Clinical studies frequently report that patients with major mental illness such as schizophrenia and bipolar disorder have co-morbid physical conditions, suggesting that systemic alterations affecting both brain and peripheral tissues might underlie the disorders. Numerous studies have reported elevated levels of anti-Toxoplasma gondii (T. gondii) antibodies in patients with major mental illnesses, but the underlying mechanism was unclear. Using multidisciplinary epidemiological, cell biological, and gene expression profiling approaches, we report here multiple lines of evidence suggesting that a major mental illness-related susceptibility factor, Disrupted in schizophrenia (DISC1), is involved in host immune responses against T. gondii infection. Specifically, our cell biology and gene expression studies have revealed that DISC1 Leu607Phe variation, which changes DISC1 interaction with activating transcription factor 4 (ATF4), modifies gene expression patterns upon T. gondii infection. Our epidemiological data have also shown that DISC1 607 Phe/Phe genotype was associated with higher T. gondii antibody levels in sera. Although further studies are required, our study provides mechanistic insight into one of the few well-replicated serological observations in major mental illness.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Insel TR. Rethinking schizophrenia. Nature. 2010;468:187–93.
Goff DC, Cather C, Evins AE, Henderson DC, Freudenreich O, Copeland PM. et al. Medical morbidity and mortality in schizophrenia: guidelines for psychiatrists. J Clin Psychiatry. 2005;66:183–94.
Montejo AL. The need for routine physical health care in schizophrenia. Eur Psychiatry. 2010;25:S3–5.
Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000;9:1415–23.
Brandon NJ, Sawa A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci. 2011;12:707–22.
Mathieson I, Munafo MR, Flint J. Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. Mol Psychiatry. 2012;17:634–41.
Sullivan PF. Questions about DISC1 as a genetic risk factor for schizophrenia. Mol Psychiatry. 2013;18:1050–2.
Porteous DJ, Thomson PA, Millar JK, Evans KL, Hennah W, Soares DC, et al. DISC1 as a genetic risk factor for schizophrenia and related major mental illness: response to Sullivan. Mol Psychiatry. 2014;19:141–3.
Farrell MS, Werge T, Sklar P, Owen MJ, Ophoff RA, O’Donovan MC, et al. Evaluating historical candidate genes for schizophrenia. Mol Psychiatry. 2015;20:555–62.
Su P, Li S, Chen S, Lipina TV, Wang M, Lai TK, et al. A dopamine D2 receptor-DISC1 protein complex may contribute to antipsychotic-like effects. Neuron. 2014;84:1302–16.
Lee FH, Fadel MP, Preston-Maher K, Cordes SP, Clapcote SJ, Price DJ, et al. Disc1 point mutations in mice affect development of the cerebral cortex. J Neurosci. 2011;31:3197–206.
Wong AH, Josselyn SA. Caution when diagnosing your mouse with schizophrenia: the use and misuse of model animals for understanding psychiatric disorders. Biol Psychiatry. 2016;79:32–8.
Di Giorgio A, Blasi G, Sambataro F, Rampino A, Papazacharias A, Gambi F, et al. Association of the SerCys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding. Eur J Neurosci. 2008;28:2129–36.
Sprooten E, Sussmann JE, Moorhead TW, Whalley HC, Ffrench-Constant C, Blumberg HP. et al. Association of white matter integrity with genetic variation in an exonic DISC1 SNP. Mol Psychiatry. 2011;16:685–9.
Raznahan A, Lee Y, Long R, Greenstein D, Clasen L, Addington A, et al. Common functional polymorphisms of DISC1 and cortical maturation in typically developing children and adolescents. Mol Psychiatry. 2011;16:917–26.
Carless MA, Glahn DC, Johnson MP, Curran JE, Bozaoglu K, Dyer TD, et al. Impact of DISC1 variation on neuroanatomical and neurocognitive phenotypes. Mol Psychiatry. 2011;16:1096–104. 1063
Tomppo L, Hennah W, Miettunen J, Jarvelin MR, Veijola J, Ripatti S, et al. Association of variants in DISC1 with psychosis-related traits in a large population cohort. Arch Gen Psychiatry. 2009;66:134–41.
Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA. 2005;102:8627–32.
Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry. 2005;62:1205–13.
