Boosting the BCG vaccine to beat tuberculosis
Tuberculosis remains a major global health threat. Although more than 3 billion doses of the BCG vaccine have been administered to fight tuberculosis, the ability of the BCG vaccine to protect adults is very limited, as is its efficacy against newly emerging isolates.
In a study appearing online on August 18 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Stefan Kaufmann and colleagues from the Max Planck Institute devise a strategy to boost the immunogenicity of BCG and describe a novel vaccine strain with high efficacy against tuberculosis. The researchers engineer a BCG strain that secretes the listeriolysin protein, which punches holes in the membranes of phagosomes where M. tuberculosis is located, allowing better T cell-mediated immunity. Because listeriolysin works optimally at a pH of 5.8, the researchers also deleted the urease C gene of BCG, which normally plays a role in pH neutralization of the phagosome. The lack of urease C allows phagosomal acidification and provides an ideal pH environment for listeriolysin.
The new BCG vaccine strain protects mice against tuberculosis significantly better than the parental BCG. Superior protection is not only induced against the laboratory strain of M. tuberculosis but also against a clinical isolate of the Beijing/W family, a straing of tuberculosis that is spreading all over the world, is drug-resistant, and is responsible for the most threatening disease outbreaks.
TITLE: Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guérin mutants that secrete listeriolysin
Max Planck Institute, Berlin, Germany
Phone: 49-30-28460-500/-506; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24617
TWEAKing the liver to regenerate after injury
Liver injury can occur as a result of alcohol toxicity, necrosis, or a host of other factors. When the liver is injured, it responds with progenitor cell (oval cell) proliferation in the remaining parts of the organ. The oval cells can become either liver cells or epithelial cells, and are vital for recovery from liver injury. But the regulation of oval cell expansion is not well understood.
In a study appearing online on August 18 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Aniela Jakubowski and colleagues from Biogen report the discovery of a novel role for the TNF family member, TWEAK, as an inducer of oval cell proliferation in the liver. This is the first demonstration of a role for this cytokine in the regulation of liver progenitor cells.
Unlike other factors that can modulate the proliferation of oval cells, the researchers show that TWEAK acts selectively on oval cells with no effect on mature liver cells. They use three independent approaches: animals overexpressing TWEAK, adenoviral delivery of TWEAK, and TWEAK blocking antibodies in a model of oval cell hyperplasia.
The potential role for the TWEAK pathway in chronic human liver diseases that are accompanied by oval cell proliferation is suggested by data showing increased expression of the receptor for TWEAK in alcoholic cirrhosis and viral hepatitis. A better understanding of the molecular pathways regulating the progenitor cell response may lead to specific therapies for liver diseases.
TITLE: TWEAK Induces Liver Progenitor Cell Proliferation
Biogen Idec Inc., Cambridge, MA USA
Phone: 617-679-6205; Fax: 617-679-3148; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=23486
Filling up on bladder function
In a study appearing online on August 18 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Gerard Apodaca and colleagues from University of Pittsburgh define the upstream signals that couple mechanical stimuli to alterations in bladder epithelial membrane traffic. The authors show that ATP plays an important upstream sensory role that signals bladder filling and regulates normal bladder function. The work may provide important insight into the physiological regulation of other mechanically sensitive epithelia including those that line the airways and gut.
Title: ATP and Purinergic Receptor-Dependent Membrane Traffic in Bladder Umbrella Cells
University of Pittsburgh, Pittsburgh, PA USA
Phone: 412-383-8893; Fax: 412-383-8955; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24086
Feeling the cold, feeling the pain
People who suffer from neuropathic and inflammatory pain have hypersensitivity to cold stimulation, which they perceive as painful. Temperature is sensed by thermoreceptors such as TRPA1 and TRPM8. These are cold-sensitive ion channels activated by temperatures under 28 degrees Celcius. The role of TRPA1 in mediating cold pain is controversial. In a study appearing online on August 18 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Koichi Noguchi and colleagues from Hyogo College show that TRPA1 in sensory neurons contributes to the development of cold hypersensitivity, and further, cold stimulation activates TRPA1 in vivo. The authors show that reduction of TRPA1 attenuated inflammation- and nerve injury-induced cold hypersensitivity. Thus, blocking TRPA1 in sensory neurons may be a useful way to treat inflammatory and neuropathic pain.
