NK cell profiling in West Nile virus encephalitis reveals potential metabolic basis for functional inhibition.

Natural killer (NK) cells are cytotoxic lymphocytes important for viral defense. West Nile virus (WNV) infection of the central nervous system (CNS) causes marked recruitment of bone marrow (BM)-derived monocytes, T cells and NK cells, resulting in severe neuroinflammation and brain damage. Despite substantial numbers of NK cells in the CNS, their function and phenotype remain largely unexplored.

Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation.

Mosquito-borne viruses can cause severe inflammatory diseases and there are limited therapeutic solutions targeted specifically at virus-induced inflammation. Chikungunya virus (CHIKV), a re-emerging alphavirus responsible for several outbreaks worldwide in the past decade, causes debilitating joint inflammation and severe pain. Here, we show that CHIKV infection activates the NLRP3 inflammasome in humans and mice.

Fc receptors in antibody-dependent enhancement of viral infections.

Sensitization of the humoral immune response to invading viruses and production of antiviral antibodies forms part of the host antiviral repertoire. Paradoxically, for a number of viral pathogens, under certain conditions, antibodies provide an attractive means of enhanced virus entry and replication in a number of cell types. Known as antibody-dependent enhancement (ADE) of infection, the phenomenon occurs when virus-antibody immunocomplexes interact with cells bearing complement or Fc receptors, promoting internalization of the virus and increasing infection.

Role of indoleamine 2,3-dioxygenase in health and disease.

IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised.

Harnessing nanoparticles for immune modulation.

Recent approaches using nanoparticles engineered for immune regulation have yielded promising results in preclinical models of disease. The number of nanoparticle therapies is growing, fueled by innovations in nanotechnology and advances in understanding of the underlying pathogenesis of immune-mediated diseases. In particular, recent mechanistic insight into the ways in which nanoparticles interact with the mononuclear phagocyte system and impact its function during homeostasis and inflammation have highlighted the potential of nanoparticle-based therapies for controlling severe inflammation while concurrently restoring peripheral immune tolerance in autoimmune disease.

Defective inflammatory monocyte development in IRF8-deficient mice abrogates migration to the West Nile virus-infected brain.

IRF8 (interferon-regulatory factor-8) plays a critical role in regulating myeloid cell differentiation. However, the role of this transcription factor in the development of Ly6C+ inflammatory monocytes and their migration to the infected brain has not been examined. We have previously shown that West Nile virus (WNV) infection of wild-type (WT) mice triggers a significant increase in numbers of Ly6C+ monocytes in the bone marrow.

The plasticity of inflammatory monocyte responses to the inflamed central nervous system.

Over the last three decades it has become increasingly clear that monocytes, originally thought to have fixed, stereotypic responses to foreign stimuli, mediate exquisitely balanced protective and pathogenic roles in disease and immunity. This balance is crucial in core functional organs, such as the central nervous system (CNS), where minor changes in neuronal microenvironments and the production of immune factors can result in significant disease with fatal consequences or permanent neurological sequelae. Viral encephalitis and multiple sclerosis are examples of important human diseases in which the pathogenic contribution of monocytes recruited from the bone marrow plays a critical role in the clinical expression of disease, as they differentiate into macrophage or dendritic cells in the CNS to carry out effector functions.

Immunomodulatory effects of bone marrow-derived mesenchymal stem cells on pro-inflammatory cytokine-stimulated human corneal epithelial cells.

Purpose: To investigate the modulatory effect of rat bone marrow mesenchymal stem cells (MSC) on human corneal epithelial cells (HCE-T) stimulated with pro-inflammatory cytokines interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in an in vitro co-cultured model.

Methods: HCE-T alone and co-cultured with MSC were stimulated with IFN-γ/TNF for 24 and 48 hours or left untreated. The expression of intracellular adhesion molecule (ICAM)-1, human leukocyte antigen ABC, DR and G (HLA-ABC, HLA-DR, HLA-G) were investigated by flow cytometry.

