The Tjalkens lab (Colorado State University) was recently awarded a grant to examine how excessive levels of the essential element manganese (Mn) during juvenile development causes inflammatory activation of glial cells that predisposes dopaminergic neurons to injury later in life. Data from this project indicate that neuro-inflammation may be a critical link between exposure to Mn early in life and heightened susceptibility to neurological dysfunction during aging. The parent grant is exploring these questions using novel transgenic reporter and knockout mice to examine the molecular pathways regulating inflammation in the brain that increase the risk for neurological disease in Mn-exposed individuals. The proposed Virtual Consortium will extend these studies to determine how Mn exposure early in life increases the risk for adverse neurological outcomes following infection with commonly encountered viruses, including Western Equine Encephalitis virus (WEEV), neuro adapted Sindbis virus and H1N1 influenza virus, the current major pandemic flu virus. Clinical and experimental evidence implicates viral infection as a risk factor for neurodegenerative diseases, including Parkinson's disease (PD). Neurotropic (or neuro-affecting) viruses induce many of the pathological features of PD, such as protein aggregation, oxidative stress, autophagy/mitophagy defects, neuro inflammation, and neuronal loss in the substantia nigra (SN). Viral infection may therefore represent an important environmental interaction that increases the risk for neurological disease following exposure to neurotoxic compounds. Excessive exposure to Mn early in life can not only have lasting effects on neurological function but also can enhance neuro inflammation during viral infection. This Virtual Consortium addresses this question by bringing together talented new collaborators in neuro virology (Richard Smeyne, St. Jude) and bioinformatics (Ric Slayden, CSU) to uncover mechanisms underlying the capacity of Mn to enhance neurodegeneration relevant to PD following exposure to commonly encountered viruses. The addition of H1N1 influenza virus, in particular, gives this Consortium a high level of clinical relevance, as does the use of vaccine developed in our laboratory used to mitigate the severity of viral infection in these models. It is our Central Hypothesis that exposure to Mn during juvenile development will enhance susceptibility to the neurological effects of WEEV and H1N1, resulting in progressive loss of dopaminergic neurons in the substantia nigra associated with inflammatory activation of glial cells. This hypothesis will be tested by new Specific Aims that will assess the capacity of Mn to exacerbate the neurological effects of infection by either WEEV/Sindbis (Tjalkens) or H1N1 (Smeyne), with host-pathogen transcriptome responses assessed using Next Generation Sequencing/RNA-Seq (Slayden). Thus, our Consortium is highly responsive to the ViCTER programmatic goals of i) conducting synergistic, trans-disciplinary research, ii) supporting the exchange of knowledge among individuals from diverse disciplines and iii) developing novel approaches for understanding the role of environmental chemicals in the etiology of disease that could impact clinical or public health practice.

Public Health Relevance

The current proposal builds upon research from the Tjalkens laboratory examining how developmental exposure to Mn can stimulate a persistent neuroinflammatory phenotype leading to neuronal injury. Our Virtual Consortium extends this work in an exciting new direction by incorporating outstanding collaborators in neurovirology (Smeyne) and bioinformatics (Slayden) to determine how Mn exposure during juvenile development may enhance sensitivity to the neurological effects of viral infection. Given widespread exposure to Mn in children from drinking water and soy-based formulas, as well as pandemic infection rates with H1N1, this work has a high degree of public health relevance and translational impact. This Virtual Consortium directly meets ViCTER programmatic goals of improving our understanding of the role of single and multiple exposures across lifespan in the etiology and progression of disease. Our combined experience and expertise represents a research team that we believe is uniquely qualified to address the question of neuroinflammation as a unifying pathogenic mechanism linking Mn exposure and viral infection to neurological disease.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DKUS-C (50))
Program Officer
Hollander, Jonathan
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Colorado State University-Fort Collins
Public Health & Prev Medicine
Schools of Veterinary Medicine
Fort Collins
United States
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Popichak, Katriana A; Afzali, Maryam F; Kirkley, Kelly S et al. (2018) Glial-neuronal signaling mechanisms underlying the neuroinflammatory effects of manganese. J Neuroinflammation 15:324
Afzali, Maryam F; Popichak, Katriana A; Burton, Lindsey H et al. (2018) A novel diindolylmethane analog, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane, inhibits the tumor necrosis factor-induced inflammatory response in primary murine synovial fibroblasts through a Nurr1-dependent mechanism. Mol Immunol 101:46-54
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