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Institute of Medicine (US) Forum on Microbial Threats; Knobler SL, O'Connor S, Lemon SM, et al., editors. The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary. Washington (DC): National Academies Press (US); 2004.

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary.

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INFECTIOUS AGENTS AND SCHIZOPHRENIA*

and .

Author Information

1 and 2.

1 Johns Hopkins School of Medicine, Baltimore, MD
2 Stanley Medical Research Institute, Bethesda, MD

Schizophrenia is a pervasive neuropsychiatric disorder of worldwide importance. This disease and related serious psychiatric diseases exact an enormous cost in terms of medical resources, lost productivity, and social ills such as crime and homelessness (see Box 1-2). Despite more than 100 years of extensive research, the causes of schizophrenia remain obscure. Much of the recent research in schizophrenia has focused on possible genetic etiologies. The rationale for this approach is based on numerous studies indicating a strong risk associated with having a biological parent with this disease. Extensive genetic analyses of families with schizophrenia have led to the identification of a number of broad genomic regions which appear to be inherited in a non-random fashion by individuals with schizophrenia. However, despite intensive searches, no genes of major, or even minor effect, have been consistently linked to the schizophrenia phenotype (see Box 1-3).

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Box 1-2

Clinical and Epidemiological Features of Schizophrenia. Positive symptoms: Hallucinations

Box Icon

Box 1-3

Genetics of Schizophrenia. Increased incidence in biological first-degree relatives: General Population ∼1 percent

Due to the limited success of genetic investigations, there has been renewed interest in the role of environmental factors in the etiopathogenesis of schizophrenia. This approach derives its rationale from a number of epidemiological studies which indicate that environmental factors may contribute to the risk of schizophrenia in some individuals. Many of these studies identify environmental events occurring during fetal development and early infancy as risk factors for the development of schizophrenia in adult life. Risk factors which have been identified include infections, nutritional deprivation, and animal exposures in pregnancy (Yolken and Torrey, 1995; Torrey et al., 2000). Additional studies have documented an association between risk of schizophrenia with place and season of birth (Torrey et al., 1997; Torrey and Yolken, 1998). While the relative risks associated with these factors are relatively modest, the common nature of these exposures indicates that they may have a large effect on a population basis (Mortensen et al., 1999).

Based on this background, we have devised the working hypothesis that most cases of schizophrenia are caused by infections and other environmental events occurring in genetically susceptible individuals (Torrey and Yolken, 2000). It is of note that infections relating to schizophrenia occurring in this context would not be expected to follow satisfy Koch's postulates since they would not lead to disease in individuals who did not have the appropriate genetic susceptibility. It is also likely that different microbial agents could lead to a similar disease process in individuals who share common genetic predispositions. It will thus be necessary to move beyond Koch's postulates in order to analyze the interaction between genetic and environmental factors as causative agents of schizophrenia and other serious psychiatric diseases.

We have applied a number of laboratory techniques to the examination of these hypotheses (Johnston-Wilson et al., 2001). These techniques have been used to analyze brain tissues obtained postmortem from individuals with psychiatric diseases and control conditions. These brains were obtained by the Stanley Foundation from a consortium of neuropathologists located in several different regions of the United States and are available to researchers with an interest in the studies of these disorders.

One of the most informative techniques which we have applied to these samples has been that of differential display. This method has indicated that there are several differences in RNA transcription in the brains of individuals with schizophrenia as compared to unaffected controls (Yee and Yolken, 1997). Sequence analysis of differentially expressed transcripts has indicated that many have a high degree of homology with a range of endogenous retroviruses. These elements are components of the human genome which arose from retrotransposition of infectious retroviruses in our evolutionary past. Endogenous retroviruses are integrated into the human genome. Upon activation, they can modulate the transcription of genes located upstream or downstream from the site of chromosomal integration (see Figure 1-8). Since they share properties of both genes and infectious agents, they are a potential link between genetic and environmental causes of human disease (Yolken et al., 2000).

FIGURE 1-8. Integration and transcription of endogenous retroviruses.

FIGURE 1-8

Integration and transcription of endogenous retroviruses.