The role of CXCR3 in DSS-induced colitis.

Inflammatory bowel disease (IBD) is a group of disorders that are characterized by chronic, uncontrolled inflammation in the intestinal mucosa. Although the aetiopathogenesis is poorly understood, it is widely believed that IBD stems from a dysregulated immune response towards otherwise harmless commensal bacteria. Chemokines induce and enhance inflammation through their involvement in cellular trafficking.

Therapeutic inflammatory monocyte modulation using immune-modifying microparticles.

Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO).

The bacteriostatic protein lipocalin 2 is induced in the central nervous system of mice with west Nile virus encephalitis.

Lipocalin 2 (Lcn2) is a bacteriostatic factor produced during the innate immune response to bacterial infection. Whether Lcn2 has a function in viral infection is unknown. We investigated the regulation and function of Lcn2 in the central nervous system (CNS) of mice during West Nile virus (WNV) encephalitis.

Inflammatory monocytes and the pathogenesis of viral encephalitis.

Monocytes are a heterogeneous population of bone marrow-derived cells that are recruited to sites of infection and inflammation in many models of human diseases, including those of the central nervous system (CNS). Ly6Chi/CCR2(hi) inflammatory monocytes have been identified as the circulating precursors of brain macrophages, dendritic cells and arguably microglia in experimental autoimmune encephalomyelitis; Alzheimer's disease; stroke; and more recently in CNS infection caused by Herpes simplex virus, murine hepatitis virus, Theiler's murine encephalomyelitis virus, Japanese encephalitis virus and West Nile virus. The precise differentiation pathways and functions of inflammatory monocyte-derived populations in the inflamed CNS remains a contentious issue, especially in regard to the existence of monocyte-derived microglia.

IFN regulatory factor 8 is a key constitutive determinant of the morphological and molecular properties of microglia in the CNS.

IFN regulatory factor (IRF) 8 is a transcription factor that has a key role in the cellular response to IFN-γ and is pivotal in myeloid cell differentiation. Whether IRF8 plays a role in the development and function of microglia, the tissue-resident myeloid cells of the brain, is unknown. Here, we show IRF8 is a constitutively produced nuclear factor in microglia, which suggested that IRF8 might also be a key homeostatic transcriptional determinant of the microglial cell phenotype.

Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis.

Aberrant T-cell activation underlies many autoimmune disorders, yet most attempts to induce T-cell tolerance have failed. Building on previous strategies for tolerance induction that exploited natural mechanisms for clearing apoptotic debris, we show that antigen-decorated microparticles (500-nm diameter) induce long-term T-cell tolerance in mice with relapsing experimental autoimmune encephalomyelitis. Specifically, intravenous infusion of either polystyrene or biodegradable poly(lactide-co-glycolide) microparticles bearing encephalitogenic peptides prevents the onset and modifies the course of the disease.

Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages.

Infiltration of Ly6C(hi) monocytes from the blood is a hallmark of viral encephalitis. In mice with lethal encephalitis caused by West Nile virus (WNV), an emerging neurotropic flavivirus, inhibition of Ly6C(hi) monocyte trafficking into the brain by anti-very late antigen (VLA)-4 integrin antibody blockade at the time of first weight loss and leukocyte influx resulted in long-term survival of up to 60% of infected mice, with subsequent sterilizing immunity. This treatment had no effect on viral titers but appeared to be due to inhibition of Ly6C(hi) macrophage immigration.

Entry of herpes simplex virus type 1 (HSV-1) into the distal axons of trigeminal neurons favors the onset of nonproductive, silent infection.

Following productive, lytic infection in epithelia, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons that is interrupted by episodes of reactivation. In order to better understand what triggers this lytic/latent decision in neurons, we set up an organotypic model based on chicken embryonic trigeminal ganglia explants (TGEs) in a double chamber system. Adding HSV-1 to the ganglion compartment (GC) resulted in a productive infection in the explants.

Microarray analysis of gene expression in West Nile virus-infected human retinal pigment epithelium.

