Card9 Broadly Regulates Host Immunity against Experimental Pulmonary 52D Infection.

The ubiquitous soil-associated fungus causes pneumonia that may progress to fatal meningitis. Recognition of fungal cell walls by C-type lectin receptors (CLRs) has been shown to trigger the host immune response. Caspase recruitment domain-containing protein 9 (Card9) is an intracellular adaptor that is downstream of several CLRs.

The IL-1 Receptor Is Required to Maintain Neutrophil Viability and Function During Airway Infection.

airway infections are associated with increased rates of hospitalizations and declining lung function in patients with chronic lung disease. While the pathogenesis of invasive infections is well studied, little is known about the development and progression of airway infections. Previous studies have demonstrated a critical role for the IL-1 cytokines, IL-1α and IL-1β in enhancing pulmonary neutrophil recruitment during invasive aspergillosis.

Gram-Negative Pneumonia Augments Non-Small Cell Lung Cancer Metastasis through Host Toll-like Receptor 4 Activation.

Introduction: Surgery is essential for cure of early-stage non-small cell lung cancer (NSCLC). Rates of postoperative bacterial pneumonias, however, remain high, and clinical data suggests that post-operative infectious complications confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory response to infection by recognizing evolutionarily conserved bacterial structures at the surface of numerous pulmonary cell types; yet, little is known about how host TLR activation influences NSCLC metastasis.

Resistance and Tolerance to Cryptococcal Infection: An Intricate Balance That Controls the Development of Disease.

is a ubiquitous environmental yeast and a leading cause of invasive fungal infection in humans. The most recent estimate of global disease burden includes over 200,000 cases of cryptococcal meningitis each year. expresses several virulence factors that may have originally evolved to protect against environmental threats, and human infection may be an unintended consequence of these acquired defenses.

-Dependent Immune and Central Nervous System Mechanisms Control Viral Replication and Inflammation during Mouse Herpes Simplex Encephalitis.

Herpes simplex encephalitis (HSE), caused by HSV type 1 (HSV-1) infection, is an acute neuroinflammatory condition of the CNS and remains the most common type of sporadic viral encephalitis worldwide. Studies in humans have shown that susceptibility to HSE depends in part on the genetic make-up of the host, with deleterious mutations in the TLR3/type I IFN axis underlying some cases of childhood HSE. Using an in vivo chemical mutagenesis screen for HSV-1 susceptibility in mice, we identified a susceptible pedigree carrying a causal truncating mutation in the gene ( ), encoding for the NF-κB transcription factor subunit c-Rel.

Contribution of IL-1RI Signaling to Protection against 52D in a Mouse Model of Infection.

Interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β) are pro-inflammatory cytokines that are induced after infection and activate the interleukin-1 receptor type I (IL-1RI). To establish the role of IL-1RI signaling in protection against cryptococcal infection, we analyzed wild-type (WT) and IL-1RI-deficient (IL-1RI) mice on the BALB/c background. IL-1RI mice had significantly reduced survival compared to WT mice after intratracheal challenge with 52D.

Immune Recognition of Fungal Polysaccharides.

The incidence of fungal infections has dramatically increased in recent years, in large part due to increased use of immunosuppressive medications, as well as aggressive medical and surgical interventions that compromise natural skin and mucosal barriers. There are relatively few currently licensed antifungal drugs, and rising resistance to these agents has led to interest in the development of novel preventative and therapeutic strategies targeting these devastating infections. One approach to combat fungal infections is to augment the host immune response towards these organisms.

The TLR4-TRIF pathway can protect against the development of experimental allergic asthma.

The Toll-like receptor (TLR) adaptor proteins myeloid differentiating factor 88 (MyD88) and Toll, interleukin-1 receptor and resistance protein (TIR) domain-containing adaptor inducing interferon-β (TRIF) comprise the two principal limbs of the TLR signalling network. We studied the role of these adaptors in the TLR4-dependent inhibition of allergic airway disease and induction of CD4 ICOS T cells by nasal application of Protollin™, a mucosal adjuvant composed of TLR2 and TLR4 agonists. Wild-type (WT), Trif or Myd88 mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges.

Gram-positive pneumonia augments non-small cell lung cancer metastasis via host toll-like receptor 2 activation.

Surgical resection of early stage nonsmall cell lung cancer (NSCLC) is necessary for cure. However, rates of postoperative bacterial pneumonias remain high and may confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory cascade by recognizing microbial products at the surface of numerous cell types in the lung; however, little is known about how host TLRs influence NSCLC metastasis.

Innate Immune B Cell Activation by Leishmania donovani Exacerbates Disease and Mediates Hypergammaglobulinemia.

Participation of B cells in the immune response by various antibody-independent mechanisms has recently been uncovered. B cells producing cytokines have been described for several infections and appear to regulate the adaptive immune response. B cell activation by Leishmania donovani results in disease exacerbation.

Divergent impact of Toll-like receptor 2 deficiency on repair mechanisms in healthy muscle versus Duchenne muscular dystrophy.

Injury to skeletal muscle, whether acute or chronic, triggers macrophage-mediated innate immunity in a manner which can be either beneficial or harmful for subsequent repair. Endogenous ligands for Toll-like receptor 2 (TLR2) are released by damaged tissues and might play an important role in activating the innate immune system following muscle injury. To test this hypothesis, we compared macrophage behaviour and muscle repair mechanisms in mice lacking TLR2 under conditions of either acute (cardiotoxin-induced) or chronic (mdx mouse genetic model of Duchenne muscular dystrophy; DMD) muscle damage.

Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells.

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.

The Cnes2 locus on mouse chromosome 17 regulates host defense against cryptococcal infection through pleiotropic effects on host immunity.

