The continuous interactions between host and pathogens during their coevolution have shaped both the immune system and the countermeasures used by pathogens. Natural killer (NK) cells are innate ...lymphocytes that are considered central players in the antiviral response. Not only do they express a variety of inhibitory and activating receptors to discriminate and eliminate target cells but they can also produce immunoregulatory cytokines to alert the immune system. Reciprocally, several unrelated viruses including cytomegalovirus, human immunodeficiency virus, influenza virus, and dengue virus have evolved a multitude of mechanisms to evade NK cell function, such as the targeting of pathways for NK cell receptors and their ligands, apoptosis, and cytokine-mediated signaling. The studies discussed in this article provide further insights into the antiviral function of NK cells and the pathways involved, their constituent proteins, and ways in which they could be manipulated for host benefit.
Influenza A virus (IAV) triggers a contagious and potentially lethal respiratory disease. A protective IL-1β response is mediated by innate receptors in macrophages and lung epithelial cells. NLRP3 ...is crucial in macrophages; however, which sensors elicit IL-1β secretion in lung epithelial cells remains undetermined. Here, we describe for the first time the relative roles of the host innate receptors RIG-I (DDX58), TLR3, and NLRP3 in the IL-1β response to IAV in primary lung epithelial cells. To activate IL-1β secretion, these cells employ partially redundant recognition mechanisms that differ from those described in macrophages. RIG-I had the strongest effect through a MAVS/TRIM25/Riplet-dependent type I IFN signaling pathway upstream of TLR3 and NLRP3. Notably, RIG-I also activated the inflammasome through interaction with caspase 1 and ASC in primary lung epithelial cells. Thus, NS1, an influenza virulence factor that inhibits the RIG-I/type I IFN pathway, strongly modulated the IL-1β response in lung epithelial cells and in ferrets. The NS1 protein derived from a highly pathogenic strain resulted in increased interaction with RIG-I and inhibited type I IFN and IL-1β responses compared to the least pathogenic virus strains. These findings demonstrate that in IAV-infected lung epithelial cells RIG-I activates the inflammasome both directly and through a type I IFN positive feedback loop.
A majority of the world population is infected with herpes simplex viruses (HSV; human herpesvirus types 1 and 2). These viruses, perhaps best known for their manifestation in the genital or oral ...mucosa, can also cause herpes simplex encephalitis, a severe and often fatal disease of the central nervous system. Antiviral therapies for HSV are only partially effective since the virus can establish latent infections in neurons, and severe pathological sequelae in the brain are common. A better understanding of disease pathogenesis is required to develop new strategies against herpes simplex encephalitis, including the precise viral and host genetic determinants that promote virus invasion into the central nervous system and its associated immunopathology. Here we review the current understanding of herpes simplex encephalitis from the host genome perspective, which has been illuminated by groundbreaking work on rare herpes simplex encephalitis patients together with mechanistic insight from single-gene mouse models of disease. A complex picture has emerged, whereby innate type I interferon-mediated antiviral signaling is a central pathway to control viral replication, and the regulation of immunopathology and the balance between apoptosis and autophagy are critical to disease severity in the central nervous system. The lessons learned from mouse studies inform us on fundamental defense mechanisms at the interface of host–pathogen interactions within the central nervous system, as well as possible rationales for intervention against infections from severe neuropathogenic viruses.
Cellular inhibitors of apoptosis proteins (cIAPs) are essential regulators of cell death and immunity. The corresponding contributions of IAPs to infectious disease outcomes are relatively ...unexplored. We find that mice deficient in cIAP2 exhibit increased susceptibility and mortality to influenza A virus infection. The lethality was not due to impaired antiviral immune functions, but rather because of death-receptor-induced programmed necrosis of airway epithelial cells that led to severe bronchiole epithelial degeneration, despite control of viral replication. Pharmacological inhibition of RIPK1 or genetic deletion of Ripk3, both kinases involved in programmed necrosis, rescued cIAP2-deficient mice from influenza-induced lethality. Genetic deletion of the death receptor agonists Fas ligand or TRAIL from the hematopoietic compartment also reversed the susceptibility of cIAP2-deficient mice. Thus, cIAP2-dependent antagonism of RIPK3-mediated programmed necrosis critically protects the host from influenza infection through maintenance of pulmonary tissue homeostasis rather than through pathogen control by the immune system.
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•cIAP2−/− mice show enhanced susceptibility to influenza infection despite virus control•cIAP2−/− epithelial cell necrosis during infection underlies impaired airway integrity•RIPK1 inhibition or RIPK3 deletion improves survival of influenza infected cIAP2−/− mice•Hematopoietic deficiency of Fas ligand or TRAIL reversed susceptibility of cIAP2−/− mice
Cellular inhibitors of apoptosis proteins (cIAPs) regulate cell death and immunity. The corresponding contributions of IAPs during infection are relatively unexplored. Rodrigue-Gervais et al. report that cIAP2 does not influence viral loads, but protects lung airway epithelial cells from influenza-induced lethality by inhibiting FAS- and TRAIL-induced, RIPK1- and RIPK3-dependent programmed necrosis.
