Cutting Edge: Overlapping Functions of TLR7 and TLR9 for Innate Defense against a Herpesvirus Infection

Abstract

As initially demonstrated with murine cytomegalovirus (MCMV), plasmacytoid dendritic cells (pDCs) are the major source of IFN-α/β in response to a variety of viruses in vivo. However, contradictory results have been obtained pertaining to the mechanisms promoting IFN-α/β production by pDCs in response to MCMV. In this study we show that TLR7 and TLR9 exert redundant functions for IFN-α/β, IL-12p40, and TNF-α production by pDCs in vivo during MCMV infection. In contrast, we confirm that systemic production of IL-12p70 strictly depends on TLR9. The combined loss of TLR7 and TLR9 recapitulates critical features of the phenotype of MyD88-deficient mice, including a dramatic decrease in systemic IFN-α/β levels, an increase in viral load, and increased susceptibility to MCMV-induced mortality. This is the first demonstration of the implication of TLR7 in the recognition of a DNA virus.

IL-4 enhances IFN-λ1 (IL-29) production by plasmacytoid DCs via monocyte secretion of IL-1Ra

“…These findings confirmed previous observations that pDCs are the major PBMC population to produce IFN-1 in response to HSV, 24 which is known to stimulate pDCs at least in part through Toll-like receptor 9 (TLR9) [26][27][28] and potentially through TLR7. 29 Unlike myeloid/classical DCs (mDCs) or MDDCs, 23 highly enriched pDCs did not produce appreciable amounts of IFN-1 in response to poly I:C or LPS, as has been previously observed. 24 This is in agreement with their selective expression of TLR7 and TLR9, and paucity of expression and/or response to TLR3 (poly I:C) or TLR4 (LPS) agonists.…”

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

“…In mice, studies have shown a direct interaction between murine cytomegalovirus (MCMV) and NK cells, where the activating NK cell receptor Ly49H recognizes the m157 glycoprotein, thereby activating the NK cell to produce cytokines important for antiviral immunity and/or to kill (Krug et al 2004;Varani et al 2007;Zucchini et al 2008) MCMV and HCM-V AIM2 dsDNA (Rathinam et al 2010;Huang et al 2017) MCMV and HCM-V cGAS-STI-NG dsDNA (Lio et al 2016) MCMV TLR3 dsRNA (Tabeta et al 2004) MCMV TLR7 ssRNA (Zucchini et al 2008) HCMV DAI dsDNA (DeFilippis et al 2010) HCMV IFI16 dsDNA (Gariano et al 2012) the virus-infected cell through release of perforins and granzymes (Brown et al 2001;Pyzik et al 2011). Indeed, m157 deletion mutant MCMV fails to activate Ly49H+ NK cells and results in enhanced virulence (Voigt et al 2003;Bubić et al 2004).…”

Unravelling the interaction of human cytomegalovirus with dendritic cells by using SuperSAGE

“…HCMV has been shown to bind to Toll-like receptor 2 (TLR2) (Compton et al, 2003) and DC-SIGN (Halary et al, 2002). Murine cytomegalovirus infection has been shown to be controlled primarily by TLR9 and TLR3 (Tabeta et al, 2004;Zucchini et al, 2008), and it is likely that other PRRs also react to HCMV infection. Many viruses thus encode molecules that attempt to block cellular responses in order to evade the immune response, such as vaccinia virus A52R (Harte et al, 2003), which blocks TLR signalling, and herpes simplex virus (HSV) virion host shutoff protein (vhs), which causes a broad downregulation of cellular mRNA (Fenwick & McMenamin, 1984).…”