Abstract
In mice, plasmacytoid dendritic cells (pDC) and natural killer (NK) cells both contribute to resistance to systemic infections with herpes viruses including mouse Cytomegalovirus (MCMV). pDCs are the major source of type I IFN (IFN-I) during MCMV infection. This response requires pDC-intrinsic MyD88-dependent signaling by Toll-Like Receptors 7 and 9. Provided that they express appropriate recognition receptors such as Ly49H, NK cells can directly sense and kill MCMV-infected cells. The loss of any one of these responses increases susceptibility to infection. However, the relative importance of these antiviral immune responses and how they are related remain unclear. In humans, while IFN-I responses are essential, MyD88 is dispensable for antiviral immunity. Hence, a higher redundancy has been proposed in the mechanisms promoting protective immune responses against systemic infections by herpes viruses during natural infections in humans. It has been assumed, but not proven, that mice fail to mount protective MyD88-independent IFN-I responses. In humans, the mechanism that compensates MyD88 deficiency has not been elucidated. To address these issues, we compared resistance to MCMV infection and immune responses between mouse strains deficient for MyD88, the IFN-I receptor and/or Ly49H. We show that selective depletion of pDC or genetic deficiencies for MyD88 or TLR9 drastically decreased production of IFN-I, but not the protective antiviral responses. Moreover, MyD88, but not IFN-I receptor, deficiency could largely be compensated by Ly49H-mediated antiviral NK cell responses. Thus, contrary to the current dogma but consistent with the situation in humans, we conclude that, in mice, in our experimental settings, MyD88 is redundant for IFN-I responses and overall defense against a systemic herpes virus infection. Moreover, we identified direct NK cell sensing of infected cells as one mechanism able to compensate for MyD88 deficiency in mice. Similar mechanisms likely contribute to protect MyD88- or IRAK4-deficient patients from viral infections.
Highlights
Type I interferons (IFN-I) orchestrate vertebrate antiviral defenses through two complementary mechanisms [1]
Intracellular Toll-like receptors (TLR) are selectively expressed in specialized immune cell types such as plasmacytoid dendritic cells, enabling them to copiously produce IFN-I upon detection of engulfed viral nucleic acids. pDC or intracellular TLR have been reported to be crucial for resistance to experimental infections with many viruses in mice but dispensable for resistance to natural infections in humans
To assess the contribution of pDC activation and endosomal TLR7/9 triggering to IFN-I responses during mouse Cytomegalovirus (MCMV) infection, we analyzed the induction of IFN-I and Interferon Stimulated Genes (ISG) in the spleen or blood of BALB/c mice knocked-out for MyD88 or TLR9, or depleted of pDC through administration of the 120G8 mAb directed against Bst2. 120G8 mAb injection dramatically reduced circulating IFN-I titers and splenic Ifnb1 expression at d1.5 after infection (Fig 1A and 1B)
Summary
Type I interferons (IFN-I) orchestrate vertebrate antiviral defenses through two complementary mechanisms [1]. These cytokines induce multiple Interferon Stimulated Genes (ISG) coding for effector molecules of cell-intrinsic antiviral immunity. Genetic deficiencies compromising IFN-I responses dramatically increase susceptibility to viral infections in mice and men [2]. In addition to IFN-I, type III interferons (IFN-III) appear critical for antiviral defense, based on the analysis of mutant mice, and on the strong association between resistance to viral infections and polymorphisms affecting these genes in humans [1, 3, 4]. While the IFN-I receptor (IFNAR) is ubiquitously expressed, the receptor for IFN-III is selectively expressed in epithelial cells [1]
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