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Robert Yolken, MD

Robert Yolken, MD. Division of Infectious Diseases Johns Hopkins School of Medicine Stanley Medical Research Institute Chevy Chase Maryland. Why study microbial exposures in a “genetic” disease?. Assessment of exposures to infectious agents and other environmental agents may

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Robert Yolken, MD

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  1. Robert Yolken, MD Division of Infectious Diseases Johns Hopkins School of Medicine Stanley Medical Research Institute Chevy Chase Maryland

  2. Why study microbial exposures in a “genetic” disease? • Assessment of exposures to infectious agents and other environmental agents may • Increase the strength of association with susceptibility genes • Identify novel genomic mechanisms • Explain the persistence of psychiatric disorders in the human population • Lead to new treatments

  3. AgentGene Function HIV CCR5 Co-Receptor HIV APOBEC RNA editing HIV TRIM5α Capsid Binding EBV XLP T-Cell Activity Hepatitis B Man BP Viral binding Mycobacteria Il12; IFN R Phagocytosis Salmonella Il12; IFN R Phagocytosis H pyloriHLA-DQ Immune Response T gondii LTA T cell response P falciparumHgS,G6PD Oxygenation Human Infectious DiseasesKnownGenetic Associations

  4. Genetic Susceptibility to Infections TB Bacteremia Cytokine Suppression Malaria Khor C et al. N Engl J Med 2010;10.1056/NEJMoa0905606 Cytokine-inducibleSRC homology 2 (SH2) domain protein (CISH), a suppressor ofcytokine signaling, controls interleukin-2 signaling.

  5. Mendel-Human traits are determined by individual genes which function independently of other genes and of environmental influences Koch-Many human diseases are caused by microbes which exert their effect independently of other microbes, environmental factors and genes Complex Human DiseasesBeyond Koch and Mendel

  6. Schizophrenia and Bipolar DisorderLifelong studies of etiology and prevention Prodromal Recent onset Neonate Child Healthy adult Established Post-Mortem Cohorts Case Control

  7. Recent Onset Psychosis Cologne/Munich Germany Toxoplasma gondii CMV Lima Peru Toxoplasma gondii CMV HSV-1 Wuhan. China Toxoplasma gondii Baltimore Md Toxoplasma gondii Measles virus HHV-6 Perinatal Exposure Boston/Providence Toxoplasma gondii HSV-2 Denmark Toxoplasma gondii HSV-2 New York Toxoplasma gondii Rubella Virus Influenza Virus Exposure to Infectious Agents and Risk of Psychosis Odds Ratios>=2

  8. Toxoplasma gondii Biology and Epidemiology • Obligate intracellular protozoan of the Family Apicomplexa • Complete life cycle in feline: Definitive hosts • Abortive life cycle in humans and other animals resulting in lifelong cysts: Intermediate hosts • 3 major well-defined genotypes I, II, III • High prevalence in humans • 8-25% in developed countries • 30%-90% in less developed countries • Additional variation by geography and diet. • Route of infection Ingestion of oocytes from cat feces Eating of undercooked meat Drinking of contaminated water

  9. Genetics, Infections and Psychiatric DisordersNeeds for International Health • Samples useful for both DNA and antibody detection • Whole blood • Plasma/serum • Infrastructure for immunoassays • Trained personnel • Equipment • Reagents • Quality Control

  10. Water Born Toxoplasma InfectionSymptoms in Immune Competent Adults • Headache 82% • Fever 78% • Malaise 78% • Myalgia 75% • Adenitis 71% • Anorexia 65% • Arthralgias 57% • Night Sweats 50% • Vomiting 36% • Rash 6.7% 155 cases over a 3 month period associated with a water source de Moura et al, Emerg Inf Dis, Feb 2006

  11. Toxoplasma Antibodies and SchizophreniaMeta-analysis Odds Ratio=2.8 3 published prospective cohort studies showing increased risk of Toxoplasma infection

  12. Toxoplasma serum and CSF antibodyFirst-episode cases and controls Never Rx Past Rx Current Rx Control N=36 N=10 N=39 N=73 2.00 * ** 1.50 IgG Antibody 1.00 0.50 Serum CSF Leweke et al.. Eur Arch Psychiatry Clin Neurosci 2004;254:4–8. * p<.04 ** p<.0006

  13. Antecedents of Schizophrenia264 Cases/528 Controls Fever in Pregnancy Pregnancy Complications Delivery Complications Urban Birth Developmental Delay Family Cat Family Dog 1 2 3 4 Scz Research 46:17-23, 2000 Odds Ratio (95% Conf)

  14. Risk of Perinatal Toxoplasma Infection by Serotype

  15. Genetic Studies with Toxoplasma • Candidate genes selected on the basis of biological function and association with infection (N~30) • Snps measured by real time PCR and compared to Toxoplasma levels, clinical diagnoses, and demographic variables • Current sample size=1251 individuals • rs9264942 (HLA-5)-Top snp associated with progression of HIV-1 identified by GWAS (Fellay et al, Science 2007). Rare C/C genotype associated with decreased viral load. • Located near HLA-C on Chromosome 6, function unknown

