ABSTRACT
In 2016, a total of 18 human infections with influenza A(H3N2) virus occurred after exposure to influenza-infected swine at 7 agricultural fairs. Sixteen of these cases were the result of infection by a reassorted virus with increasing prevalence among US swine containing a hemagglutinin gene from 2010-11 human seasonal H3N2 strains.
Subject(s)
Influenza A Virus, H3N2 Subtype/classification , Influenza, Human/epidemiology , Orthomyxoviridae Infections/epidemiology , Reassortant Viruses/classification , Swine Diseases/epidemiology , Animal Husbandry , Animals , Disease Outbreaks , Epidemiological Monitoring , Humans , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/isolation & purification , Influenza, Human/transmission , Influenza, Human/virology , Michigan/epidemiology , Ohio/epidemiology , Orthomyxoviridae Infections/transmission , Orthomyxoviridae Infections/virology , Phylogeny , Reassortant Viruses/genetics , Reassortant Viruses/isolation & purification , Swine , Swine Diseases/transmission , Swine Diseases/virologyABSTRACT
ISG15 is an interferon (IFN)-α/ß-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune functions, but not in antiviral immunity. Namely, free extracellular ISG15 is crucial in IFN-γ-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-α/ß signalling. Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice. Furthermore, fibroblasts derived from ISG15-deficient patients display enhanced antiviral protection, and expression of ISG15 attenuates viral resistance to WT control levels. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans, a mechanism not operating in mice.
Subject(s)
Cytokines/metabolism , Ubiquitins/metabolism , Virus Diseases/immunology , Animals , Cell Line , Cytokines/genetics , Cytokines/immunology , Female , Gene Expression Regulation , Humans , Interferons/metabolism , Mice , Primary Cell Culture , Ubiquitin Thiolesterase/metabolism , Ubiquitins/genetics , Ubiquitins/immunologyABSTRACT
UNLABELLED: Human noroviruses (HuNoV) are the leading cause of nonbacterial gastroenteritis worldwide. Similar to HuNoV, murine noroviruses (MNV) are enteric pathogens spread via the fecal-oral route and have been isolated from numerous mouse facilities worldwide. Type I and type II interferons (IFN) restrict MNV-1 replication; however, the antiviral effectors impacting MNV-1 downstream of IFN signaling are largely unknown. Studies using dendritic cells, macrophages, and mice deficient in free and conjugated forms of interferon-stimulated gene 15 (ISG15) revealed that ISG15 conjugation contributes to protection against MNV-1 both in vitro and in vivo. ISG15 inhibited a step early in the viral life cycle upstream of viral genome transcription. Directly transfecting MNV-1 RNA into IFN-stimulated mouse embryonic fibroblasts (MEFs) and bone marrow-derived dendritic cells (BMDC) lacking ISG15 conjugates bypassed the antiviral activity of ISG15, further suggesting that ISG15 conjugates restrict the MNV-1 life cycle at the viral entry/uncoating step. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection both in vitro and in vivo and for the first time implicate the ISG15 pathway in the regulation of early stages of MNV-1 replication. IMPORTANCE: Type I IFNs are important in controlling murine norovirus 1 (MNV-1) infections; however, the proteins induced by IFNs that restrict viral growth are largely unknown. This report reveals that interferon-stimulated gene 15 (ISG15) mitigates MNV-1 replication both in vitro and in vivo. In addition, it shows that ISG15 inhibits MNV-1 replication by targeting an early step in the viral life cycle, MNV-1 entry and/or uncoating. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection both in vitro and in vivo and for the first time implicate the ISG15 pathway in the regulation of viral entry/uncoating.
Subject(s)
Antiviral Agents/metabolism , Cytokines/genetics , Cytokines/metabolism , Interferon Type I/metabolism , Life Cycle Stages/genetics , Norovirus/genetics , Animals , Cell Line , Dendritic Cells/metabolism , Dendritic Cells/virology , Fibroblasts/metabolism , Fibroblasts/virology , Genome, Viral/genetics , Interferon Type I/genetics , Macrophages/metabolism , Macrophages/virology , Mice , Mice, Inbred C57BL , Transcription, Genetic/genetics , Ubiquitins/genetics , Ubiquitins/metabolism , Virus Replication/geneticsABSTRACT
NK cell-mediated resistance to viruses is subject to genetic control in humans and mice. Here we used classical and quantitative genetic strategies to examine NK-mediated murine cytomegalovirus (MCMV) control in genealogically related New Zealand white (NZW) and black (NZB) mice. NZW mice display NK cell-dependent MCMV resistance while NZB NK cells fail to limit viral replication after infection. Unlike Ly49H(+) NK resistance in C57BL/6 mice, NZW NK-mediated MCMV control was Ly49H-independent. Instead, MCMV resistance in NZW (Cmv2) involves multiple genetic factors. To establish the genetic basis of Cmv2 resistance, we further characterized a major chromosome X-linked resistance locus (DXMit216) responsible for innate MCMV control in NZW x NZB crosses. We found that the DXMit216 locus affects early MCMV control in New Zealand F(2) crosses and demonstrate that the NZB-derived DXMit216 allele enhances viral resistance in F(2) males. The evolutionary conservation of the DXMit216 region in mice and humans suggests that a Cmv2-related mechanism may affect human antiviral responses.
