<i>In Vivo</i>
            Conditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b
            <sup>+</sup>
            Cells upon Thogoto Virus Infection

Kochs, Georg; Anzaghe, Martina; Kronhart, Stefanie; Wagner, Valentina; Gogesch, Patricia; Scheu, Stefanie; Lienenklaus, Stefan; Waibler, Zoe

doi:10.1128/jvi.00744-16

Cited by 8 publications

(21 citation statements)

References 48 publications

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“…This is a credible theory, given that Ghosn et al identified a population of large peritoneal macrophages (LPMs) which seem to have a similar phenotype as the CD11b ϩ myeloid cells described by Kochs et al (52,53). These LPMs can migrate to the omentum, a fat tissue that connects the abdominal organs, upon inflammation (54), which is in agreement with the disappearance of the CD11b ϩ myeloid cell population from the peritoneal cavity after THOV infection (52). From the omentum, the LPMs can reach the liver of infected mice.…”

Section: Discussionsupporting

confidence: 58%

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Mx1 in Hematopoietic Cells Protects against Thogoto Virus Infection

Spitaels

Hoecke

Roose

et al. 2019

J Virol

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Myxovirus resistance 1 (Mx1) is an interferon-induced gene that encodes a GTPase that plays an important role in the defense of mammalian cells against influenza A and other viruses. The Mx1 protein can restrict a number of viruses independently of the expression of other interferon-induced genes. Mx genes are therefore considered to be an important part of the innate antiviral immune response. However, the possible impact of Mx expression in the hematopoietic cellular compartment has not been investigated in detail in the course of a viral infection. To address this, we performed bone marrow chimera experiments using congenic B6.A2G Mx1+/+ and B6.A2G Mx1−/− mice to study the effect of Mx1 expression in cells of hematopoietic versus nonhematopoietic origin. Mx1+/+ mice were protected and Mx1−/− mice were susceptible to influenza A virus challenge infection, regardless of the type of bone marrow cells (Mx1+/+ or Mx1−/−) the animals had received. Infection with Thogoto virus, however, revealed that Mx1−/− mice with a functional Mx1 gene in the bone marrow compartment showed reduced liver pathology compared with Mx1−/− mice that had been grafted with Mx1−/− bone marrow. The reduced pathology in these mice was associated with a reduction in Thogoto virus titers in the spleen, lung, and serum. Moreover, Mx1+/+ mice with Mx1−/− bone marrow failed to control Thogoto virus replication in the spleen. Mx1 in the hematopoietic cellular compartment thus contributes to protection against Thogoto virus infection. IMPORTANCE Mx proteins are evolutionarily conserved in vertebrates and can restrict a wide range of viruses in a cell-autonomous way. The contribution to antiviral defense of Mx1 expression in hematopoietic cells remains largely unknown. We show that protection against influenza virus infection requires Mx1 expression in the nonhematopoietic cellular compartment. In contrast, Mx1 in bone marrow-derived cells is sufficient to control disease and virus replication following infection with a Thogoto virus. This indicates that, in addition to its well-established antiviral activity in nonhematopoietic cells, Mx1 in hematopoietic cells can also play an important antiviral function. In addition, cells of hematopoietic origin that lack a functional Mx1 gene contribute to Thogoto virus dissemination and associated disease.

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Section: Discussionsupporting

confidence: 58%

“…Recently, Kochs et al postulated that THOV has a tropism for CD11b ϩ cells with a clear myeloid/macrophage phenotype (double positive for surface markers CD11b and F4/80) in the peritoneum (52). Therefore, it is conceivable that these cells could be partially protected against THOV infection by Mx1 expression.…”

Section: Discussionmentioning

confidence: 99%

Mx1 in Hematopoietic Cells Protects against Thogoto Virus Infection

Spitaels

Hoecke

Roose

et al. 2019

J Virol

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“…For the influenza virus-like orthomyxovirus Thogoto virus (THOV) type I IFN production in the peritoneal cavity was mainly attributed to CD11b + F4/80 + myeloid cells that was independent of the type I IFN receptor mediated feedback loop and coincided with the tropism of this virus (121).…”

