Type I interferon receptor-independent interferon-α induction upon infection with a variety of negative-strand RNA viruses

Abstract

Type I interferons (IFNs) are a first line of defence against viral infections. Upon infection, a first small wave of early type I IFN, mainly IFN-β and particularly IFN-α4, are induced and bind to the type I IFN receptor (IFNAR) to amplify the IFN response. It was shown for several viruses that robust type I IFN responses require this positive feedback loop via the IFNAR. Recently, we showed that infection of IFNAR knockout mice with the orthomyxovirus Thogoto virus lacking the ML open reading frame (THOV(ML-)) results in the expression of unexpected high amounts of type I IFN. To investigate if IFNAR-independent IFN responses are unique for THOV(ML-), we performed infection experiments with several negative-strand RNA viruses using different routes and dosages for infection. A variety of these viruses induced type I IFN responses IFNAR-independently when using the intraperitoneal (i.p.) route for infection. In vitro studies demonstrated that myeloid dendritic cells (mDC) are capable of producing IFNAR-independent IFN-α responses that are dependent on the expression of the adaptor protein mitochondrial antiviral-signalling protein (MAVS) whereas pDC where entirely depending on the IFNAR feedback loop in vitro. Thus, depending on dose and route of infection, the IFNAR feedback loop is not strictly necessary for robust type I IFN expression and an IFNAR-independent type I IFN production might be the rule rather than the exception for infections with numerous negative-strand RNA viruses.

Interleukin-36γ is causative for liver damage upon infection with Rift Valley fever virus in type I interferon receptor-deficient mice

“…As shown before (7), IFNAR -/mice succumb to infection with RVFV cl13, which is accompanied by body weight loss and a drop in body temperature, while their WT counterparts survive the infection and do not show such symptoms (Figures 1A-C). In line with this, WT mice mount IFN-a responses 12 hpi while IFNAR -/mice produced high amounts of IFN-a (up to ~4500 pg/ml) at 30 hpi indicating uncontrolled IFN-a production in the course of infection (Supplementary Figure 1).…”

“…CD4Cre IFNAR flox/flox and CD19Cre IFNAR flox/flox mice (37), LysMCre IFNARflox/flox mice (38), and CD11cCre IFNARflox/flox (6) have been described before. To obtain MyD88 -/-IFNAR -/double-deficient mice and MAVS -/-IFNAR -/double-deficient mice, MyD88 -/mice or MAVS -/mice were intercrossed with IFNAR -/mice as described before (7). All mice were bred under specific pathogen free conditions at the Zentrale Tierhaltung of the Paul-Ehrlich-Institut.…”

“…Isolation of PEC was described elsewhere (7,11). For FACS analyses, cells were stained for 20 min at 4°C with the following fluorochrome-labeled monoclonal antibodies: anti-CD11callophycocyanin (APC), anti-B220-PE (both from BD PharMingen), anti-CD11b-Pacific Blue (from Caltag/Invitrogen), and anti-F4/80-APC (AbD Serotec).…”

“…Small amounts of early type I IFN, mainly IFN-a 4 and IFN-b, bind to the IFNAR in order to induce the production of high amounts of type I IFN (4)(5)(6). Nevertheless, depending on dose and route of infection, the IFNAR feedback loop is not strictly necessary for robust type I IFN expression upon infection with a variety of RNA-encoded viruses (7).…”

Type-I interferons promote innate immune tolerance in macrophages exposed to Mycobacterium ulcerans vesicles

“…Besides, the activation of TLR2, the major TLR involved in the recognition of M. ulcerans vesicles [11], has been previously shown to induce the expression of type-I interferons as well [38]. Also, another study has shown that the IFNAR feedback loop is not strictly necessary for robust type I IFN expression in the context of viral infection [44]. We therefore hypothesized that either the first wave of IFN-β or ISGs induced in an IFNAR pathway-independent manner may promote macrophage tolerance to M. ulcerans despite the presence of mycolactone.…”