Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 208, Issue 10, Pages 2083-2098Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20101568
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Funding
- Rockefeller University Center for Clinical and Translational Science [5UL1RR024143-04]
- Rockefeller University
- Institut National de la Sante et de la Recherche Medicale
- Paris Descartes University
- St. Giles Foundation
- Eppley Foundation
- Jeffrey Modell Foundation
- Talecris Biotherapeutics
- Thrasher Research Found
- National Research Agency
- GIS Maladies Rares
- March of Dimes
- Programme for Advanced Medical Education
- Fundacao Calouste Gulbenkian
- Fundacao Champalimaud
- Ministerio da Saude
- Fundacao para a Ciencia e Tecnologia, Portugal
- National Institutes of Health [R21 AI085523-01]
- Baylor Healthcare System Foundation
- MRC [G0900867] Funding Source: UKRI
- Medical Research Council [G0900867] Funding Source: researchfish
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Autosomal dominant TLR3 deficiency has been identified as a genetic etiology of childhood herpes simplex virus 1 (HSV-1) encephalitis (HSE). This defect is partial, as it results in impaired, but not abolished induction of IFN-beta and -lambda in fibroblasts in response to TLR3 stimulation. The apparently normal resistance of these patients to other infections, viral illnesses in particular, may thus result from residual TLR3 responses. We report here an autosomal recessive form of complete TLR3 deficiency in a young man who developed HSE in childhood but remained normally resistant to other infections. This patient is compound heterozygous for two loss-of-function TLR3 alleles, resulting in an absence of response to TLR3 activation by polyinosinic-polycytidylic acid (poly(I:C)) and related agonists in his fibroblasts. Moreover, upon infection of the patient's fibroblasts with HSV-1, the impairment of IFN-beta and -lambda production resulted in high levels of viral replication and cell death. In contrast, the patient's peripheral blood mononuclear cells responded normally to poly(I:C) and to all viruses tested, including HSV-1. Consistently, various TLR3-deficient leukocytes from the patient, including CD14(+) and/or CD16(+) monocytes, plasmacytoid dendritic cells, and in vitro derived monocyte-derived macrophages, responded normally to both poly(I:C) and HSV-1, with the induction of antiviral IFN production. These findings identify a new genetic etiology for childhood HSE, indicating that TLR3-mediated immunity is essential for protective immunity to HSV-1 in the central nervous system (CNS) during primary infection in childhood, in at least some patients. They also indicate that human TLR3 is largely redundant for responses to double-stranded RNA and HSV-1 in various leukocytes, probably accounting for the redundancy of TLR3 for host defense against viruses, including HSV-1, outside the CNS.
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