Selected Grantee Publications
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- 18 results found
- Immunology
- T32
Epigenetic MLH1 Silencing Concurs With Mismatch Repair Deficiency in Sporadic, Naturally Occurring Colorectal Cancer in Rhesus Macaques
Deycmar et al., Journal of Translational Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38504345
Rhesus macaques serve as a useful model for colorectal cancer (CRC) in humans, but more data are needed to understand the molecular pathogenesis of these cancers. Using male and female rhesus macaques, researchers investigated mismatch repair status, microsatellite instability, genetic mutations, transcriptional differences, and epigenetic alterations associated with CRC. Their data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. This work provides a uniquely informative model for human CRC. Supported by ORIP (P51OD011092, R24OD010947, R24OD021324, P40OD012217, U42OD010426, T35OD010946, T32OD010957), NCATS, and NCI.
The Gene Expression Profile and Cell of Origin of Canine Peripheral T-Cell Lymphoma
Owens et al., BMC Cancer. 2024.
https://pubmed.ncbi.nlm.nih.gov/38166662/
Peripheral T-cell lymphoma (PTCL) refers to a heterogenous group of T-cell neoplasms with poor treatment responses and survival times. Canine PTCL clinically and immunophenotypically resembles the most common human subtype, PTCL-NOS (PTCL-not otherwise specified), and is a naturally occurring model for human PTCL. Gene expression profiling in human PTCL-NOS has helped characterize this ambiguous diagnosis into distinct subtypes, but similar gene expression profiling in canine PTCL is lacking. Canine CD4+ PTCL most closely resembles the GATA3-PTCL subtype of PTCL-NOS and may originate from an earlier stage of T-cell development than the more conventionally posited mature T-helper cell origin. Supported by ORIP (T32OD010437).
Interferon Regulatory Factor 7 Modulates Virus Clearance and Immune Responses to Alphavirus Encephalomyelitis
Troisi et al., Journal of Virology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37772825/
Interferon regulatory factor 7 (IRF7)–deficient mice develop fatal paralysis after CNS infection with Sindbis virus, while wild-type mice recover. Irf7-/- mice produce low levels of IFN-α but high levels of IFN-β with induction of IFN-stimulated genes, so the reason for this difference is not understood. The current study shows that Irf7-/- mice developed inflammation earlier but failed to clear virus from motor neuron–rich regions of the brainstem and spinal cord. Therefore, IRF7 is either necessary for the neuronal response to currently identified mediators of clearance or enables the production of additional antiviral factor(s) needed for clearance. Supported by ORIP (T32OD011089, R01OD01026529) NINDS, and NIAID.
The Eotaxin-1/CCR3 Axis and Matrix Metalloproteinase-9 Are Critical in Anti-NC16A IgE-Induced Bullous Pemphigoid
Jordan et al., Journal of Immunology. 2023.
Bullous pemphigoid is associated with eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies. Researchers previously established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice. In this study, they characterized the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury. Their work establishes the eotaxin-1/CCR3 axis and matrix metalloproteinase-9 as key players in the disease and as candidate therapeutic targets for drug development and testing. Supported by ORIP (T32OD011130) and NIAMS.
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.
Innate Lymphoid Cells and Interferons Limit Neurologic and Articular Complications of Brucellosis
Moley et al., American Journal of Pathology. 2023.
https://www.sciencedirect.com/science/article/pii/S0002944023001980?via%3Dihub=
Brucellosis is a globally significant zoonotic disease. The current study investigated the role of innate lymphoid cells (ILCs) in the pathogenesis of focal brucellosis caused by Brucella melitensis. Following pulmonary infection with B. melitensis, mice lacking adaptive immune cells and ILCs developed arthritis, neurologic complications, and meningitis. Transcriptional analysis of Brucella-infected brains revealed marked upregulation of genes associated with inflammation and interferon responses. Collectively, these findings indicate that ILCs and interferons play an important role in prevention of focal complications during Brucella infection and that mice with deficiencies in ILCs or interferons can be used to study pathogenesis of neurobrucellosis. Supported by ORIP (T32OD011126) and NIAID.
Effect of Single Housing on Innate Immune Activation in Immunodeficiency Virus–Infected Pigtail Macaques (Macaca nemestrina) as a Model of Psychosocial Stress in Acute HIV Infection
Castell et al., Psychosomatic Medicine. 2022.
https://www.doi.org/10.1097/PSY.0000000000001132
Psychosocial stress is associated with immune system dysregulation and worsened clinical outcomes in people with HIV. Investigators performed a retrospective analysis of acute simian immunodeficiency virus (SIV) infection of male pigtail macaques to compare the innate immune responses of social and single housing. The singly housed macaques showed reduced expansion of classical and intermediate monocytes, prolonged thrombocytopenia, and suppression of platelet activation during the first 2 weeks after inoculation. These findings indicate that psychosocial stress might induce clinically significant immunomodulatory effects in the innate immune system during acute SIV infection. Supported by ORIP (P40OD013117, K01OD018244, T32OD011089, U42OD013117), NIAID, NIMH, and NINDS.
Progression and Resolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Golden Syrian Hamsters
Mulka et al., The American Journal of Pathology. 2022.
https://www.doi.org/10.1016/j.ajpath.2021.10.009
To catalyze SARS-CoV-2 research, disease progression was characterized in a robust model. Male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 to track clinical, pathology, virology, and immunology outcomes. Inoculated animals lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses dominated in the lung. These lesions resolved over time. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19. Supported by ORIP (T32OD011089).