Li Y, Liu B, Hou B, Qin W, Wang D, Yu C, et al. Less efficient information transfer in Cys-allele Carriers of DISC1: a brain network study based on diffusion MRI. Cereb Cortex. 2012;23:1715–25.
Eastwood SL, Walker M, Hyde TM, Kleinman JE, Harrison PJ. The DISC1 Ser704Cys substitution affects centrosomal localization of its binding partner PCM1 in glia in human brain. Hum Mol Genet. 2010;19:2487–96.
Eastwood SL, Hodgkinson CA, Harrison PJ. DISC-1 Leu607Phe alleles differentially affect centrosomal PCM1 localization and neurotransmitter release. Mol Psychiatry. 2009;14:556–7.
Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.
van Os J, Kenis G, Rutten BP. The environment and schizophrenia. Nature. 2010;468:203–12.
Boothroyd JC. Toxoplasma gondii: 25 years and 25 major advances for the field. Int J Parasitol. 2009;39:935–46.
Hunter CA, Remington JS. Immunopathogenesis of toxoplasmic encephalitis. J Infect Dis. 1994;170:1057–67.
Hunter CA, Sibley LD. Modulation of innate immunity by Toxoplasma gondii virulence effectors. Nat Rev Microbiol. 2012;10:766–78.
Laliberte J, Carruthers VB. Host cell manipulation by the human pathogen Toxoplasma gondii. Cell Mol Life Sci. 2008;65:1900–15.
Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;363:1965–76.
Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010;167:261–80.
Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry. 2011;168:1303–10.
Prasad KM, Watson AM, Dickerson FB, Yolken RH, Nimgaonkar VL. Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia. Schizophr Bull. 2012;38:1137–48.
Tedla Y, Shibre T, Ali O, Tadele G, Woldeamanuel Y, Asrat D, et al. Serum antibodies to Toxoplasma gondii and Herpesvidae family viruses in individuals with schizophrenia and bipolar disorder: a case-control study. Ethiop Med J. 2011;49:211–20.
Pearce BD, Kruszon-Moran D, Jones JL. The relationship between Toxoplasma gondii infection and mood disorders in the third National Health and Nutrition Survey. Biol Psychiatry. 2012;72:290–5.
Hamdani N, Daban-Huard C, Lajnef M, Richard JR, Delavest M, Godin O, et al. Relationship between Toxoplasma gondii infection and bipolar disorder in a French sample. J Affect Disord. 2013;148:444–8.
Holub D, Flegr J, Dragomirecka E, Rodriguez M, Preiss M, Novak T, et al. Differences in onset of disease and severity of psychopathology between toxoplasmosis-related and toxoplasmosis-unrelated schizophrenia. Acta Psychiatr Scand. 2013;127:227–38.
Torrey EF, Yolken RH. Schizophrenia and toxoplasmosis. Schizophr Bull. 2007;33:727–8.
Torrey EF, Bartko JJ, Lun ZR, Yolken RH. Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. Schizophr Bull. 2007;33:729–36.
Alcais A, Abel L, Casanova JL. Human genetics of infectious diseases: between proof of principle and paradigm. J Clin Invest. 2009;119:2506–14.
Vannberg FO, Chapman SJ, Hill AV. Human genetic susceptibility to intracellular pathogens. Immunol Rev. 2011;240:105–16.
Suzuki Y, Wong SY, Grumet FC, Fessel J, Montoya JG, Zolopa AR, et al. Evidence for genetic regulation of susceptibility to toxoplasmic encephalitis in AIDS patients. J Infect Dis. 1996;173:265–8.
Jamieson SE, de Roubaix LA, Cortina-Borja M, Tan HK, Mui EJ, Cordell HJ, et al. Genetic and epigenetic factors at COL2A1 and ABCA4 influence clinical outcome in congenital toxoplasmosis. PLoS ONE. 2008;3:e2285.
Niwa M, Jaaro-Peled H, Tankou S, Seshadri S, Hikida T, Matsumoto Y, et al. Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids. Science. 2013;339:335–9.
Dickerson F, Boronow JJ, Stallings C, Origoni AE, Cole SK, Yolken RH. Cognitive functioning in schizophrenia and bipolar disorder: comparison of performance on the repeatable battery for the assessment of neuropsychological status. Psychiatry Res. 2004;129:45–53.