Purpose: To identify key genes differentially expressed in the human retinal pigment epithelium (hRPE) following low-level West Nile virus (WNV) infection.

Methods: Primary hRPE and retinal pigment epithelium cell line (ARPE-19) cells were infected with WNV (multiplicity of infection 1). RNA extracted from mock-infected and WNV-infected cells was assessed for differential expression of genes using Affymetrix microarray.

Mice deficient in STAT1 but not STAT2 or IRF9 develop a lethal CD4+ T-cell-mediated disease following infection with lymphocytic choriomeningitis virus.

Interferon (IFN) signaling is crucial for antiviral immunity. While type I IFN signaling is mediated by STAT1, STAT2, and IRF9, type II IFN signaling requires only STAT1. Here, we studied the roles of these signaling factors in the host response to systemic infection with lymphocytic choriomeningitis virus (LCMV).

Flavivirus infection induces indoleamine 2,3-dioxygenase in human monocyte-derived macrophages via tumor necrosis factor and NF-κB.

Infection with West Nile virus (WNV) via a mosquito bite results in local viral replication in the skin, followed by viremia. Thus, tissue macrophages are ideally located to prevent the dissemination of WNV throughout the host. The current study shows that WNV infection of human monocyte-derived macrophages (MDM) results in increased WNV mRNA, protein, and infectious virions at 24 h p.

Effects of β(2) Agonists, Corticosteroids, and Novel Therapies on Rhinovirus-Induced Cytokine Release and Rhinovirus Replication in Primary Airway Fibroblasts.

Rhinovirus-(RV-) induced asthma exacerbations account for high asthma-related health costs and morbidity in Australia. The cellular mechanism underlying this pathology is likely the result of RV-induced nuclear-factor-kappa-B-(NF-κB-) dependent inflammation. NF-κB may also be important in RV replication as inhibition of NF-κB inhibits replication of other viruses such as human immunodeficiency virus and cytomegalovirus.

IL-22 and non-ELR-CXC chemokine expression in chronic hepatitis B virus-infected liver.

Hepatitis B virus infection is still a major global health problem, despite decades of research. Interleukin (IL)-22 induces acute phase reactants and chemokines, favors anti-microbial defence and protects tissues from damage. IL-22 is important in chronic skin inflammation, but its role in chronic hepatitis B (CHB) is unclear.

Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells.

Ag-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein/peptide Ags linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-coupled splenocytes [Ag-SP]) has been demonstrated to be a highly efficient method for inducing peripheral, Ag-specific T cell tolerance for treatment of autoimmune disease. However, little is understood about the mechanisms underlying this therapy.

Rhinovirus infection induces extracellular matrix protein deposition in asthmatic and nonasthmatic airway smooth muscle cells.

Airway remodeling, which includes increases in the extracellular matrix (ECM), is a characteristic feature of asthma and is correlated to disease severity. Rhinovirus (RV) infections are associated with increased risk of asthma development in young children and are the most common cause of asthma exacerbations. We examined whether viral infections can increase ECM deposition and whether this increased ECM modulates cell proliferation and migration.

Accelerated dendritic cell differentiation from migrating Ly6C(lo) bone marrow monocytes in early dermal West Nile virus infection.

No study has investigated the participation of Ly6C(+) monocytes in the earliest phase of skin infection with the mosquito-borne West Nile virus. In a novel murine model mimicking natural dermal infection, CCL2-dependent bone marrow (BM)-derived monocyte migration, differentiation into Ly6C(+) dendritic cells (DC), and accumulation around dermal deposits of infected fibroblasts by day 1 postinfection were associated with increasing numbers of monocyte-derived TNF/inducible NO synthase-producing DC by day 2 postinfection in draining auricular lymph nodes (ALN). Adoptive transfer demonstrated simultaneous migration of bone marrow-derived Ly6C(lo) monocytes to virus-infected dermis and ALN, where they first become Ly6C(hi) DC within 24 h and then Ly6C(lo) DC by 72 h.