Type I IFN Receptor Regulates Neutrophil Functions and Innate Immunity to Leishmania Parasites

Abstract

Type I IFNs exert diverse effector and regulatory functions in host immunity to viral and nonviral infections; however, the role of endogenous type I IFNs in leishmaniasis is unclear. We found that type I IFNR-deficient (IFNAR−/−) mice developed attenuated lesions and reduced Ag-specific immune responses following infection with Leishmania amazonensis parasites. The marked reduction in tissue parasites, even at 3 d in IFNAR−/− mice, seemed to be indicative of an enhanced innate immunity. Further mechanistic analyses indicated distinct roles for neutrophils in parasite clearance; IFNAR−/− mice displayed a rapid and sustained infiltration of neutrophils, but a limited recruitment of CD11b+Ly-6C+ inflammatory monocytes, into inflamed tissues; interactions between IFNAR−/−, but not wild-type (WT) or STAT1−/−, neutrophils and macrophages greatly enhanced parasite killing in vitro; and infected IFNAR−/− neutrophils efficiently released granular enzymes and had elevated rates of cell apoptosis. Furthermore, although coinjection of parasites with WT neutrophils or adoptive transfer of WT neutrophils into IFNAR−/− recipients significantly enhanced infection, the coinjection of parasites with IFNAR−/− neutrophils greatly reduced parasite survival in WT recipients. Our findings reveal an important role for type I IFNs in regulating neutrophil/monocyte recruitment, neutrophil turnover, and Leishmania infection and provide new insight into innate immunity to protozoan parasites.

Type I interferons suppress CD4+ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

“…Other studies of protozoan parasite infections suggest a requirement for IFN-I in mediating innate and adaptive immune responses [38][39][40]. Our study is the first to demonstrate that IFN-I impedes primary, adaptive immune responses during infection with a protozoan parasite.…”

“…By employing IFN-aR1 À/À mice, which are deficient in IFN-I signalling, we clearly showed that IFN-I indirectly suppressed CD4 1 T-cell responses during blood-stage infection, and impeded control of parasites in two different murine blood-stage malaria models. IFN-I are known to play a crucial role in protection against viruses [36,37], but their role in Plasmodium infections and other protozoan parasite infections has not been extensively studied [38][39][40]. The role of IFN-I during blood-stage Plasmodium infection is not clear, although early studies detected IFN activity in the blood after Plasmodium infection [41].…”

The integrated endoplasmic reticulum stress response in Leishmania amazonensis macrophage infection: the role of X‐box binding protein 1 transcription factor

“…We have shown that L. amazonensis parasites induce IFN1-b expression via RNAdependent protein kinase (PKR) in a TLR2-dependent manner (3) and that IFN1-b favors parasite growth. In addition, IFN1-a receptor (IFNAR) signaling favors L. amazonensis infection in mice (4). Another component of host immune defense subverted by L. amazonensis is the reactive oxygen species (ROS) defense mechanism.…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Treatment of infected human macrophages with poly I:C promotes parasite replication in a PKR-dependent manner, although the role of type I IFN was not formally established. In vivo, L. amazonensis-infected Ifnar1 2/2 mice show reduced parasite load, as well as decreased pathology, compared with WT mice (152). The increased resistance is associated with enhanced recruitment of neutrophils.…”

“…The increased resistance is associated with enhanced recruitment of neutrophils. In this case, neutrophils are believed to mediate pathogen killing by releasing enzymes, such as elastase and myeloperoxidase (152).…”