  16. Risk Associated with Toxoplasma and HLA_c Genotype 10.6 7.1 2.4 1.9 2.4 1.9 Toxoplasma-All Toxo+HLAc C/C Genotype

  17. Infections and Human Brain DiseaseThe “Why” Question • Why should an infection result in altered animal behavior? • Evolution favors the development of parasites which can complete their life-cycle. • One strategy for promoting reproduction is to increase the likelihood of contact of the infected incomplete host with the host which can support the completion of the life-cycle

  18. Toxoplasma Life cycle Cats are the definitive host, where sexual reproduction can take place All other animals are dead-end hosts. The life cycle can only be completed by getting back into a cat How can I get back into a cat? Having 2 methods of transmission makes Toxoplasma a highly successful parasite, even in developed countries.

  19. How do cats catch rodents?

  20. Reaction to predator odours? Berdoy, Webster et al, Proc R Soc Lond B Biol Sci. 2000 Aug 7;267(1452):1591 Even naïve laboratory rats without cat contact for 1000’s generations still show strong behavioural and physiological aversive reactions when confronted with cat odours. Such innate anti-predator behaviour is, from the parasite’s point of view, and obvious obstacle militating against successful transmission to the cat definitive host.

  21. 2 x 2 metre outdoor run – within enclosure. Rabbit – control for a mammalian non-predator. Behavioural videoed over each 10-hour night (670 rat-hour observation)

  22. 10 5 0 cumulative preference (cat - rabbit) 21+ . 2 4 6 8 10 12 14 16 18 20 Sorties -5 uninfected -10 Bars represent 95% C.I.’s in uninfected rats: the more active the rat, the more visible the aversion (N=32, p<0.001).

  23. 10 T.gondii infected 5 cumulative preference (cat - rabbit) 0 21+ . 2 4 6 8 10 12 14 16 18 20 Sorties -5 uninfected -10 But in T.gondii-infected rats, preference for cat-scented areas increases with rat activity (N=23, p<0.05) Toxoplasma infected rats do not lose their aversion to non-feline predators such as mink and owls

  24. Roy critical after tiger attack LAS VEGAS, Nevada (CNN) -- A 7-year-old white tiger attacked Roy Horn of Siegfried and Roy during a Friday night performance on the Las Vegas strip -- the magician and trainer's 59th birthday. Illusionist says tiger was just trying to help

  25. Toxoplasma and Automobile AccidentsFlegyr et al, BMC Infectious Diseases 2002, 2:11

  26. Toxoplasma and Automobile Accidents Yereli et a, Forensic Sci Int. 2005 Age Gender

  27. Toxoplasma Infection and Suicide Attempts • Turkey (Yagmur et al, Forensic Sci Int. 2010) • N=200 suicide attempters and controls • Odds Ratio 1.46 p<.001 • Baltimore (Arling et al, J Nerv Mental 197: Dec 2009) • 99 suicide attempters and controls • Odds ratio 1.55, p<.006 • No association with depression in individuals who did not attempt suicide • Prospective studies in progress

  28. Infectious Agents and Animal BehaviorMechanisms that increase transmission • Rabies • Increased aggression and biting of hosts • Malaria • Listlessness-Increased mosquito exposure • Borrelia • Increased exposure to ticks • Respiratory viruses • Coughing in the vicinity with other hosts • Herpesviruses • Cognitive Impaiment • HIV • Increased sexual activity

  29. Psychiatric disorders and evolution • Why have psychiatric disorders persisted in the population despite a clear decrease in reproductive fitness • Balanced removal of genes and new mutations? • Increased reproductive fitness of genetic carriers? • Unrecognized beneficial effect of psychiatric disorders? • One answer to this question is to consider that most humans carry parasitic organisms which are under their own set of evolutionary pressures that are often contrary to that of the host • Some of these parasites have developed the ability to modify human behavior by the hijacking of brain processes

  30. Toxoplasma gondii contains genes which encode Tyrosine Hydroxylase and D4 Receptorhttp://toxodb.org/toxo/

  31. Localized dopamine staining in cysts3D reconstruction lectin DAPI anti DA

  32. Tyrosine HydroxylaseToxoplasma vs Leishmania

  33. Association between Leishmania and Bipolar disorder also found in Egypt Several other protozoa and bacteria also have Tyrosine hydroxylase Neospora Chlamydia Mycoplasma Leishmania Antibodies and Risk of Psychiatric Disorders Baltimore Maryland OR>4; P<.00001

  34. Artemisinin Compounds • Derived from a plant used in Chinese medicine Multiple compounds purified and found to be effective against Malaria parasites in the 1960’s and Toxoplasma in the 1980’s • Opportunities for synthetic modifications for: • Increased oral absorption • Increased CNS penetration • New compounds being developed as part of worldwide effort to eradicate malaria

  35. Toxoplasma Growth Inhibition assay Ongoing Clinical Trials Artemisin-Baltimore USA Artemether-Wuhan China Trimethoprim-Addis Ethiopia