Further studies were performed on cerebrospinal fluids (CSFs) obtained from living individuals with early symptoms of schizophrenia. Amplification of RNA extracted from these fluids indicated an increased rate of transcription of an endogenous retrovirus called HERV-W. This endogenous retrovirus was found in the CSFs of approximately 30 percent of individuals with recent-onset schizophrenia and 5 percent of individuals with chronic forms of the disease (see Figure 1-9). HERV-W transcription was not detected in the CSF of individuals without psychiatric disorders (Karlsson et al., 2001). HERV-W is of interest since its transcription has also been found to be increased in the CSFs of individuals with multiple sclerosis (Perron et al., 1997). It has also been demonstrated to be active during human fetal development and to encode a protein with syncytium forming activity in the human placenta (Mi et al., 2000). Furthermore , the envelope protein of HERV-W is capable of causing polyclonal T-lymphocyte activation (Perron et al., 2001). HERV-W may thus also provide a link between environmental events active both during fetal development and adult life.

FIGURE 1-9. Endogenous retrovirus was found in the CSFs of approximately 30 percent of individuals with recent-onset schizophrenia and 5 percent of individuals with chronic forms of the disease.

FIGURE 1-9

Endogenous retrovirus was found in the CSFs of approximately 30 percent of individuals with recent-onset schizophrenia and 5 percent of individuals with chronic forms of the disease. SOURCE: Karlsson et al. (2001).

The transcription of endogenous retroviruses can be activated by a number of infectious agents and other environmental factors. We have examined the prevalence of potential activating infections in different stages of schizophrenia. We have found an increased level of antibodies to Toxoplasma gondii in individuals with the recent onset of schizophrenia (see Figure 1-10) (Yolken et al., 2001). This finding is consistent with epidemiological studies documenting an increased rate in schizophrenia in individuals who were exposed to cats in early life (Torrey et al., 2000). We have also found that serological evidence of infection with Herpes Simplex Virus Type 1 and Toxoplasma gondii are associated with increased levels of cognitive and memory impairments in individuals with established forms of schizophrenia (Dickerson et al., 2003b). We also examined the possible association between infections in pregnancy in the occurrence of schizophrenia in later life. These analyses were accomplished by the testing of sera which had been obtained from healthy pregnant women as part of the National Collaborative Perinatal Study performed in the United States during the 1950s and 1960s. Initial analyses of this cohort indicates that the offspring of mothers who had evidence of infection, as indicated by increased levels of IgG, IgM, and of IgG antibodies to Herpes Simplex Virus type 2, have higher rates of schizophrenia in adult life (see Figure 1-11) (Buka et al., 2001). There was also a risk of schizophrenia associated with IgM antibodies to Toxoplasma gondii, although the antigenic source of these antibodies is still under investigation.

FIGURE 1-10. An increased level of antibodies to Toxoplasma gondii is found in individuals with recent onset of schizophrenia.

FIGURE 1-10

An increased level of antibodies to Toxoplasma gondii is found in individuals with recent onset of schizophrenia. SOURCE: Yolken et al. (2001).

FIGURE 1-11. Association between HSV infections in pregnant women and the occurrence of schizophrenia in their adult offspring.

FIGURE 1-11

Association between HSV infections in pregnant women and the occurrence of schizophrenia in their adult offspring. The adult offspring of mothers whose sera showed evidence of HSV infection during pregnancy have higher rates of schizophrenia than the (more...)

These studies indicate that infectious agents play a role in the generation of schizophrenia in some individuals. The activation of endogenous retroviruses within the central nervous system is likely to be one of several mechanisms by means of which infections can lead to disease. If this is the case, it is possible that the treatment of infectious agents which activate retroviral transcription may be capable of modulating the course of disease at different times in the lifelong course of disease. For example, the treatment of active infection with herpes simplex virus might prevent endogenous retrovirus activation due to this organism. It is of note in this regard that several of the medications which are commonly used for the treatment of schizophrenia also have the ability to inhibit the replication of infectious agents (Jones-Brando et al., 1997). Preliminary analysis of a clinical trial of the anti-herpesvirus medication valacyclovir indicates that it is effective in reducing the symptoms of some individuals with schizophrenia (Dickerson et al., 2003a). Ongoing studies are directed at the further evaluation of the role of anti-viral and anti-parasitic agents in the treatment of schizophrenia. The definitive establishment of the role of infectious agents in the etiopathogenesis of schizophrenia may lead to new methods for the diagnosis, prevention, and treatment of this devastating disease.

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The research described in this presentation was supported by the Stanley Medical Research Institute.

Footnotes

*

The research described in this presentation was supported by the Stanley Medical Research Institute.

Copyright © 2004, National Academy of Sciences.
Bookshelf ID: NBK83686
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