Infectious agents like the human habitat well enough, and some even prefer our nervous systems. As researchers debate whether infections contribute to schizophrenia risk, some scientists are beginning to ask whether infectious agents can also alter mental processes in people already diagnosed with schizophrenia.
Robert Yolken of Johns Hopkins University provided an overview of this “epidiagnostic” idea, which sees the vagaries of infection as possible modulators of processes such as cognitive functions among patients.
Researchers are now specifically exploring whether the cognitive impairments in schizophrenia are modified by infections with herpes simplex virus 1 (HSV1) and the parasite Toxoplasma gondii. Konasale Prasad of the University of Pittsburgh described work on HSV1, which, once it infects a person, remains in the nervous system throughout life, alternating between dormant and active states. HSV1-exposed people with schizophrenia exhibit worse cognitive symptoms in the realms of working memory, verbal memory, and executive function compared with unexposed patients with schizophrenia. Preliminary experiments now suggest that treatment with anti-herpes medications can improve these impairments. Importantly, even people without schizophrenia perform less well on specific cognitive tasks if they have been exposed to HSV1. Because the integrity of the immune system could modulate vulnerability to infection in the first place, Vishwajit Nimgaonkar of the University of Pittsburgh discussed potential interactions between infection and host genetic variation at the major histocompatibility complex (MHC) locus, a region containing immune-related genes that has been implicated in schizophrenia. This has offered up a potential interaction between a common variant in the region and HSV1 exposure on schizophrenia risk, and further studies are needed.
Toxoplasma gondii, a notorious resident of cats' litter boxes, may instigate cognitive deficits in humans upon infecting their nervous systems. Animal models of T. gondii infection have been developed to study this process in detail, and Mikhail Pletnikov of Johns Hopkins University discussed work in rodents infected with the parasite. These show impairments in spatial learning and memory analogous to impairments found in schizophrenia. Exploring these diverse questions may open up some novel avenues for treatment of cognitive impairments and provide some insight into the epidemiological hints of roles for infection in schizophrenia.
Great topic! Myself, I have recently started to think about the same issue, in particular, how to answer this question in a "quasi-experimental" setting (as part of a population-based cohort study) project in preparation.
This Webinar group has made an enormous contribution regarding the roles of pathogens in schizophrenia and related disorders. Although pathogens have been implicated in most diseases, there has been a certain reluctance in accepting any causal relationship (despite odds ratios generally higher than those of most genes (Torrey et al., 2012; Arias et al., 2012). This is partly due to the high prevalence of infection, compared with the much lower incidence of disease. For example, Toxoplasmosis may infect 30 percent of the global population (Henriquez et al., 2009), versus a schizophrenia incidence of about 1 percent (Saha et al., 2005).
Genetic studies currently hold center stage and have yielded an enormous amount of useful information concerning the pathology of numerous disorders, although in the psychiatric field, this has not yet led to the development of radically new therapeutic approaches.
Genetic risk variants also exist in the control population (at lower frequency), and any effects of either genes or environmental factors are likely to be conditioned by many other influences, including epistasis, other genes in similar pathways, and by gene/environment interactions. I have been particularly interested in the last, showing that several genes implicated in schizophrenia or Alzheimer’s disease can be related to the life cycles of diverse suspect pathogens (Carter, 2009; Carter, 2011), and I have recently analyzed an extensive T. gondii host/pathogen interactome (J. Pathogens, in press; see provisional PDF) with the following main conclusions. The parasite binds to numerous proteins, increases brain dopamine levels, secretes or scavenges many other substrates, and modifies the expression of many messenger RNAs, creating an interactome of almost 3,000 host genes. This dataset is heavily enriched in the susceptibility genes for schizophrenia, but also in those of a number of other diseases (multiple sclerosis, Alzheimer’s disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson’s disease, attention deficit hyperactivity disorder, and autism). The interactome creates a mesh of signaling networks, and the pathways primarily affected by the susceptibility gene/interactome overlap are relatively specific and relevant to each disease.
The parasite clearly affects a very large number of pathways. Its effects on some may be disease promoting, while effects on others might well be in some way protective. Because the susceptibility genes relate to the pathogen’s life cycle, they may be able to orient its attentions in one direction or another, allowing it to promote or protect against different sub-pathologies or endophenotypes. In other words, the susceptibility genes may act as a selectivity filter, allowing the same pathogen to cause or prevent the underlying features of a variety of diseases.
Others have commented on the fact that susceptibility genes in human disease lie at the host/pathogen interface (in a study relating to the Epstein-Barr virus and the papillomavirus; Gulbahce et al., 2012), and this may well be a general phenomenon. If so, pathogens may well be the cause of many diseases, acting in concert with the genes and their protein products.
This has obvious therapeutic implications. However, particularly in the psychiatric field, the deleterious effects of infection appear to be related to prenatal or childhood infections, with the disease developing much later (Brown, 2012; Harvey and Boksa, 2012; Kneeland and Fatemi, 2012), and the use of antiviral or antimicrobial agents may be less feasible as treatment. However, a clearer understanding of these multiple interactions, and perhaps a resurgence of pharmaceutical and research interest in virology and microbiology, could lead to better strategies for prevention and cure. There is also a pressing need to understand the role of autoantibodies (potentially derived from pathogens with homologous proteins) and of the immune system, whose activation is an evident consequence of infection.
The pathogens discussed in this Webinar represent a tiny portion of an extensive microbiome, whose influence in psychiatry has yet to be studied. While the pathology and symptomatology in psychiatry are clearly cerebral, the causes of disease may well relate to microbial communities residing in other areas.
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