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Infectious Disease

Calcium, cancer and killing: The role of calcium in killing cancer cells by cytotoxic T lymphocytes and natural killer cells

By | Infectious Disease

Calcium, cancer and killing: The role of calcium in killing cancer cells by cytotoxic T lymphocytes and natural killer cells

Eva C. Schwarz, Bin Qu, Markus Hoth ⁎
Department of Biophysics, Saarland University, Homburg, Germany

Killing cancer cells by cytotoxic T lymphocytes (CTL) and by natural killer (NK) cells is of vital importance. Cancer cell proliferation and apoptosis depend on the intracellular Ca2+ concentration, and the expression of numerous ion channels with the ability to control intracellular Ca2+ concentrations has been correlated with cancer. A rise of intracellular Ca2+ concentrations is also required for efficient CTL and NK cell function and thus for killing their targets, in this case cancer cells. Here, we review the data on Ca2+-dependent killing of cancer cells by CTL and NK cells. In addition, we discuss emerging ideas and present a model how Ca2+ may be used by CTL and NK cells to optimize their cancer cell killing efficiency. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.

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Human and Mouse Eosinophils Have Antiviral Activity against Parainfluenza Virus

By | Infectious Disease

Human and Mouse Eosinophils Have Antiviral Activity against Parainfluenza Virus

Matthew G. Drake1*, Elizabeth R. Bivins-Smith1*, Becky J. Proskocil1, Zhenying Nie1, Gregory D. Scott2, James J. Lee3,
Nancy A. Lee4, Allison D. Fryer1, and David B. Jacoby1
1Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon; 3Department of Biochemistry
and Molecular Biology, Division of Pulmonary Medicine, and 4Department of Biochemistry and Molecular Biology, Divisions of
Hematology and Oncology, Mayo Clinic in Arizona, Scottsdale, Arizona; 2Department of Pathology, Stanford University School of
Medicine, Stanford, California

Respiratory viruses cause asthma exacerbations. Because eosinophils are the prominent leukocytes in the airways of 6070% of patients with asthma, we evaluated the effects of eosinophils on a common respiratory virus, parainfluenza 1, in the lung. Eosinophils recruited to the airways of wild-type mice after ovalbumin sensitization and challenge significantly decreased parainfluenza virus RNA in the lungs 4 days after infection compared with nonsensitized animals. This antiviral effect was also seen in IL-5 transgenic mice with an abundance of airway eosinophils (NJ.1726) but was lost in transgenic eosinophil-deficient mice (PHIL) and in IL-5 transgenic mice crossed with eosinophil-deficient mice (NJ.1726-PHIL). Loss of the eosinophil granule protein eosinophil peroxidase, using eosinophil peroxidasedeficient transgenic mice, did not reduce eosinophilsantiviral effect. Eosinophil antiviral mechanisms were also explored in vitro. Isolated human eosinophils significantly reduced parainfluenza virus titers. This effect did not involve degradation of viral RNA by eosinophil granule RNases. However, eosinophils treated with a nitric oxide synthase inhibitor lost their antiviral activity, suggesting eosinophils attenuate viral infectivity through production of nitric oxide. Consequently, eosinophil nitric oxide production was measured with an intracellular fluorescent probe. Eosinophils produced nitric oxide in response to virus and to a synthetic agonist of the virus-sensing innate immune receptor, Toll-like receptor (TLR) 7. IFNg increased expression of eosinophil TLR7 and potentiated TLR7-induced nitric oxide production. These results suggest that eosinophils promote viral clearance in the lung and contribute to innate immune responses against respiratory virus infections in humans.

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Unravelling the Interplay between Extracellular Acidosis and Immune Cells

By | Infectious Disease

Unravelling the Interplay between Extracellular Acidosis and Immune Cells

Fernando Erra Díaz , Ezequiel Dantas, and Jorge Geffner
Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires, CONICET,
Ciudad de Buenos Aires, Argentina

The development of an acidic tissue environment is a hallmark of a variety of inflammatory processes and solid tumors. However, little attention has been paid so far to analyze the influence exerted by extracellular pH on the immune response. Tissue acidosis(pH 6.0 to 7.0) is usually associated with the course of infectious processes in peripheral tissues. Moreover, it represents a prominent feature of solid tumors. In fact, values of pH ranging from 5.7 to 7.0 are usually found in a number of solid tumors such as breast cancer, brain tumors, sarcomas, malignant melanoma, squamous cell carcinomas, and adenocarcinomas. Both the innate and adaptive arms of the immune response appear to be finely regulated by extracellular acidosis in the range of pH values found at inflammatory sites and tumors. Low pH has been shown to delay neutrophil apoptosis, promoting their differentiation into a proangiogenic profile. Acting on monocytes and macrophages, it induces the activation of the inflammasome and the production of IL-1β, while the exposure of conventional dendritic cells to low pH promotes the acquisition of a mature phenotype. Overall, these observations suggest that high concentrations of protons could be recognized by innate immune cells as a danger-associated molecular pattern (DAMP). On the other hand, by acting on T lymphocytes, low pH has been shown to suppress the cytotoxic response mediated by CD8+ T cells as well as the production of IFN-γ by TH1 cells. Interestingly, modulation of tumor microenvironment acidity has been shown to be able not only to reverse anergy in human and mouse tumor-infiltrating T lymphocytes but also to improve the antitumor immune response induced by checkpoint inhibitors. Here, we provide an integrated view of the influence exerted by low pH on immune cells and discuss its implications in the immune response against infectious agents and tumor cells.