  36. Toxoplasma and Psychiatric DiseasesOngoing Research • Prospective cohort studies • Schizophrenia and Bipolar Disorder • Suicide • Accidents • Genetic Studies • Candidate genes of the immune system • Genome wide association studies • Animal models • Interaction with food antigens • DNA methylation and gene expression • Role of antimicrobial prevention and treatment in psychiatric disorders

  37. Toxoplasma and Psychiatric DisordersCurrent Limitations –And Some Answers • Many individuals with Toxoplasma do not have evidence of a psychiatric disorder • Human genes may be associated with higher risk of schizophrenia • Individuals with Toxoplasma infection may have other psychiatric manifestations • Many individuals with schizophrenia do not have evidence of infection with Toxoplasma • Other infectious agents may share with Toxoplasma the ability to alter gene expression and human behavior • Areas with high prevalence rates of Toxoplasma do not necessarily have high rates of schizophrenia • Areas of the world differ in terms of the Toxoplasma genotype and the genetic makeup of the hosts • The role of Toxoplasma on the physical and psychiatric health of high prevalence areas is an important topic for study

  38. Evolutionary Genetics of Human Psychiatric Diseases-Conclusions • Human psychiatric disorders are diseases involving the genome. • Genomes involved include: • Human genome • Replicating zoonotic protozoa capable of altering neurotransmission and human gene expression • Many of these contributing infections are occurring during pregnancy and early life. • The prevention of these infections may result in a dramatic decrease in the massive personal, social and economic impact of these disorders. Multiple genomes

  39. Johns Hopkins University Loraine Brando J-C Xiao Sarven Subunciyan Emily Severance Andy Feinberg Misha Pletnikov Geetha Kannan Akira Sawa Shin-Ichi Kano Brown University Steve Buka UCLA Ty Cannon University of Aarhaus Preban Mortensen Sheppard Pratt Hospital Faith Dickerson Cassie Stallings Crystal Vaughan Andrea Origoni Sunil Khushalani Erin Burke University of London Joanne Webster University of Leeds Gerald McConkey Stanley Brain Laboratory E Fuller Torrey Maree Webster Karolinska Institute Hakan Karlsson Infectious Agents and Human Behavior-Collaborators

  40. Infections, Genes, and Psychiatric Disorders • Microbial pathogens such as viruses and protozoa are etiological agents of some cases of schizophrenia and bipolar disorder • The clinical expression of microbial infection is dependent upon • Genetic susceptibility • Timing of infection • Pathogenic potential of infectious agent • The identification of microbial agents will lead to methods for disease prevention and treatment

  41. Perinatal Infections and SchizophreniaCollaborators

  42. ? Schizophrenia-Questions Raised by Genetic Studies • Is the strong familial association of schizophrenia and related disorders based to some extent on perinatal transmission of infectious agents and other shared environmental factors which have epigenetic effects on gene expression? • Why should a disease associated with decreased reproductive fitness in cases and first degree relatives persist in the population despite strong evolutionary pressure for the breeding out of relevant genetic loci?

  43. Evolutionary Genetics of Human Psychiatric Diseases-Conclusions • Human psychiatric disorders are diseases involving the genome. • Genomes involved include: • Human genome • Replicating zoonotic protozoa capable of altering neurotransmission • Viruses and other retroelements which establish persistence within the central nervous system • Many of these contributing infections are occurring during pregnancy and early life. • The prevention of these infections may result in a dramatic decrease in the massive personal, social and economic impact of these disorders. Multiple genomes

  44. Psychiatric disorders and evolution • Why have psychiatric disorders persisted in the population despite a clear decrease in reproductive fitness • Balanced removal of genes and new mutations? • Increased reproductive fitness of genetic carriers? • Unrecognized beneficial effect of psychiatric disorders? • One answer to this question is to consider that most humans carry parasitic organisms which are under their own set of evolutionary pressures that are often contrary to that of the host • Some of these parasites have developed the ability to modify human behavior by the hijacking of brain processes

  45. Infections, Genes, and Psychiatric Disorders • Microbial pathogens such as viruses and protozoa are etiological agents of some cases of schizophrenia and bipolar disorder • The clinical expression of microbial infection is dependent upon • Genetic susceptibility • Timing of infection • Pathogenic potential of infectious agent • The identification of microbial agents will lead to methods for disease prevention and treatment

  46. Human Infectious DiseasesKnownGenetic Associations AgentGene Function HIV CCR5 Co-Receptor HIV APOBEC RNA editing HIV TRIM5α Capsid Binding EBV XLP T-Cell Activity Hepatitis B Man BP Viral binding Mycobacteria Il12; IFN R Phagocytosis Salmonella Il12; IFN R Phagocytosis H pyloriHLA-DQ Immune Response T gondii LTA T cell response P falciparumHgS,G6PD Oxygenation

  47. Dopaminergic cells express and release elevated dopamine when infected

  48. Distribution of Delayed Memory Scores by Toxoplasma Serostatus

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