Title: TRPA1 induced in sensory neurons contributes to cold pain hypersensitivity after inflammation and nerve injury
Hyogo College of Medicine, Hyogo, Japan
Phone: 81-798-45-6415; Fax: 81-798-45-6417; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=25437
How to bar Epstein Barr
In a study appearing online on August 18 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Alan Rickinson and colleagues from University of Birmingham address the immunology of long-term oropharyngeal shedding of Epstein-Barr virus at a time when infection of circulating lymphocytes is well-controlled.
The authors used three groups of patients at different stages of infection, representing different positions of the virus-host balance: acute infectious mononucleosis (IM) patients undergoing primary infection, post-IM patients shortly after resolution of acute infection, and long-term asymptomatic virus carriers.
During the acute disease and shortly after its resolution, CD8+ T cells specific for virus replicative epitopes are not efficiently targeted to oropharyngeal sites of viral replication, coincident with prolonged viral shedding from these sites. By contrast, responses to virus latent cycle epitopes begin to accumulate more quickly in the tonsil post-IM and the latent infection is more rapidly controlled. In long-term virus carriers where both lytic and latent infections have been reduced to very low levels, both types of virus-specific response are dramatically enriched in tonsils compared to blood. Indeed, in healthy asymptomatic carriers total reactivities to defined EBV epitopes can account for up to 20% of the entire tonsillar CD8 population. The data suggest that efficient control of EBV infection requires appropriate CD8 T cell homing to oropharyngeal sites.
Title: Tonsillar homing of Epstein-Barr virus-specific CD8 T cells and the virus-host balance
University of Birmingham, Birmingham, UK
Phone: 44-121-414-4492; Fax: 44-121-414-4486; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24810
Looking at autoimmune diabetes, literally
A major problem for understanding and treating type1 diabetes is that we are unable to directly, but non-invasively, visualize the inflammatory lesions in the pancreas that cause the disease. In a study appearing online on August 18 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Diane Mathis and colleagues from Joslin diabetes Center describe a novel magnetic resonance imaging (MRI) strategy to non-invasively monitor autoimmune inflammation in the pancreas of a living animal.
The researchers were able to track the pancreatic islet infiltrate that accompanies autoimmune diabetes in mice, and follow the resolution of inflammation after successful reversal of diabetes with therapy. This new imaging strategy provides preclinical data on mouse models of Type-1 diabetes that can guide the application of an in vivo MRI technique to patients with autoimmune diabetes.
Title: Seeing autoimmunity - noninvasive imaging of type 1 diabetes and its reversal
Joslin Diabetes Center, Boston, MA USA
Phone: 617-264-2701; Fax: 617-264-2744; E-mail: Diane.Mathis@joslin.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25048
Neuronal injury in AIDS? The answer does not come from the brain
About 30% of patients with HIV also develop neurological symptoms, but the mechanisms by which the immune system contributes to central nervous system (CNS) disease were unclear. In a study appearing online on August 18 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Kenneth Williams and colleagues from Beth Israel Deaconess Medical Center use a model of neuroAIDS in rhesus monkeys infected with Simian Immunodeficiency Virus (SIV).
The researchers document changes in blood monocyte activation and SIV infection that occur with neuronal injury. They also use combination anti-retroviral therapy on the monkeys during primary infection, and show little effect on plasma viral load, but inhibition of subsequent activation and infection of blood monocytes. The inhibition of blood monocyte activation and infection with retroviral therapy rapidly reduces CNS neuronal injury. Animals on retroviral therapy show no accumulation of macrophages in the CNS or detectable virus, in contrast to non-treated animals.
This data underscores the role of the continuous traffic of activated and infected monocytes to the CNS that is required for CNS disease and neuronal injury in this model, and shows the role of plasma virus, monocytes, and CD8 T lymphocytes outside of the brain in controlling CNS disease.
Title: Magnetic resonance spectroscopy reveals a role of activated monocytes contributing to neuronal injury in simian immunodeficiency virus neuroAIDS
Beth Isreal Deaconess Medical Center, Boston, MA USA
Phone: 617 667 2064; Fax: 617 667 8210; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=22953
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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