Section: Viral Infectionsmentioning

confidence: 99%

Sources of Type I Interferons in Infectious Immunity: Plasmacytoid Dendritic Cells Not Always in the Driver's Seat

et al. 2019

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Type I Interferons (IFNs) are hallmark cytokines produced in immune responses to all classes of pathogens. Type I IFNs can influence dendritic cell (DC) activation, maturation, migration, and survival, but also directly enhance natural killer (NK) and T/B cell activity, thus orchestrating various innate and adaptive immune effector functions. Therefore, type I IFNs have long been considered essential in the host defense against virus infections. More recently, it has become clear that depending on the type of virus and the course of infection, production of type I IFN can also lead to immunopathology or immunosuppression. Similarly, in bacterial infections type I IFN production is often associated with detrimental effects for the host. Although most cells in the body are thought to be able to produce type I IFN, plasmacytoid DCs (pDCs) have been termed the natural “IFN producing cells” due to their unique molecular adaptations to nucleic acid sensing and ability to produce high amounts of type I IFN. Findings from mouse reporter strains and depletion experiments in in vivo infection models have brought new insights and established that the role of pDCs in type I IFN production in vivo is less important than assumed. Production of type I IFN, especially the early synthesized IFNβ, is rather realized by a variety of cell types and cannot be mainly attributed to pDCs. Indeed, the cell populations responsible for type I IFN production vary with the type of pathogen, its tissue tropism, and the route of infection. In this review, we summarize recent findings from in vivo models on the cellular source of type I IFN in different infectious settings, ranging from virus, bacteria, and fungi to eukaryotic parasites. The implications from these findings for the development of new vaccination and therapeutic designs targeting the respectively defined cell types are discussed.

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“…Using replication-incompetent THOV-derived virus-like particles, the authors demonstrated that an infected host can use alternative pathways to induce type I IFN responses, independently of type I IFN receptor, induced by viral polymerase activity, but being largely independent of viral replication. This fact has an important relevance to understand how type I IFN can be produced in large amounts in specialized cell types independently of the IFNAR-dependent enhancement, broaden our view of host strategies to fight viral pathogens [63].…”

Section: Family Orthomyxoviridaementioning

confidence: 99%

Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor

Marín-López

Calvo-Pinilla²,

Moreno³

et al. 2019

Viruses

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Arboviruses are arthropod-borne viruses that exhibit worldwide distribution and are a constant threat, not only for public health but also for wildlife, domestic animals, and even plants. To study disease pathogenesis and to develop efficient and safe therapies, the use of an appropriate animal model is a critical concern. Adult mice with gene knockouts of the interferon α/β (IFN-α/β) receptor (IFNAR(−/−)) have been described as a model of arbovirus infections. Studies with the natural hosts of these viruses are limited by financial and ethical issues, and in some cases, the need to have facilities with a biosafety level 3 with sufficient space to accommodate large animals. Moreover, the number of animals in the experiments must provide results with statistical significance. Recent advances in animal models in the last decade among other gaps in knowledge have contributed to the better understanding of arbovirus infections. A tremendous advantage of the IFNAR(−/−) mouse model is the availability of a wide variety of reagents that can be used to study many aspects of the immune response to the virus. Although extrapolation of findings in mice to natural hosts must be done with care due to differences in the biology between mouse and humans, experimental infections of IFNAR(−/−) mice with several studied arboviruses closely mimics hallmarks of these viruses in their natural host. Therefore, IFNAR(−/−) mice are a good model to facilitate studies on arbovirus transmission, pathogenesis, virulence, and the protective efficacy of new vaccines. In this review article, the most important arboviruses that have been studied using the IFNAR(−/−) mouse model will be reviewed.

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In Vivo Conditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b ⁺ Cells upon Thogoto Virus Infection

Cited by 8 publications

References 48 publications

Mx1 in Hematopoietic Cells Protects against Thogoto Virus Infection

Mx1 in Hematopoietic Cells Protects against Thogoto Virus Infection

Sources of Type I Interferons in Infectious Immunity: Plasmacytoid Dendritic Cells Not Always in the Driver's Seat

Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor

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In Vivo Conditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b + Cells upon Thogoto Virus Infection

Cited by 8 publications

References 48 publications

Mx1 in Hematopoietic Cells Protects against Thogoto Virus Infection

Mx1 in Hematopoietic Cells Protects against Thogoto Virus Infection

Sources of Type I Interferons in Infectious Immunity: Plasmacytoid Dendritic Cells Not Always in the Driver's Seat

Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor

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Product

Resources

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In Vivo Conditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b ⁺ Cells upon Thogoto Virus Infection