Abstract
Associations between influenza infection and psychosis have been reported since the eighteenth century, with acute “psychoses of influenza” documented during multiple pandemics. In the late 20th century, reports of a season-of-birth effect in schizophrenia were supported by large-scale ecological and sero-epidemiological studies suggesting that maternal influenza infection increases the risk of psychosis in offspring. We examine the evidence for the association between influenza infection and schizophrenia risk, before reviewing possible mechanisms via which this risk may be conferred. Maternal immune activation models implicate placental dysfunction, disruption of cytokine networks, and subsequent microglial activation as potentially important pathogenic processes. More recent neuroimmunological advances focusing on neuronal autoimmunity following infection provide the basis for a model of infection-induced psychosis, potentially implicating autoimmunity to schizophrenia-relevant protein targets including the N-methyl-D-aspartate receptor. Finally, we outline areas for future research and relevant experimental approaches and consider whether the current evidence provides a basis for the rational development of strategies to prevent schizophrenia.
Highlights
WHAT IS THE EVIDENCE FOR AN ASSOCIATION BETWEEN INFLUENZA AND SCHIZOPHRENIA?Schizophrenia risk is associated with a variety of environmental and genetic factors [1], including those associated with immunity and inflammation [2]
While many organisms and infection types have been implicated in schizophrenia risk, the influenza virus has special status: is maternal influenza infection the most well-replicated infective risk factor for schizophrenia, but the history of schizophrenia research has been shaped at crucial points by observations concerning the apparent, sometimes surprising, role of influenza as an exposure
Protective immune responses from the cell occur; the viral hemagglutinin, neuraminidase, and matrix 2 (M2) proteins are targeted by antibodies; matrix 1 (M1) proteins are targeted by T cells [80]; and nucleoproteins are targeted by T cells [80] and nonneutralizing antibodies [81]
Summary
Schizophrenia risk is associated with a variety of environmental and genetic factors [1], including those associated with immunity and inflammation [2]. Influenza (including serologically documented infection) has been reported as a risk factor for BD with psychotic features but not nonpsychotic BD [reviewed in [22,23,24]]. A substantial body of work from Scandinavian (largely Danish) health register studies supports the notion that clinically diagnosed maternal, childhood, or adulthood infection is a pluripotent risk factor for the subsequent development of psychiatric disorder, with effects observed across diagnostic boundaries [13,14,15,16, 26, 27]. While suggestive, these reports do not provide evidence of a causal link between influenza infection and psychotic disorders. Renewed interest in the second half of the 20th century shifted focus towards maternal infection, following consistent findings
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