model Shows the Contribution of Resident Microbiota to Human-Specific Pathogen Infection
Wahl et al., Nature Biotechnology. 2023.
https://www.nature.com/articles/s41587-023-01906-5
Germ-free (GF) mice are of limited value in the study of human-specific pathogens because they do not support their replication. In this report, investigators developed a GF humanized mouse model using the bone marrow–liver–thymus platform to provide a robust and flexible in vivo model that can be used to study the role of resident microbiota in human health and disease. They demonstrated that resident microbiota promote viral acquisition and pathogenesis by using two human-specific pathogens, Epstein–Barr virus and HIV. Supported by ORIP (P40OD010995), FIC, NIAID, NCI, and NIDDK.