Influenza-induced immune suppression to methicillin-resistant Staphylococcus aureus is mediated by TLR9.

Bacterial lung infections, particularly with methicillin-resistant Staphylococcus aureus (MRSA), increase mortality following influenza infection, but the mechanisms remain unclear. Here we show that expression of TLR9, a microbial DNA sensor, is increased in murine lung macrophages, dendritic cells, CD8+ T cells and epithelial cells post-influenza infection. TLR9-/- mice did not show differences in handling influenza nor MRSA infection alone.

CCR2 mediates increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17.

Post influenza bacterial pneumonia is associated with significant mortality and morbidity. Dendritic cells (DCs) play a crucial role in host defense against bacterial pneumonia, but their contribution to post influenza-susceptibility to secondary bacterial pneumonia is incompletely understood. WT and CCR2 mice were infected with 100 plaque forming units (pfu) H1N1 intranasally alone or were challenged on day 5 with 7 × 10 colony forming units (cfu) methicillin-resistant Staphylococcus aureus intratracheally.

MicroRNA-155 regulates host immune response to postviral bacterial pneumonia via IL-23/IL-17 pathway.

Postinfluenza bacterial pneumonia is associated with significant mortality and morbidity. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. miR-155 has recently emerged as a crucial regulator of innate immunity and inflammatory responses and is induced in macrophages during infection.

Linezolid has unique immunomodulatory effects in post-influenza community acquired MRSA pneumonia.

Introduction: Post influenza pneumonia is a leading cause of mortality and morbidity, with mortality rates approaching 60% when bacterial infections are secondary to multi-drug resistant (MDR) pathogens. Staphylococcus aureus, in particular community acquired MRSA (cMRSA), has emerged as a leading cause of post influenza pneumonia.

Hypothesis: Linezolid (LZD) prevents acute lung injury in murine model of post influenza bacterial pneumonia.

IRAK-M promotes alternative macrophage activation and fibroproliferation in bleomycin-induced lung injury.

Idiopathic pulmonary fibrosis is a devastating lung disease characterized by inflammation and the development of excessive extracellular matrix deposition. Currently, there are only limited therapeutic intervenes to offer patients diagnosed with pulmonary fibrosis. Although previous studies focused on structural cells in promoting fibrosis, our study assessed the contribution of macrophages.

TLR9-dependent IL-23/IL-17 is required for the generation of Stachybotrys chartarum-induced hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease that develops after repeated exposure to inhaled particulate Ag. Stachybotrys chartarum is a dimorphic fungus that has been implicated in a number of respiratory illnesses, including HP. In this study, we have developed a murine model of S.

TLR signaling prevents hyperoxia-induced lung injury by protecting the alveolar epithelium from oxidant-mediated death.

Mechanical ventilation using high oxygen tensions is often necessary to treat patients with respiratory failure. Recently, TLRs were identified as regulators of noninfectious oxidative lung injury. IRAK-M is an inhibitor of MyD88-dependent TLR signaling.

Cathelicidin-related antimicrobial peptide is required for effective lung mucosal immunity in Gram-negative bacterial pneumonia.

Cathelicidins are a family of endogenous antimicrobial peptides that exert diverse immune functions, including both direct bacterial killing and immunomodulatory effects. In this study, we examined the contribution of the murine cathelicidin, cathelicidin-related antimicrobial peptide (CRAMP), to innate mucosal immunity in a mouse model of Gram-negative pneumonia. CRAMP expression is induced in the lung in response to infection with Klebsiella pneumoniae.

Early induction of CCL7 downstream of TLR9 signaling promotes the development of robust immunity to cryptococcal infection.

We investigated mechanisms by which TLR9 signaling promoted the development of the protective response to Cryptococcus neoformans in mice with cryptococcal pneumonia. The afferent (week 1) and efferent (week 3) phase immune parameters were analyzed in the infected wild-type (TLR9(+/+)) and TLR-deficient (TLR9(-/-)) mice. TLR9 deletion diminished 1) accumulation and activation of CD11b(+) dendritic cells (DCs), 2) the induction of IFN-γ and CCR2 chemokines CCL7, CCL12, but not CCL2, at week 1, and 3) pulmonary accumulation and activation of the major effector cells CD4(+) and CD8(+) T cells, CD11b(+) lung DCs, and exudate macrophages at week 3.

TLR4-dependent GM-CSF protects against lung injury in Gram-negative bacterial pneumonia.

Toll-like receptors (TLRs) are required for protective host defense against bacterial pathogens. However, the role of TLRs in regulating lung injury during Gram-negative bacterial pneumonia has not been thoroughly investigated. In this study, experiments were performed to evaluate the role of TLR4 in pulmonary responses against Klebsiella pneumoniae (Kp).

Stachybotrys chartarum-induced hypersensitivity pneumonitis is TLR9 dependent.

