Influenza A virus is an important human pathogen causing significant morbidity and mortality every year and threatening the human population with epidemics and pandemics. Therefore, it is important to understand the biology of this virus to develop strategies to control its pathogenicity. Here we demonstrate that live influenza A virus infection causes accumulation of autophagosomes by blocking their fusion with lysosomes. Matrix protein 2 is sufficient and necessary for this inhibition of autophagosome degradation. Macroautophagy inhibition compromises cell survival of influenza virus infected cells, but does not influence viral replication. We propose that influenza A virus, which also encodes pro-apoptotic proteins, is able to determine the death of its host cell by inducing apoptosis and blocking macroautophagy.
The human tumor viruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) establish persistent infections in B cells. KSHV is linked to primary effusion lymphoma (PEL), and 90% of PELs also contain EBV. Studies on persistent KSHV infection in vivo and the role of EBV co-infection in PEL development have been hampered by the absence of small animal models. We developed mice reconstituted with human immune system components as a model for KSHV infection and find that EBV/KSHV dual infection enhanced KSHV persistence and tumorigenesis. Dual-infected cells displayed a plasma cell-like gene expression pattern similar to PELs. KSHV persisted in EBV-transformed B cells and was associated with lytic EBV gene expression, resulting in increased tumor formation. Evidence of elevated lytic EBV replication was also found in EBV/KSHV dually infected lymphoproliferative disorders in humans. Our data suggest that KSHV augments EBV-associated tumorigenesis via stimulation of lytic EBV replication.
Key Points• Human CD1411 cDCs not only produce IL-12 but also yield large amounts of IFN-a after TLR3 stimulation with synthetic dsRNA.• Targeting of antigen to DEC-205 and synthetic dsRNA as adjuvant for CD141 1 cDCs maturation induces CD4 1 T cell responses in humanized mice.Functional differences between human dendritic cell (DC) subsets and the potential benefits of targeting them with vaccines remain poorly defined. Here we describe that mice with reconstituted human immune system components (huNSG mice) develop all human conventional and plasmacytoid DC compartments in lymphoid organs. Testing different Toll-like receptor agonists for DC maturation in vivo, we found that IL-12p70 and interferon (IFN)-a production correlated with the maturation of CD141 1 (BDCA3
Efficient clearance of bacteremia prevents life-threatening disease. Platelet binding to intravascular bacteria, a process involving platelet glycoprotein GPIb and bacterial opsonization with activated complement C3, influences blood clearance and anti-infective immunity. Using intravital microscopy of the bloodstream of mice infected with Listeria monocytogenes, we show that bacterial clearance is not a uniform process but a "dual-track" mechanism consisting of parallel "fast" and "slow" pathways. "Slow clearance" is regulated by time-dependent bacterial opsonization, stochastic platelet binding, and capture of bacteria-platelet-complexes via the complement receptor of the immunoglobulin superfamily, CRIg. The mechanism spares some bacteria from "fast clearance" and rapid destruction in the liver via Kupffer cell scavenger receptors, keeping them available for adaptive immunity induction by splenic CD8α(+) dendritic cells. We consistently find "fast" and "slow" clearance patterns for a broad panel of other Gram+ and Gram- bacteria. Thus, dual-track clearance balances rapid restoration of blood sterility with induction of specific antibacterial immunity.