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Eosinophils and their Interactions with Respiratory Virus Pathogens

By | Infectious Disease

Eosinophils and their Interactions with Respiratory Virus Pathogens

Helene F. Rosenberg1,3, Kimberly D. Dyer1, and Joseph B. Domachowske2
1 Eosinophil Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, Maryland 2 Department of Pediatrics,
SUNY Upstate Medical University, Syracuse, New York

Eosinophils are implicated in the pathophysiology of respiratory virus infection, most typically in negative roles, such as promoting wheezing and bronchoconstriction in conjunction with virusinduced exacerbations of reactive airways disease and in association with aberrant hypersensitivity responses to antiviral vaccines. However, experiments carried out in vitro and in vivo suggest positive roles for eosinophils, as they have been shown to reduce virus infectivity in tissue culture and promote clearance of the human pathogen, respiratory syncytial virus (RSV) in a mouse challenge model. The related natural rodent pathogen, pneumonia virus of mice (PVM) is highly virulent in mice, and is not readily cleared by eosinophils in vivo. Interestingly, PVM replicates in eosinophils and promotes cytokine release. The molecular basis of virus infection in eosinophils and its relationship to disease outcome is currently under study.

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The Avian Coronavirus Infectious Bronchitis Virus Undergoes Direct Low-pH-Dependent Fusion Activation during Entry into Host Cells

By | Infectious Disease

The Avian Coronavirus Infectious Bronchitis Virus Undergoes Direct Low-pH-Dependent Fusion Activation during Entry into Host Cells

Victor C. Chu, Lisa J. McElroy, Vicky Chu, Beverley E. Bauman, and Gary R. Whittaker*
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853

Coronaviruses are the causative agents of respiratory disease in humans and animals, including severe acute respiratory syndrome. Fusion of coronaviruses is generally thought to occur at neutral pH, although there is also evidence for a role of acidic endosomes during entry of a variety of coronaviruses. Therefore, the molecular basis of coronavirus fusion during entry into host cells remains incompletely defined. Here, we examined coronavirus-cell fusion and entry employing the avian coronavirus infectious bronchitis virus (IBV). Virus entry into cells was inhibited by acidotropic bases and by other inhibitors of pH-dependent endocytosis. We carried out fluorescence-dequenching fusion assays of R18-labeled virions and show that for IBV, coronaviruscell fusion occurs in a low-pH-dependent manner, with a half-maximal rate of fusion occurring at pH 5.5. Fusion was reduced, but still occurred, at lower temperatures (20°C). We observed no effect of inhibitors of endosomal proteases on the fusion event. These data are the first direct measure of virus-cell fusion for any coronavirus and demonstrate that the coronavirus IBV employs a direct, low-pH-dependent virus-cell fusion activation reaction. We further show that IBV was not inactivated, and fusion was unaffected, by prior exposure to pH 5.0 buffer. Virions also showed evidence of reversible conformational changes in their surface proteins, indicating that aspects of the fusion reaction may be reversible in nature.

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The Influence of Virus Infection the Extracellular pH of the Host Cell Detected on Cell Membrane

By | Infectious Disease

The Influence of Virus Infection the Extracellular pH of the Host Cell Detected on Cell Membrane

Hengjun Liu 1*, HisatakaMaruyama1, TaisukeMasuda1, AyaeHonda2 and FumihitoArai 1
1 DepartmentofMicro-NanoSystemsEngineering,NagoyaUniversity,Nagoya,Japan, 2 DepartmentofFrontierBioscience,
HoseiUniversity,Tokyo,Japan
Influenzavirusinfectioncanresultinchangesinthecellularionlevelsat2–

Influenza virus infection can result in changes in the cellular ion levels at 2–3h post infection. More H+ is produced by glycolysis, and the viral M2 proton channel also plays a role in the capture and release of H+ during both viral entry and egress.  Then the cells might regulate the intracellular pH by increasing the export of H+ from the intracellular compartment. Increased H+ export could lead indirectly to increased extracellular acidity.  To detect changes in extracellular pH of both virus infected and uninfected cells, pH sensors were synthesized using polystyrene beads(#1μm) containing Rhodamine B and Fluorescein isothiocyanate (FITC). The fluorescence intensity of FITC can respond to both pH and temperature.

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New insights into Lyme disease

By | Infectious Disease, Lyme

New insights into Lyme disease

Brandon N. Peacock n,1, Teshome B. Gherezghiher 1, Jennifer D. Hilario, Gottfried H. Kellermann

Lyme borreliosis is transmitted through the bite of a tick that is infected by the bacterial spirochete Borrelia burgdorferi. Clinical manifestation of the disease can lead to heart conditions, neurological dis- orders, and inflammatory disorders. Oxidative stress has been implicated in the pathogenesis of many human diseases. The aim of this study was to investigate the mechanisms of oxidative stress and intracellular communication in Lyme borreliosis patients. Mitochondrial superoxide and cytosolic ionized calcium was measured in peripheral blood mononuclear cells (PBMCs) of Lyme borreliosis patients and healthy controls. Mitochondrial superoxide levels were significantly higher (po0.0001) in Lyme bor- reliosis patients (n1⁄432) as compared to healthy controls (n1⁄430). Significantly low (po0.0001) levels of cytosolic ionized calcium were also observed in Lyme borreliosis patients (n1⁄411) when compared to healthy controls (n1⁄411). These results indicate that there is an imbalance of reactive oxygen species and cytosolic calcium in Lyme borreliosis patients. The results further suggest that oxidative stress and interrupted intracellular communication may ultimately contribute to a condition of mitochondrial dysfunction in the immune cells of Lyme borreliosis patients.

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