Hypersensitivity pneumonitis (HP), an inflammatory lung disease, develops after repeated exposure to inhaled particulate antigen and is characterized by a vigorous T helper type 1-mediated immune response, resulting in the release of IL-12 and interferon (IFN)-γ. These T helper type 1 cytokines may participate in the pathogenesis of HP. Stachybotrys chartarum (SC) is a dimorphic fungus implicated in a number of respiratory illnesses, including HP.

TLR9-induced interferon β is associated with protection from gammaherpesvirus-induced exacerbation of lung fibrosis.

Background: We have shown previously that murine gammaherpesvirus 68 (γHV68) infection exacerbates established pulmonary fibrosis. Because Toll-like receptor (TLR)-9 may be important in controlling the immune response to γHV68 infection, we examined how TLR-9 signaling effects exacerbation of fibrosis in response to viral infection, using models of bleomycin- and fluorescein isothiocyanate-induced pulmonary fibrosis in wild-type (Balb/c) and TLR-9-/- mice.

Results: We found that in the absence of TLR-9 signaling, there was a significant increase in collagen deposition following viral exacerbation of fibrosis.

IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis.

Sepsis results in a profound state of immunosuppression, which is temporally associated with impaired leukocyte function. The mechanism of leukocyte reprogramming in sepsis is incompletely understood. In this study, we explored mechanisms contributing to dysregulated inflammatory cytokine expression by pulmonary macrophages during experimental sepsis.

TLR9 signaling is required for generation of the adaptive immune protection in Cryptococcus neoformans-infected lungs.

To determine whether TLR9 signaling contributes to the development of the adaptive immune response to cryptococcal infection, wild-type (TLR9+/+) and TLR9 knockout (TLR9-/-) BALB/c mice were infected intratracheally with 10(4) C. neoformans 52D. We evaluated 1) organ microbial burdens, 2) pulmonary leukocyte recruitment, 3) pulmonary and systemic cytokine induction, and 4) macrophage activation profiles.

Cooperative interactions between TLR4 and TLR9 regulate interleukin 23 and 17 production in a murine model of gram negative bacterial pneumonia.

Toll like receptors play an important role in lung host defense against bacterial pathogens. In this study, we investigated independent and cooperative functions of TLR4 and TLR9 in microbial clearance and systemic dissemination during Gram-negative bacterial pneumonia. To access these responses, wildtype Balb/c mice, mice with defective TLR4 signaling (TLR4(lps-d)), mice deficient in TLR9 (TLR9(-/-)) and TLR4/9 double mutant mice (TLR4(lps-d)/TLR9(-/-)) were challenged with K.

Critical role of IL-1 receptor-associated kinase-M in regulating chemokine-dependent deleterious inflammation in murine influenza pneumonia.

Influenza virus is a common cause of respiratory infection and morbidity, which is often due to deleterious host immune responses directed against the pathogen. We investigated the role of IL-1 receptor-associated kinase-M (IRAK-M), an inhibitor of MyD88-dependent TLR signaling, in modulating the innate inflammatory response during influenza pneumonia using a murine model. The intranasal administration of influenza resulted in the upregulation of IRAK-M mRNA and protein levels in the lungs within 2 d after infectious challenge.

Cytokine networks in the infected lung.

The generation of an innate immune response is essential for rapid clearance of microbes from the respiratory tract, whereas acquired immunity is required for the generation of cellular immunity necessary for the killing of certain intracellular pathogens and the development of immunological memory. Cytokines play an integral role in host defense by serving as leukocyte chemoattractants, leukocyte-activating factors or afferent signals in the induction or regulation of other effector molecules. This review assesses the contribution of cytokine networks to the generation of antimicrobial host defenses in the lung, with an emphasis on cytokines/cytokine networks that are instrumental in innate antibacterial responses, including mucosal immunity, and also introduces networks that instruct the development of adaptive immunity.

Toll-like receptor 9 regulates the lung macrophage phenotype and host immunity in murine pneumonia caused by Legionella pneumophila.

Experiments were performed to determine the contribution of TLR9 to the generation of protective immunity against the intracellular respiratory bacterial pathogen Legionella pneumophila. In initial studies, we found that the intratracheal (i.t.

TLR9 is required for protective innate immunity in Gram-negative bacterial pneumonia: role of dendritic cells.

In this study, experiments were performed to determine the contribution of TLR9 to the generation of protective innate immunity against virulent bacterial pathogens of the lung. In initial studies, we found that the intratracheal administration of Klebsiella pneumoniae in wild-type (WT) BALB/c mice resulted in the rapid accumulation of dendritic cells (DC) expressing TLR9. As compared with WT mice, animals deficient in TLR9 (TLR9-/-) displayed significantly increased mortality that was associated with a >50-fold increase in lung CFU and a >400-fold increase in K.