TSE/Prion and Retroviral Pathogenesis Section
James A. Carroll, Ph.D.
Major Areas of Research
- Neuroinflammation during preclinical and clinical prion infection.
- Influence of microglia and neurotoxic astrocytes on prion pathogenesis.
- Alterations in cell populations and gene expression in the central nervous system and retina after prion infection.
- Regional tropism of sporadic CJD subtypes in human brain organoids
Our research section is interested in understanding how neuroinflammation and glial cell activation (astrocytes and microglia) influence prion pathogenesis and neurodegeneration. Initially, it was assumed that prion diseases lack an immunological reaction due to the absence of a prominent antibody or interferon response. Our research has shown that prion infection has a substantial inflammatory component, and that many of these inflammatory components are in response to the infection and not the actual cause of the pathology.
To address the potential impact of microglia in prion disease, we performed several studies using the potent CSF-R1 inhibitor, PLX5622, to reduce microglia in the CNS. These studies indicated that microglia were indispensable to host defense against prion disease. Moreover, we implicated astrocytes as potentially affecting pathology during disease, where when microglia were absent the astrocytes were more highly active expressing numerous disease-related components. This has led to further investigations to assess astrogliosis during prion infection.
Using high-throughput deep sequencing of RNA transcripts in longitudinal studies, we have identified numerous differentially expressed genes in the CNS during prion infection. These investigations have yielded compelling results and suggest that microglia in the prion-infected brain assume an alternative phenotype that is distinct from those seen in other brain disorders, and that microglia likely are activated through the engagement of the heterodimeric integrin receptor CD11c/18. Furthermore, our initial bulk RNA-seq studies also indicated that reactive astrocytes likely assume an unexpected expression signature that is not reliant on the canonical signals that are described in other neuroinflammatory models of neurodegenerative diseases. We have begun to analyze the individual cellular changes in the brain using single nucleus RNA sequencing to better understand the relevant changes in the cell populations in the complex milieu of the CNS during infection.
Ph.D., 1997, University of Georgia
Dr. James A. Carroll earned his Ph.D. in 1997 from the University of Georgia from the Department of Microbiology studying virulence-associated membrane proteins expressed by Borrelia burgdorferi, the causative agent of Lyme disease. Following a postdoctoral fellowship at Rocky Mountain Laboratories (RML), NIAID, NIH investigating the environmental cues that influence gene regulation and virulence determinants in Borrelia burgdorferi, he joined the faculty of the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine as an assistant professor in 2002. In late 2009, he was recruited back to RML to develop proteomics approaches in the search for additional biomarkers in prion diseases. Later he branched out into transcriptomics to better assess the role of glia cells and neuroinflammation in the process of neurodegeneration that occurs in the late phase of prion infection. For his contributions to the Borrelia burgdorferi field, he received two awards from the Centers for Disease Control in 2011 (the James H. Nakano Citation and the Charles C. Shepard Science Award), and he was awarded the title of Associate Scientist in recognition of exceptional achievements in prion research as an investigator at the NIAID Division of Intramural Research.
Carroll, J.A., B. Race, K. Williams, J. Striebel, and B. Chesebro. 2021. Innate immune responses after stimulation with Toll-like-receptor agonists in ex vivo microglial cultures and an in vivo model using mice with reduced microglia. J Neuroinflammation 18:194; doi.org/10.1186/s12974-021-02240-w. PMID: 34488805
Carroll J.A., Foliaki, S.T., and C.L. Haigh. 2021. A 3D cell culture approach for studying neuroinflammation. J Neurosci Methods. Apr 28:109201. doi:10.1016/j.jneumeth.2021.109201. PMID: 33932455
Carroll, J.A., B. Race, K. Williams, J. Striebel, and B. Chesebro. 2020. RNA-seq and network analysis reveal unique glial gene expression signatures during prion infection. Mol Brain. 13(1):71. doi:10.1186/s13041-020-00610-8. PMID: 32381108
Carroll, J.A., B. Race, K. Williams, J. Striebel, and B. Chesebro. 2018. Microglia are critical in host defense against prion disease. J. Virol. 17;92(15):e00549-18. doi:10.1128/JVI.00549-18. PMID: 29769333
Carroll J.A., J.F. Striebel, A. Rangel, T. Woods, K. Phillips, K.E. Peterson, B. Race, and B. Chesebro. 2016. Prion strain differences in accumulation of PrPSc on neurons and glia are associated with similar expression profiles of neuroinflammatory genes: comparison of three prion strains. PLoS Path. Apr 5;12(4):e1005551. doi:10.1371/journal.ppat.1005551. PMID: 27046083
Carroll J.A., J.F. Striebel, B. Race, K. Phillips, and B. Chesebro. 2015. Prion infection of mouse brain reveals multiple new upregulated genes involved in neuroinflammation or signal transduction. J. Virol. 89(4):2388-2404. doi: 10.1128/JVI.02952-14. PMID: 25505076
- 1990 Graduated Cum Laude from Clemson University.
- 1993 and 1994 Recipient: Outstanding performance in research and teaching merit award from the Graduate School of the University of Georgia.
- 1997-2002 Recipient: Intramural Research Training Award (IRTA), NIAID, NIH.
- 2001 Recipient: NIAID Richard Asofsky Special Achievement Award in Equal Employment Opportunity in recognition of participation in the B.R.A.S.S. program.
- 2011 Recipient: the James H. Nakano Citation from the Centers for Disease Control for outstanding scientific article Gilmore et al. 2010. PNAS. 107(16):7515-7520.
- 2011 Recipient: the Charles C. Shepard Science Award, the highest CDC award for excellence in science, for outstanding scientific article published in 2010 (Gilmore et al. PNAS. 107(16):7515-7520).
- 2019 Recipient: National Institutes of Health, NIAID 10 Years of Service award.
- 2021 Recipient: Honorific title of Associate Scientist in recognition of exceptional achievements as a Staff Scientist in the NIAID Division of Intramural Research.