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Macrophages.

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Lung macrophages are essential for alveolar homeostasis and foreign body removal. Macrophage dysfunction can result in a pathological accumulation of surfactants, lipids and proteins in the alveoli called pulmonary alveolar proteinosis (PAP). Inhalation of indium-containing particles (ICPs) such as indium-tin oxide (ITO) is specifically associated with macrophage toxicity and PAP development. In vitro studies have demonstrated that ITO particles are phagocytosed and dissolved by macrophages which subsequently release ionic indium, the primary cytotoxic compound for these cells. Here, we performed in vivo and ex vivo studies to determine how ITP particles affect alveolar (AM) and interstitial (IM) macrophages, the two main macrophage populations of the lungs. After ITO instillation in mice, we observed a depletion of the AM subpopulation that coincided with PAP formation. In contrast, IM were persistently accumulated in treated mice, suggesting that AM is the main target of ITO toxicity. Paradoxically, IM phagocytosed more ITO particles and were more sensitive to ITO exposure than AM ex vivo. In contrast, ionic indium was highly cytotoxic for AM in comparison to IM. Our data obtained by using AM and IM co-cultures and endocytosis inhibitors suggested that IM phagocytose ITO particles and release ionic indium that forms complexes particularly cytotoxic for AM. These results suggested that both IM and AM contribute to ITO-induced PAP in mice. In addition, the specific depletion of AM in ITO-treated mice was related to a defect of IL-1α (not GM-CSF), an essential autocrine cytokine for AM replenishment during lung responses to particles. We concluded that alveolar clearance defect and PAP development after ICPs exposure result from the release of ionic indium and the abrogation of AM self-maintenance.

Lung Diseases, Interstitial --- Macrophages --- Pulmonary Wedge Pressure

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Dengue is the most important mosquito-transmitted viral disease in humans. Half of the world population is at risk of infection, mostly in tropical and sub-tropical areas. The World Health Organization (WHO) estimates that 50 to 100 million infections occur yearly, with 50,000 to 100,000 deaths related to dengue, mainly in children. Recent estimates show higher numbers, up to three times more, with 390 million estimated dengue infections per year, among which 96 million apparent infections (Bhatt et al. 2013). Initially localized to South-East Asia, dengue virus (DENV) started its spread in Latin America in the 80s. Little is known about DENV spread in Africa, but multiple seroprevalence surveys over several years are now clearly showing endemic areas in East and West Africa (Brady et al. 2013). Finally, due to global warming and intense traveling there is a risk of global spread towards more temperate regions, and both US Key islands (FL) and southern Europe recently faced DENV outbreaks. There are currently no specific treatments or vaccines available. Even though several dengue vaccines are in the pipeline, clear correlates of protection are still lacking. The recent failure of the live-attenuated Sanofi vaccine Phase 2b trial (Sabchareon et al. 2013) and the lack of correlation between clinical protection and in vitro neutralization assays, clearly underlines the necessity to better understand the role of the different components of the immune system in protection against dengue virus infection and the requirement for the development of additional and/or improved predictive assays. The aim of this research topic is to provide novel data, opinions and literature reviews on the best immune correlates of protection and recent advances in the immune response to DENV infection that can allow rapid progress of dengue vaccines. Authors can choose to submit original research papers, reviews or opinions on pre-clinical or clinical observations that will help unify the field, with perspectives from epidemiology, virology, immunology and vaccine developers. This research topic will discuss different aspects of the protective immune response to DENV that can influence vaccine development. It will include a review of epidemiological data generated in the field, which will address spatio-temporal diversity of DENV epidemics, the importance of cross-reactive protection and of the time-interval between infections as a predictor of disease. It will further include a review of the role of both the innate and adaptive immunity in DENV infection control, and discuss the usefulness of new improved animal models in dissecting the role of each immunological compartment, which will help define new correlate of immune protection. New data concerning the DENV structure and anti-dengue antibody structure will address the necessity of improved neutralization assays. The ultimate test to prove vaccine efficacy and study immune correlates of protection in humans before large trials will open up the discussion on human DENV challenges using controlled attenuated viral strains. Finally, the role of vaccines, administered in flavi-immune populations, in the modification of future epidemics will also be approached and will include novel studies on mosquitoes infection thresholds.