The genetic basis of natural susceptibility to progressive Cryptococcus neoformans infection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformans susceptibility (Cnes1, Cnes2, and Cnes3).

Unc93b1 -Dependent Endosomal Toll-Like Receptor Signaling Regulates Inflammation and Mortality during Coxsackievirus B3 Infection.

Coxsackievirus strain B serotype 3 (CVB3)-induced myocarditis is an important human disease that causes permanent tissue damage and can lead to death from acute infection or long-term morbidity caused by chronic inflammation. The timing and magnitude of immune activation following CVB3 infection can mediate a positive host outcome or increase tissue pathology. To better elucidate the role of endosomal Toll-like receptor (TLR) signaling in acute CVB3 infection, we studied mice with a loss-of-function mutation, known as Letr for 'loss of endosomal TLR response', in Unc93b1, which is a chaperone protein for TLR3, TLR7 and TLR9.

Gram negative bacteria increase non-small cell lung cancer metastasis via Toll-like receptor 4 activation and mitogen-activated protein kinase phosphorylation.

Surgery is required for the curative treatment of lung cancer but is associated with high rates of postoperative pneumonias predominantly caused by gram negative bacteria. Recent evidence suggests that these severe infectious complications may decrease long term survival after hospital discharge via cancer recurrence, but the mechanism is unclear. Lung cancer cells have recently been demonstrated to express Toll-like receptors (TLR) that mediate pathogen recognition.

Concomitant exposure to ovalbumin and endotoxin augments airway inflammation but not airway hyperresponsiveness in a murine model of asthma.

Varying concentrations of lipopolysaccharide (LPS) in ovalbumin (OVA) may influence the airway response to allergic sensitization and challenge. We assessed the contribution of LPS to allergic airway inflammatory responses following challenge with LPS-rich and LPS-free commercial OVA. BALB/c mice were sensitized with LPS-rich OVA and alum and then underwent challenge with the same OVA (10 µg intranasally) or an LPS-free OVA.

Other viral pneumonias: coronavirus, respiratory syncytial virus, adenovirus, hantavirus.

Severe viral pneumonia is an increasing problem among adults. The incidence and number of viruses known to cause pneumonia and respiratory failure have also expanded in recent years. This article provides an overview of severe respiratory disease caused by coronavirus, respiratory syncytial virus, adenovirus, and hantavirus.

IL-33 signaling regulates innate and adaptive immunity to Cryptococcus neoformans.

Susceptibility to progressive infection with the fungus Cryptococcus neoformans is associated with an allergic pattern of lung inflammation, yet the factors that govern this host response are not clearly understood. Using a clinically relevant mouse model of inhalational infection with virulent C. neoformans H99, we demonstrate a role for IL-33-dependent signaling in host immune defense.

Inhaled birch pollen extract induces airway hyperresponsiveness via oxidative stress but independently of pollen-intrinsic NADPH oxidase activity, or the TLR4-TRIF pathway.

Oxidative stress in allergic asthma may result from oxidase activity or proinflammatory molecules in pollens. Signaling via TLR4 and its adaptor Toll-IL-1R domain-containing adapter inducing IFN-β (TRIF) has been implicated in reactive oxygen species-mediated acute lung injury and in Th2 immune responses. We investigated the contributions of oxidative stress and TLR4/TRIF signaling to experimental asthma induced by birch pollen exposure exclusively via the airways.

Dose-dependent effects of IL-17 on IL-13-induced airway inflammatory responses and airway hyperresponsiveness.

The Th2 cytokine IL-13 regulates several aspects of the asthmatic phenotype, including airway inflammation, airway hyperresponsiveness, and mucus production. The Th17 cytokine IL-17A is also implicated in asthma and has been shown to both positively and negatively regulate Th2-dependent responses in murine models of allergic airways disease. Our objective in this study was to better understand the role of IL-17 in airway inflammation by examining how IL-17 modifies IL-13-induced airway inflammatory responses.

Susceptibility to progressive Cryptococcus neoformans pulmonary infection is regulated by loci on mouse chromosomes 1 and 9.

Genetic factors that regulate the pathogenesis of pneumonia caused by the fungus Cryptococcus neoformans are poorly understood. Through a phenotypic strain survey we observed that inbred C3H/HeN mice develop a significantly greater lung fungal burden than mice of the resistant CBA/J strain 4 weeks following intratracheal infection with C. neoformans ATCC 24067.

ICOS-expressing CD4 T cells induced via TLR4 in the nasal mucosa are capable of inhibiting experimental allergic asthma.

Modulation of adaptive immune responses via the innate immune pattern recognition receptors, such as the TLRs, is an emerging strategy for vaccine development. We investigated whether nasal rather than intrapulmonary application of Protollin, a mucosal adjuvant composed of TLR2 and TLR4 ligands, is sufficient to elicit protection against murine allergic lower airway disease. Wild-type, Tlr2(-/-), or Tlr4(-/-) BALB/c mice were sensitized to a birch pollen allergen extract (BPEx), then received either intranasal or intrapulmonary administrations of Protollin or Protollin admixed with BPEx, followed by consecutive daily BPEx challenges.

Inhibition of mammalian target of rapamycin augments lipopolysaccharide-induced lung injury and apoptosis.

Acute lung injury during bacterial infection is associated with neutrophilic inflammation, epithelial cell apoptosis, and disruption of the alveolar-capillary barrier. TLR4 is required for lung injury in animals exposed to bacterial LPS and initiates proinflammatory responses in part via the transcription factor NF-κB. Ligation of TLR4 also initiates a proapoptotic response by activating IFN-β and STAT1-dependent genes.