MedicalResearch.com Interview with:
Rima McLeod, M.D., F.A.C.P, F.I.D.S.A
Professor of Ophthalmology and Visual Sciences,Pediatrics (Infectious Diseases), and The College,
Director, Toxoplasmosis Center,
Senior Fellow,Institute of Genomics, Genetics and Systems Biology, Member, Commitees on Immunology, and Molecular Medicine and Pathogenesis,
Member Global Health Center, Affiliate CHeSS;
Attending Physician, Chicago Medicine,
The University of Chicago
MedicalResearch.com: What is the background for this study?
* One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii.
* Approximately fifteen million of these have congenital toxoplasmosis.
* The parasite interconverts between slow-growing, encysted bradyzoites and rapid-growing tachyzoites.
* In mice, T. gondii creates a chronic intra-neuronal infection and an inflammatory process.
* Mice with acute and chronic infection have alterations in neurotransmitters, memory, seizures, and neurobehavior.
* Some epidemiologic-serologic studies show associations between seropositivity for T. gondii and human neurologic diseases, for example, Parkinson’s and Alzheimer’s diseases.
* Although neurobehavioral disease is associated with seropositivity, causality is unproven.
* Serologic studies of humans with diverse genetics are not optimal to detect strong associations or directionality.
* Epidemiologic associations also do not reveal parasite-modulated gene networks in human brain that could provide insights into how to cure and prevent resultant diseases.
* We need integrative approaches to examine relationships between brain parasitism and other brain diseases, to provide a foundation to identify key pathways and molecules for drug and vaccine design
* To address these problems, we considered two central questions: (i) If chronic brain parasitism associates with other neurologic diseases, what are they? And (ii) Which macromolecular networks are modulated by the parasite in human brain that lead to neuropathology which could underpin and facilitate design of treatments?
* We hypothesized that a systems approach integrating multiple levels of host parasite interactions might resolve these questions.
* To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain.
MedicalResearch.com: What are the main findings?
* We identified susceptibility genes for congenital toxoplasmosis in our cohort of infected humans and found these genes are expressed in human brain.
* Transcriptomic and quantitative proteomic analyses of infected human, primary, neuronal stem and monocytic cells revealed effects on neurodevelopment and plasticity in neural, immune, and endocrine networks.
* These findings were supported by identification of protein and miRNA biomarkers in sera of ill children reflecting brain damage and T. gondii infection.
* These data were deconvoluted using three systems biology approaches:
* “Orbital-deconvolution” elucidated upstream, regulatory pathways interconnecting human susceptibility genes, biomarkers, proteomes, and transcriptomes.
* “Cluster-deconvolution” revealed visual protein-protein interaction clusters involved in processes affecting brain functions and circuitry, including lipid metabolism, leukocyte migration and olfaction.
* Finally, “disease-deconvolution” identified associations between the parasite-brain interactions and epilepsy, movement disorders, Alzheimer’s disease, and cancer.
* This “reconstruction-deconvolution” logic provides templates of progenitor cells’ potentiating effects, and components affecting human brain parasitism and diseases.
* This work supports the hypothesis that it is at the interface of genetic susceptibility to toxoplasmosis, genetic susceptibility to these other diseases and pathogenic mechanisms, and presence of this infection, infection with toxoplasma can lead to or potentiate other brain diseases, and other illnesses.
MedicalResearch.com: What should clinicians and patients take away from your report?
* Human chronic diseases are a complex interplay of genetic and environmental factors, requiring modified approaches to reconstruct their multifactorial etiology and cascades of developmental-plasticity mechanisms in precipitating disease.
* Human brain parasitism by T. gondii provides a model and template to examine development of brain diseases.
* All of our findings together support the notion that the dormant parasite, which sometimes interconverts to active tachyzoites when cysts rupture, and are present in chronic T. gondii infection in the brain of 2 billion persons, also has potential to contribute to these disease pathways of human epilepsy, neurodegeneration and cancer.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
* This work provides a systems roadmap to design medicines and vaccines to repair and prevent neuropathologic effects of T. gondii infection of the human brain.
* Further, our original template provides a novel method to integrate multiple levels of intrinsic and extrinsic factors highlighting a way to unravel complexity in brain parasitism, toxoplasmosis,specifically, and other complex diseases.
MedicalResearch.com: Is there anything else you would like to add?
* From Dennis Steindler to John Easton:
* “This study is a paradigm shifter,” said co-author Dennis Steinler, PhD, director of the Neuroscience and Aging Lab at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. “We now have to insert infectious disease into the equation of neurodegenerative diseases, epilepsy and neural cancers.”
“At the same time,” he added, “we have to translate aspects of this study into preventive treatments that include everything from drugs to diet to life style, in order to delay disease onset and progression.”
Disclosures: There are no disclosures pertinent to this work. I am helping Sanofi with a literature review but it is not really a disclosure relative to this work.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer
Seesandra V Rajagopala, Craig W Roberts, Fiona L Henriquez, Alexandre Montpetit, Jenefer M Blackwell, Sarra E Jamieson, Kelsey Wheeler, Ian J Begeman, Carlos Naranjo-Galvis, Ney Alliey-Rodriguez, Roderick G Davis, Liliana Soroceanu, Charles Cobbs, Dennis A Steindler, Kenneth Boyer, A Gwendolyn Noble, Charles N Swisher, Peter T Heydemann, Peter Rabiah, Shawn Withers, Patricia Soteropoulos, Leroy Hood, Rima McLeod
Sci Rep 2017 Sep 13;7(1):11496. Epub 2017 Sep 13.
The University of Chicago, Chicago, IL, 60637, USA
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