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Abstract
The genetic theory of infectious diseases has proposed that susceptibility to life-threatening infectious diseases in childhood, occurring in the course of primary infection, results mostly from individually rare but collectively diverse single-gene variants. Recent evidence of an ever-expanding spectrum of genes involved in susceptibility to infectious disease indicates that the paradigm has important implications for diagnosis and treatment. One such pathology is childhood herpes simplex encephalitis, which shows a pattern of rare but diverse disease-disposing genetic variants. The present report shows how proteomics can help to understand susceptibility to childhood herpes simplex encephalitis and other viral infections, suggests that proteomics may have a particularly important role to play, emphasizes that variation over the population is a critical issue for proteomics and notes some new challenges for proteomics and related bioinformatics tools in the context of rare but diverse genetic defects.
Acknowledgements
The authors thank the members of the Laboratory of Human Genetics of Infectious Diseases (The Rockefeller University, New York, NY, USA). The authors thank the patients and their families for their participation in this study, which was supported by the Groupement d’Intérêt Scientifique Maladies Rares, the Action Concertée Incitative de Microbiologie, the March of Dimes, the Agence Nationale pour la Recherche, the Eppley Foundation, the National Institute of Allergy and Infectious Diseases grant number R01AI088364, the Thrasher Research Fund, the Jeffrey Modell Foundation, Talecris Biotherapeutics, the St. Giles Foundation, the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) grant number 8UL1TR000043 and the Rockefeller University.
Financial & competing interests disclosure
R Pérez de Diego is supported by the ‘Ramon y Cajal’ program (MINECO, Spain). J-L Casanova was an international investigator of the Howard Hughes Medical Institute since 2013. The work was supported by a Wellcome Trust Grant to J Godovac-Zimmermann. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
Herpes simplex virus (HSV-1) encephalitis (HSE) is a devastating infection of the CNS, the most common form of sporadic viral encephalitis in western countries and typically produces neurological sequelae in patients, especially young children.
In keeping with the genetic theory of infectious diseases, mutations in five diverse genes have been implicated in susceptibility to HSE, but only a low percentage of patients exhibit these mutations. They show that the Toll-like receptor-3 (TLR3) signaling pathway is crucial for primary infection.
Different phenotypes have been identified among patients, for example, approximately 30% of HSE patients have normal interferon type I and III production after TLR3 stimulation, implying that pathways beyond the TLR3-IFN pathway must be involved.
Use of a new strategy in which large numbers of proteins in patient samples are compared with population variation for healthy individuals and with systems biology functional information helped identify additional pathways and proteins that are implicated in susceptibility to HSE.
Initial evidence has been obtained that new pathways and proteins identified with this strategy can contribute to therapeutic treatments.
The results indicate that normal variation over the population in healthy individuals is a crucial issue for proteomics and that new measures of significance and new forms of data analysis are needed to deal with population variation.
The results were obtained in the context of a unified theory of genetic predisposition to infectious disease, but similar paradigms should be expected for complex genetic diseases and population variation.
Efforts to approach these complex problems from the perspective of the genetic theory of infectious disease may have a crucial advantage in that ‘infection’ can provide a defined, controllable tool to initiate cellular responses in ways that can be easily exploited by proteomics.
Response of cells to dsRNA is a characteristic of many viral infections and the approach described here should be widely applicable to viral infection.
Integration of proteomics information with genetic, metabolomics and medical information is important to develop ‘functional-network-based’ conceptual models of normal function, disease, diagnostics and therapy.