Viral respiratory tract infections are the main causative agents of the onset of infection-induced asthma and asthma exacerbations that remain mechanistically unexplained. Here we found that ...deficiency in signaling via type I interferon receptor led to deregulated activation of group 2 innate lymphoid cells (ILC2 cells) and infection-associated type 2 immunopathology. Type I interferons directly and negatively regulated mouse and human ILC2 cells in a manner dependent on the transcriptional activator ISGF3 that led to altered cytokine production, cell proliferation and increased cell death. In addition, interferon-γ (IFN-γ) and interleukin 27 (IL-27) altered ILC2 function dependent on the transcription factor STAT1. These results demonstrate that type I and type II interferons, together with IL-27, regulate ILC2 cells to restrict type 2 immunopathology.
Herpes simplex virus type 1 (HSV-1) is the predominant cause of herpes simplex encephalitis (HSE), a condition characterized by acute inflammation and viral replication in the brain. Host genetics ...contribute to HSE onset, including monogenic defects in type I interferon signaling in cases of childhood HSE. Mouse models suggest a further contribution of immune cell-mediated inflammation to HSE pathogenesis. We have previously described a truncating mutation in the c-Rel transcription factor (Rel
) that drives lethal HSE in 60% of HSV-1-infected Rel
mice. In this study, we combined dual host-virus RNA sequencing with flow cytometry to explore cell populations and mechanisms involved in Rel
-driven HSE. At day 5 postinfection, prior to HSE clinical symptom onset, elevated HSV-1 transcription was detected together with augmented host interferon-stimulated and inflammatory gene expression in the brainstems of high-responding Rel
mice, predictive of HSE development. This early induction of host gene expression preceded pathological infiltration of myeloid and T cells in Rel
mice at HSE onset by day 7. Thus, we establish c-Rel as an early regulator of viral and host responses during mouse HSE. These data further highlight the importance of achieving a balanced immune response and avoiding excess interferon-driven inflammation to promote HSE resistance.
Additive manufacturing of objects made of composite materials is an emerging technology of great interest for high-technological applications allowing fast and precise fabrication of functional ...objects with tuned properties and few geometrical restrictions. Herein, we report on the synthesis by solution casting of homogeneous composites with tuned amount of gas-atomized metallic particles embedded in polymer. Composites were extruded into filaments for 3D-printing by Fused Deposition Modeling. The obtained results reveal that composites filling factor, suited to obtain continuous and flexible filament, is strongly influenced by particle size and its distribution. Magnetometry appears as a low-time consuming technique for accurately quantifying the magnetic composites filling factor. Moreover, the analysis of magnetic properties of composites and filaments revealed no deterioration of particles during processing. The reported processing techniques were demonstrated to be suitable to produce metal-based filaments for 3D-printing of pieces with non-restricted shape and potential applicability in aeronautics and aerospace sectors.
Host plant penetration is the gateway to survival for holoparasitic Cuscuta and requires host cell wall degradation. Compositional differences of cell walls may explain why some hosts are amenable to ...such degradation while others can resist infection.
Antibody-based techniques for comprehensive profiling of cell wall epitopes and cell wall-modifying enzymes were applied to several susceptible hosts and a resistant host of Cuscuta reflexa and to the parasite itself.
Infected tissue of Pelargonium zonale contained high concentrations of de-esterified homogalacturonans in the cell walls, particularly adjacent to the parasite's haustoria. High pectinolytic activity in haustorial extracts and high expression levels of pectate lyase genes suggest that the parasite contributes directly to wall remodeling. Mannan and xylan concentrations were low in P. zonale and in five susceptible tomato introgression lines, but high in the resistant Solanum lycopersicum cv M82, and in C. reflexa itself.
Knowledge of the composition of resistant host cell walls and the parasite's own cell walls is useful in developing strategies to prevent infection by parasitic plants.
Natural killer (NK) cells have the potential to deliver both direct antimicrobial effects and regulate adaptive immune responses, but NK cell yields have been reported to vary greatly during ...different viral infections. Activating receptors, including the Ly49H molecule recognizing mouse cytomegalovirus (MCMV), can stimulate NK cell expansion. To define Ly49H's role in supporting NK cell proliferation and maintenance under conditions of uncontrolled viral infection, experiments were performed in Ly49h(-/-), perforin 1 (Prf1)(-/-), and wild-type (wt) B6 mice. NK cell numbers were similar in uninfected mice, but relative to responses in MCMV-infected wt mice, NK cell yields declined in the absence of Ly49h and increased in the absence of Prf1, with high rates of proliferation and Ly49H expression on nearly all cells. The expansion was abolished in mice deficient for both Ly49h and Prf1 (Ly49h(-/-)Prf1(-/-)), and negative consequences for survival were revealed. The Ly49H-dependent protection mechanism delivered in the absence of Prf1 was a result of interleukin 10 production, by the sustained NK cells, to regulate the magnitude of CD8 T cell responses. Thus, the studies demonstrate a previously unappreciated critical role for activating receptors in keeping NK cells present during viral infection to regulate adaptive immune responses.
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