Dengue viruses. --- Vaccines. --- Monocytes --- NK cells --- Dendritic Cells --- Dengue --- Antibodies --- protection --- Vaccines --- T cells --- Macrophages --- Immunity

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Dengue is the most important mosquito-transmitted viral disease in humans. Half of the world population is at risk of infection, mostly in tropical and sub-tropical areas. The World Health Organization (WHO) estimates that 50 to 100 million infections occur yearly, with 50,000 to 100,000 deaths related to dengue, mainly in children. Recent estimates show higher numbers, up to three times more, with 390 million estimated dengue infections per year, among which 96 million apparent infections (Bhatt et al. 2013). Initially localized to South-East Asia, dengue virus (DENV) started its spread in Latin America in the 80s. Little is known about DENV spread in Africa, but multiple seroprevalence surveys over several years are now clearly showing endemic areas in East and West Africa (Brady et al. 2013). Finally, due to global warming and intense traveling there is a risk of global spread towards more temperate regions, and both US Key islands (FL) and southern Europe recently faced DENV outbreaks. There are currently no specific treatments or vaccines available. Even though several dengue vaccines are in the pipeline, clear correlates of protection are still lacking. The recent failure of the live-attenuated Sanofi vaccine Phase 2b trial (Sabchareon et al. 2013) and the lack of correlation between clinical protection and in vitro neutralization assays, clearly underlines the necessity to better understand the role of the different components of the immune system in protection against dengue virus infection and the requirement for the development of additional and/or improved predictive assays. The aim of this research topic is to provide novel data, opinions and literature reviews on the best immune correlates of protection and recent advances in the immune response to DENV infection that can allow rapid progress of dengue vaccines. Authors can choose to submit original research papers, reviews or opinions on pre-clinical or clinical observations that will help unify the field, with perspectives from epidemiology, virology, immunology and vaccine developers. This research topic will discuss different aspects of the protective immune response to DENV that can influence vaccine development. It will include a review of epidemiological data generated in the field, which will address spatio-temporal diversity of DENV epidemics, the importance of cross-reactive protection and of the time-interval between infections as a predictor of disease. It will further include a review of the role of both the innate and adaptive immunity in DENV infection control, and discuss the usefulness of new improved animal models in dissecting the role of each immunological compartment, which will help define new correlate of immune protection. New data concerning the DENV structure and anti-dengue antibody structure will address the necessity of improved neutralization assays. The ultimate test to prove vaccine efficacy and study immune correlates of protection in humans before large trials will open up the discussion on human DENV challenges using controlled attenuated viral strains. Finally, the role of vaccines, administered in flavi-immune populations, in the modification of future epidemics will also be approached and will include novel studies on mosquitoes infection thresholds.

Dengue viruses. --- Vaccines. --- Monocytes --- NK cells --- Dendritic Cells --- Dengue --- Antibodies --- protection --- Vaccines --- T cells --- Macrophages --- Immunity

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The release of cytokines, chemokines, and other immune-modulating mediators released from innate immune cells, including eosinophils, neutrophils, macrophages, dendritic cells, mast cells, and epithelial cells, is an important event in immunity. Cytokine synthesis and transportation occurs through the canonical protein trafficking pathway associated with endoplasmic reticulum and Golgi. How cytokines are released upon their exit from the trans-Golgi network varies enormously between cell types, and in many cells this has not yet been characterized. This issue delves into the plethora of cytokines released by innate immune cells, and where possible, shines light on specific mechanisms that regulate trafficking and release of Golgi-derived vesicles. Each cell type also shows varying degrees of dependency on microtubule organization and actin cytoskeleton remodeling for cytokine secretion. Understanding the mechanisms of cytokine secretion will reveal the inner workings of individual innate immune cell types, and allow identification of critical regulatory steps in cytokine release.

Cytokines. --- Chemokines. --- secretory granules --- Dendritic Cells --- GTPases --- SNAREs --- Neutrophils --- Epithelial Cells --- degranulation --- Macrophages --- Recycling endosomes --- Eosinophils --- secretory granules --- Dendritic Cells --- GTPases --- SNAREs --- Neutrophils --- Epithelial Cells --- degranulation --- Macrophages --- Recycling endosomes --- Eosinophils