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Accepted (AM)Open Access (License Unspecified), Open
Journal article
HTLV-1 Infection and Neuropathogenesis in the Context of Rag1 -/- γc -/- (RAG1-Hu) and BLT Mice
Journal of neuroimmune pharmacology, v 12(3), pp 504-520
Sep 2017
PMID: 28374110
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
To date, the lack of a suitable small animal model has hindered our understanding of Human T-cell lymphotropic virus (HTLV)-1 chronic infection and associated neuropathogenesis defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The host immune response plays a critical role in the outcome of HTLV-1 infection, which could be better tested in the context of humanized (hu) mice. Thus, we employ here the Balb/c-Rag1
γc
or Rag1 as well as Bone marrow-Liver-Thymic (BLT) mouse models for engraftment of human CD34
hematopoietic stem cells. Flow cytometry and histological analyses confirmed reconstitution of Rag1 and BLT mice with human immune cells. Following HTLV-1 infection, proviral load (PVL) was detected in the blood of Rag-1 and BLT hu-mice as early as 2 weeks post-infection (wpi) with sustained elevation in the subsequent weeks followed by Tax expression. Additionally, infection was compared between adult and neonatal Rag1 mice with both PVL and Tax expression considerably higher in the adult Rag1 mice as compared to the neonates. Establishment of peripheral infection led to lymphocytic infiltration with concomitant Tax expression and resulting myelin disruption within the central nervous system of infected mice. In addition, up-regulation in the expression of several immune checkpoint mediators such as programmed cell death-1 (PD-1), T-cell Ig and ITIM domain (TIGIT), and T cell Ig and mucin domain-3 protein (Tim-3) were observed on CD8
T cells in various organs including the CNS of infected hu-mice. Collectively, these studies represent the first attempt to establish HTLV-1 neuropathogenesis in the context of Rag-1 and BLT hu-mice as potential novel tools for understanding HTLV-1 neuropathogenesis and testing of novel therapies such as immune checkpoint blockade in the amelioration of chronic HTLV-1 infection.
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Details
- Title
- HTLV-1 Infection and Neuropathogenesis in the Context of Rag1 -/- γc -/- (RAG1-Hu) and BLT Mice
- Creators
- Rashida Ginwala - Drexel UniversityBreanna Caruso - National Institutes of HealthZafar K Khan - Drexel UniversityAjinkya Pattekar - Drexel UniversityGlen M Chew - University of Hawaii at ManoaMichael J Corley - University of Hawaii at ManoaRonak Loonawat - Drexel UniversitySteven Jacobson - National Institutes of HealthSreesha Sreedhar - Drexel UniversityLishomwa C Ndhlovu - University of Hawaii at ManoaPooja Jain - Drexel University
- Publication Details
- Journal of neuroimmune pharmacology, v 12(3), pp 504-520
- Publisher
- Springer Nature
- Grant note
- R01 CA054559 / NCI NIH HHS P20 GM113134 / NIGMS NIH HHS R01 NS097147 / NINDS NIH HHS P30 CA071789 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000406359000010
- Scopus ID
- 2-s2.0-85016955263
- Other Identifier
- 991019167128004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences
- Pharmacology & Pharmacy