Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

Fabien G. Lafaille et al. Nature. 491, 769–775 (2012).

Speaker: Alan Hsu (許翊輝)                                  Time: 13:00~14:00, Jan 9, 2013

Commentator: Dr. Chang Yao (張堯 老師)         Place: Room 601

Abstract

Herpes simplex virus (HSV) is a virus that has evolved along the course of human evolution, playing a never-ending game of chess with the human immune system, each trying to outwit the other. HSV is most known for its dual life cycle, the lytic state which causes blisters, cold sores, encephalitis and meningitis. After initial infection, the viruses are transported to the sensory nerve cell bodies, where they become latent and stay under the radar and reside lifelong causing prolonged infection.   In this study we are going to discuss a more specific scenario of HSV infection, namely the primary infection of children with inborn errors of the TLR signaling pathway, more specifically TLR-3, which are prone for HSV encephalitis (HSE).The authors used induced pluripotent stem cells (iPSC) derived from dermal fibroblasts and differentiated them into purified populations of neurons, oligodendrocytes, astrocytes, and neuron stem cells (NSCs). These differentiated cells had the same profiles and markers as their target cells, while only different in origin and specific manual manipulation. They found that while stimulated with poly(I:C) the production of immune factors IFN-β and IFN-λ1 was dependent on the function of TLR3 and UNC-93B which helps traffic TLRs within the cell. Also the IFN-β and/or IFN-λ1 response against HSV infection was impaired in UNC-93B-deficient neurons and oligodendrocytes while being more susceptible to HSV infection, but this phenomenon was not seen in UNC-93B-deficient NSCs and astrocytes. Furthermore, TLR3-deficient neurons were also found to be more susceptible to HSV infection. The complementation of UNC-93B and TLR3 with the wild type alleles respectfully rescued the infection profile, and the addition of exogenous type 1 interferons (IFN-α/β) but not IFN-λ1 further rescued the status.

Thus they suggested that children with TLR3-pathway deficiencies, namely impaired TLR3 and UNC-93B which abrogates IFN-a/b intrinsic immunity to HSV infection in the neurons and oligodendrocytes, may underlie the pathogenesis of HSE.

References:

1.      Casrouge, A. et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314, 308–312 (2006).

2.      Zhang, S. Y. et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science 317, 1522–1527 (2007).