Selected Grantee Publications
Targeted Suppression of Human IBD-Associated Gut Microbiota Commensals by Phage Consortia for Treatment of Intestinal Inflammation
Federici et al., Cell. 2022.
https://www.doi.org/10.1016/j.cell.2022.07.003
Human gut commensals increasingly are suggested to affect noncommunicable diseases, such as inflammatory bowel disease (IBD), yet their targeted suppression remains an unmet challenge. In this report, investigators identified a clade of Klebsiella pneumoniae (Kp) strains—featuring a unique antibiotic resistance and mobilome signature—that is associated strongly with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice of both sexes enhances intestinal inflammation. An orally administered combination phage therapy targeting sensitive and resistant IBD-associated Kp clade members enables effective Kp suppression, suggesting the feasibility of avoiding antibiotic resistance while effectively inhibiting noncommunicable disease–contributing pathobionts. Supported by ORIP (P40OD010995) and NIDDK.
Obesity Alters Pathology and Treatment Response in Inflammatory Disease
Bapat et al., Nature. 2022.
https://www.doi.org/10.1038/s41586-022-04536-0
Obesity and metabolic disease have been shown to affect immunotherapeutic outcomes. By studying classical type 2 T helper cells (TH2) in lean and obese male mouse models for atopic dermatitis, investigators found that the biologic therapies protected lean mice but exacerbated disease in obese mice. RNA sequencing and genome analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells in obese mice when compared to lean mice, indicating that PPARγ is required to prevent aberrant non-TH2 inflammation. Understanding the effects of obesity on immunological disease could inform a potential precision medicine approach to target obesity-induced immune dysregulation. Supported by ORIP (S10OD023689), NIAID, NCI, NIDDK, and NIGMS.
Common and Divergent Features of T Cells From Blood, Gut, and Genital Tract of Antiretroviral Therapy–Treated HIV+ Women
Xie et al., Journal of Immunology. 2022.
https://www.doi.org/10.4049/jimmunol.2101102
T cells residing in mucosal tissues play important roles in homeostasis and defense against microbial pathogens, but how organ system environments affect the properties of resident T cells is relatively unknown. Researchers phenotyped T cells in the gut and reproductive tract using blood and tissue samples from women with HIV who have achieved viral suppression via antiretroviral therapy. The T cells exhibited differing expression of CD69 and CD103 markers, whereas resident memory CD8+ T cells from the female reproductive tract expressed PD1 preferentially. Additionally, CXCR4+ T inflammatory mucosal cells expressed multiple chemokine receptors differentially. These results suggest that T cells take on distinct properties in different mucosal sites, which allows them to tailor activities to their surrounding milieu. This study offers important insights for reproductive medicine in women. Supported by ORIP (S10OD018040), NHLBI, NIAID, and NIDDK.
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.
Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques
Boby et al., Frontiers in Immunology. 2022.
https://www.doi.org/10.3389/fimmu.2022.835686
Recent studies suggest that people with HIV—particularly those not receiving antiretroviral therapy or those with low CD4 cell counts—are at increased risk of severe illness from SARS‑CoV-2 coinfection. Angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, is likely to play an important role in modulating physiological and pathological events during HIV infection. In this study, the researchers used a rhesus macaque model to characterize the expression profiles of ACE2, other renin-angiotensin system (RAS)–associated genes (AGTR1/2, ADAM17, and TMPRSS2), and inflammatory cytokines (IL-1β, IL-6, and TNF‑α) in the jejunum and lung during simian immunodeficiency virus (SIV) infection. SIV infection was associated with multiple changes in gene expression, including downregulation of ACE2, which could lead to loss of gut homeostasis. Further studies could provide insight on the role of RAS-associated proteins during HIV and SARS-CoV-2 co-infection. Supported by ORIP (P51OD011104) and NIDDK.
Complement Blockade in Recipients Prevents Delayed Graft Function and Delays Antibody-mediated Rejection in a Nonhuman Primate Model of Kidney Transplantation
Eerhart et al., Transplantation. 2022.
Investigators evaluated the efficacy of a high-dose recombinant human C1 esterase inhibitor (rhC1INH) in preventing delayed graft function (DGF) in a rhesus macaque (RM) model for kidney transplantation after brain death and prolonged cold ischemia. The majority (4 of 5) of vehicle-treated recipients developed DGF, whereas DGF was observed in only 1 of 8 rhC1INH-treated recipients. RMs treated with rhC1INH also had faster creatine recovery, superior urinary output, and reduced biomarkers of allograft injury for the first week. The results suggest high-dose C1INH treatment in transplant recipients is an effective strategy to reduce kidney injury and inflammation, prevent DGF, delay antibody-mediated rejection development, and improve transplant outcomes. Supported by ORIP (P51OD011106), NIAID, and NIDDK.
Cannabinoid Control of Gingival Immune Activation in Chronically SIV-Infected Rhesus Macaques Involves Modulation of the Indoleamine-2,3-Dioxygenase-1 Pathway and Salivary Microbiome
McDew-White et al., EBioMedicine. 2021.
https://pubmed.ncbi.nlm.nih.gov/34954656/
HIV-associated periodontal disease (PD) affects people living with HIV (PLWH) on combination anti-retroviral therapy (cART). Researchers used a systems biology approach to investigate the molecular, metabolome, and microbiome changes underlying PD and its modulation by phytocannabinoids (Δ9-THC) in rhesus macaques. Δ9-THC reduced IDO1 protein expression. The findings suggest that phytocannabinoids may help reduce gingival/systemic inflammation, salivary dysbiosis, and potentially metabolic disease in PLWH on cART. Supported by ORIP (P51OD011104, P51OD011133, U42OD010442), NIAID, NIDA, NIDDK, NIDCR, and NIMH.
Deep Learning Is Widely Applicable to Phenotyping Embryonic Development and Disease
Naert et al., Development. 2021.
https://pubmed.ncbi.nlm.nih.gov/34739029/
Genome editing simplifies the generation of new animal models for congenital disorders. The authors illustrate how deep learning (U-Net) automates segmentation tasks in various imaging modalities. They demonstrate this approach in embryos with polycystic kidneys (pkd1 and pkd2) and craniofacial dysmorphia (six1). They provide a library of pre-trained networks and detailed instructions for applying deep learning to datasets and demonstrate the versatility, precision, and scalability of deep neural network phenotyping on embryonic disease models. Supported by ORIP (P40OD010997, R24OD030008), NICHD, NIDDK, and NIMH.
Western-Style Diet Consumption Impairs Maternal Insulin Sensitivity and Glucose Metabolism During Pregnancy in a Japanese Macaque Model
Elsakr et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-92464-w
Using a Japanese macaque model, investigators assessed the metabolic effects of obesity and a calorically dense, Western-style diet (WSD; 36.3% fat), either alone or together, on maternal glucose tolerance and insulin levels in dams during pregnancy (n = 95 females followed over multiple pregnancies [n = 273]). With prolonged WSD feeding, multiple diet switches, and/or increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. The results suggest that prolonged or recurrent calorically dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. Supported by ORIP (P51OD011092), NIDDK and NIMH.
Mineralocorticoid Receptor Blockade Normalizes Coronary Resistance in Obese Swine Independent of Functional Alterations in Kv Channels
Goodwill et al., Basic Research in Cardiology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34018061/
Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of Kv channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening. Supported by ORIP (U42OD011140, S10OD023438), NHLBI, and NIBIB.