A Systematic Analysis of Host Factors Reveals a Med23-Interferon-? Regulatory Axis against Herpes Simplex Virus Type 1 Replication

Griffiths, Samantha J.; Koegl, Manfred; Boutell, Chris; Zenner, Helen L.; Crump, Colin M.; Pica, Francesca; Gonzalez, Orland; Friedel, Caroline C.; Barry, Gerald; Martin, Kim; Craigon, Marie H.; Chen, Rui; Kaza, Lakshmi N.; Fossum, Even; Fazakerley, John K.; Efstathiou, Stacey; Volpi, Antonio; Zimmer, Ralf; Ghazal, Peter; Haas, Jürgen

HSV infection controlled by a complex, interconnected and highly regulated network of cytokines expressed by innate immune cells. Type I IFNs mainly produced by HSV-infected keratinocytes [68] and pDCs [69] inhibit the spread from neurons to epithelial cells and between epithelial cells [70] , similar to IFN-c. Type III IFNs are also able to directly inhibit HSV-1 infection in primary neurons, astrocytes, macrophages and dendritic cells [71, 72] . IFN-c levels produced by peripheral blood CD4+ T-cells correlate with the frequency of HSV-1 reactivation [73] . IFN-l is able to induce expression of both itself and the type I IFNs, and a similar effect has also been observed for type I IFNs which induce both type I and III IFNs [71, 72] . Type III IFNs are mainly expressed by myeloid dendritic cells (mDC) and monocyte-derived macrophages [74] , and signal through the heterodimeric IL10RB/IL28RA receptor complex whose expression is largely restricted to cells of epithelial origin and plasmacytoid dendritic cells (pDC), in contrast to the broadly expressed type I IFN receptor (IFN-aR1/2) [75, 76] . Since primary HSV-1 infection and reactivation affects skin and mucosa in the majority of cases, IFN-l may play a much greater role in the control of HSV-1 pathogenesis, likely in a complex network of coregulated type I and II IFNS, than previously thought. We hypothesize that HSV-infected DCs at the site of the lesion (such as skin Langerhans DCs whose role in IFN-l production is currently unknown, or intruding myeloid DCs) in individuals with the rs12979860 T/T or C/T haplotype express reduced levels of type III IFNs, and, in consequence, of type I IFNs, which leads to a reduced inhibition of local HSV-1 replication and the occurrence of fresh skin lesions. However, the relative contribution of IFN-l1 and l2/3 to the interferonmediated control of HSV-1 replication in vivo, and indeed the role of Med23 in this, remains to be seen.