Talkowski ME, Kirov G, Bamne M, Georgieva L, Torres G, Mansour H, et al. A network of dopaminergic gene variations implicated as risk factors for schizophrenia. Hum Mol Genet. 2008;17:747–58.
Knight BC, Kissane S, Falciani F, Salmon M, Stanford MR, Wallace GR. Expression analysis of immune response genes of Muller cells infected with Toxoplasma gondii. J Neuroimmunol. 2006;179:126–31.
Mortensen PB, Norgaard-Pedersen B, Waltoft BL, Sorensen TL, Hougaard D, Yolken RH. Early infections of Toxoplasma gondii and the later development of schizophrenia. Schizophr Bull. 2007;33:741–4.
Niebuhr DW, Millikan AM, Cowan DN, Yolken R, Li Y, Weber NS. Selected infectious agents and risk of schizophrenia among U.S. military personnel. Am J Psychiatry. 2008;165:99–106.
Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Ruslanova I, Yolken RH. Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Arch Gen Psychiatry. 2003;60:466–72.
Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Cole S, Leister F, et al. The catechol O-methyltransferase Val158Met polymorphism and herpes simplex virus type 1 infection are risk factors for cognitive impairment in bipolar disorder: additive gene-environmental effects in a complex human psychiatric disorder. Bipolar Disord. 2006;8:124–32.
Rastogi A, Zai C, Likhodi O, Kennedy JL, Wong AH. Genetic association and post-mortem brain mRNA analysis of DISC1 and related genes in schizophrenia. Schizophr Res. 2009;114:39–49.
Horiuchi Y, Kano S, Ishizuka K, Cascella NG, Ishii S, Talbot CC Jr, et al. Olfactory cells via nasal biopsy reflect the developing brain in gene expression profiles: utility and limitation of the surrogate tissues in research for brain disorders. Neurosci Res. 2013;77:247–50.
Lappalainen J, Long JC, Eggert M, Ozaki N, Robin RW, Brown GL, et al. Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch Gen Psychiatry. 1998;55:989–94.
de Vellis J, Cole R. Preparation of mixed glial cultures from postnatal rat brain. Methods Mol Biol. 2012;814:49–59.
Lee JK, Tansey MG. Microglia isolation from adult mouse brain. Methods Mol Biol. 2013;1041:17–23.
Ozeki Y, Pickard BS, Kano S, Malloy MP, Zeledon M, Sun DQ, et al. A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: altered l-serine level associated with disruption of PSAT1 gene expression. Neurosci Res. 2011;69:154–60.
Jones-Brando L, Torrey EF, Yolken R. Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr Res. 2003;62:237–44.
Kano S, Sato K, Morishita Y, Vollstedt S, Kim S, Bishop K, et al. The contribution of transcription factor IRF1 to the interferon-gamma-interleukin-12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells. Nat Immunol. 2008;9:34–41.
Kano S, Colantuoni C, Han F, Zhou Z, Yuan Q, Wilson A, et al. Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia. Mol Psychiatry. 2013;18:740–2.
Shahani N, Seshadri S, Jaaro-Peled H, Ishizuka K, Hirota-Tsuyada Y, Wang Q, et al. DISC1 regulates trafficking and processing of APP and Abeta generation. Mol Psychiatry. 2014;20:874–9.
Blanchard N, Dunay IR, Schluter D. Persistence of Toxoplasma gondii in the central nervous system: a fine-tuned balance between the parasite, the brain and the immune system. Parasite Immunol. 2015;37:150–8.
Flegr J. Effects of toxoplasma on human behavior. Schizophr Bull. 2007;33:757–60.
Carruthers VB, Suzuki Y. Effects of Toxoplasma gondii infection on the brain. Schizophr Bull. 2007;33:745–51.
Liang Q, Deng H, Sun CW, Townes TM, Zhu F. Negative regulation of IRF7 activation by activating transcription factor 4 suggests a cross-regulation between the IFN responses and the cellular integrated stress responses. J Immunol. 2011;186:1001–10.
Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519–29.
Woo CW, Cui D, Arellano J, Dorweiler B, Harding H, Fitzgerald KA, et al. Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling. Nat Cell Biol. 2009;11:1473–80.