IntroductionNatural killer (NK) cells are innate lymphocytes that are primarily thought to curb viral infections and tumor cell expansion until antigen-specific adaptive immune responses can be primed to eradicate these threats to human health. 1 In contrast to adaptive lymphocytes like T and B cells, NK cells recognize their targets through germ line encoded receptors. These receptors transmit either activating or inhibitory signals. 2,3 The activating receptors recognize primarily stress-induced molecules on infected and transformed cells, including major histocompatibility complex (MHC) class I-like molecules that serve as ligands for the activating NK-cell receptor NKG2D, PVR and Nectin-2 as ligands for the activating NK-cell receptor DNAM-1, and B7-H6, as well as ligands of still poorly defined identity for the natural cytotoxicity receptors (NCRs) NKp30, NKp46, and NKp44. 4,5 Ligands for these activating receptors are up-regulated upon for example DNA damage or heat shock, 6,7 but are also constitutively present on some hematopoietic cells, including myeloid dendritic cells (DCs), 8 microglia, 9 and activated macrophages. 10 These activating signals are balanced by inhibitory receptor engagement, recognizing classical and nonclassical MHC class I molecules. In humans, killer immunoglobulin-like receptors (KIRs) recognize polymorphic determinants of classical MHC class I molecules, and C-type lectin receptors like the CD94/NKG2 heterodimer engage the nonclassical MHC class I molecule human leukocyte antigen (HLA)-E. 11 The balance of transmitted activating and inhibitory signals decides if NK cells will mount effector functions against conjugated target cells.The main effector characteristics of NK cells are cytokine secretion and cytotoxicity, 12 and humans carry NK-cell subsets that preferentially mediate one or the other of these functions. CD56 bright CD16 Ϫ KIR Ϫ NK cells respond primarily with production of interferon-␥ (IFN-␥), tumor necrosis factor, and granulocytemacrophage colony-stimulating factor to activation, and only exert cytotoxicity after prolonged activation. 13 In contrast, CD56 dim CD16 ϩ KIR ϩ NK cells are constitutively loaded with perforin and granzymes and are the primary human cytotoxic NK-cell subset. 14 While the latter population constitutes the majority of peripheral blood (PB) NK cells, CD56 bright CD16 Ϫ KIR Ϫ NK cells are enriched in human secondary lymphoid organs. 15,16 They have been proposed to limit pathogen invasion and polarize adaptive immune responses at these sites. 12,17 Thus cytotoxic NK cells patrol primarily the periphery, while immunoregulatory NK cells support Th1 polarization in secondary lymphoid organs.The developmental pathways leading to the functionally distinct human NK-cell subsets are still being defined. 18 So far 3 alternative pathways have been proposed. Originally, it was proposed that NK cells develop exclusively in the bone marrow from which they populate the periphery as constitutively reactive innate lymphocytes. 1 After the discovery that t...
Epstein Barr virus (EBV) infection expands CD8+ T cells specific for lytic antigens to high frequencies during symptomatic primary infection, and maintains these at significant numbers during persistence. Despite this, the protective function of these lytic EBV antigen-specific cytotoxic CD8+ T cells remains unclear. Here we demonstrate that lytic EBV replication does not significantly contribute to virus-induced B cell proliferation in vitro and in vivo in a mouse model with reconstituted human immune system components (huNSG mice). However, we report a trend to reduction of EBV-induced lymphoproliferation outside of lymphoid organs upon diminished lytic replication. Moreover, we could demonstrate that CD8+ T cells against the lytic EBV antigen BMLF1 can eliminate lytically replicating EBV-transformed B cells from lymphoblastoid cell lines (LCLs) and in vivo, thereby transiently controlling high viremia after adoptive transfer into EBV infected huNSG mice. These findings suggest a protective function for lytic EBV antigen-specific CD8+ T cells against EBV infection and against virus-associated tumors in extra-lymphoid organs. These specificities should be explored for EBV-specific vaccine development.
Many pathogens relevant to human disease do not infect other animal species. Therefore, animal models that reconstitute or harbour human tissues are explored as hosts for these. In this review, we will summarize recent advances to utilize mice with human immune system components, reconstituted from hematopoietic progenitor cells in vivo. Such mice can be used to study human pathogens that replicate in leucocytes. In addition to studying the replication of these pathogens, the reconstituted human immune system components can also be analyzed for initiating immune responses and control against these infections. Moreover, these new animal models of human infectious disease should replicate the reactivity of the human immune system to vaccine candidates and, especially, the adjuvants contained in them, more faithfully.
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