Malavasi EL, Ogawa F, Porteous DJ, Millar JK. DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription. Hum Mol Genet. 2012;21:2779–92.
Sawamura N, Ando T, Maruyama Y, Fujimuro M, Mochizuki H, Honjo K. et al. Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly. Mol Psychiatry. 2008;13:1138–48.
Soda T, Frank C, Ishizuka K, Baccarella A, Park Y, Flood Z, et al. DISC1-ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1. Mol Psychiatry.2013;18:898–908.
Bogunovic D, Byun M, Durfee LA, Abhyankar A, Sanal O, Mansouri D, et al. Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency. Science. 2012;337:1684–8.
Kreins AY, Ciancanelli MJ, Okada S, Kong XF, Ramirez-Alejo N, Kilic SS, et al. Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med. 2015;212:1641–62.
Blader IJ, Manger ID, Boothroyd JC. Microarray analysis reveals previously unknown changes in Toxoplasma gondii-infected human cells. J Biol Chem. 2001;276:24223–31.
Mashayekhi M, Sandau MM, Dunay IR, Frickel EM, Khan A, Goldszmid RS, et al. CD8alpha(+) dendritic cells are the critical source of interleukin-12 that controls acute infection by Toxoplasma gondii tachyzoites. Immunity. 2011;35:249–59.
Fox BA, Gigley JP, Bzik DJ. Toxoplasma gondii lacks the enzymes required for de novo arginine biosynthesis and arginine starvation triggers cyst formation. Int J Parasitol. 2004;34:323–31.
Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR, et al. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc Natl Acad Sci USA. 2004;101:12604–9.
Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2012;37:4–15.
Ho BC, Andreasen NC, Dawson JD, Wassink TH. Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psychiatry. 2007;164:1890–9.
Tunbridge EM, Harrison PJ, Weinberger DR. Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry. 2006;60:141–51.
Martinon F, Chen X, Lee AH, Glimcher LH. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010;11:411–8.
Richardson CE, Kooistra T, Kim DH. An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature. 2010;463:1092–5.
Yamamoto M, Ma JS, Mueller C, Kamiyama N, Saiga H, Kubo E, et al. ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18. J Exp Med. 2011;208:1533–46.
Seshadri S, Kamiya A, Yokota Y, Prikulis I, Kano S, Hayashi-Takagi A, et al. Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. Proc Natl Acad Sci USA. 2010;107:5622–7.
Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science. 2005;310:1187–91.
Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373–9.
Birey F, Andersen J, Makinson CD, Islam S, Wei W, Huber N, et al. Assembly of functionally integrated human forebrain spheroids. Nature. 2017;545:54–9.
Quadrato G, Nguyen T, Macosko EZ, Sherwood JL, Min Yang S, Berger DR, et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature. 2017;545:48–53.
We thank Dr. Wayne Yu and microarray facility at Sidney Kimmel Comprehensive Cancer Center (Johns Hopkins University) for microarray experiments; Drs. Jian-Chun (J-C) Xiao, Teppei Tanaka, Minori Koga for technical advice; Indigo VL Rose, Pamela Talalay, Nao Gamo, and Noah Elkins for critically reading the manuscript. This work was supported by U.S. Public Health Service Grants MH-069853 (AS), Silvio O. Conte Center grant MH-094268 (AS), MH-105660 (AS), MH-107730 (AS), K99/R00MH-093458 (SK), MH-113645 (SK); by foundation grants from Stanley Medical Research Institute (AS, FD), S-R (AS), RUSK (AS), NARSAD (AS, SK), JSPS (SK); by the Hammerschlag family (SK).
Conflict of Interest:
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Kano, Si., Hodgkinson, C.A., Jones-Brando, L. et al. Host–parasite interaction associated with major mental illness. Mol Psychiatry 25, 194–205 (2020). https://doi.org/10.1038/s41380-018-0217-z
This article is cited by
Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders
Molecular Psychiatry (2021)
Reply to Brune M and Theiss C: Remaining questions in the relationship between T. gondii infection and major mental illness
Molecular Psychiatry (2020)
Commentary on: “Host-parasite interaction associated with major mental illness”. Why we need integrative explanations based on evolutionary theory
Molecular Psychiatry (2020)