NEW BACTERIAL GENE PROVIDES MENINGITIS MECHANISM
Bacterial meningitis is the most common nervous system infection and a major cause of childhood death. In a new study appearing in the September 1 print issue of The Journal of Clinical Investigation, Kelly Doran and colleagues from UCSD investigate the mechanisms responsible for the penetration of the human blood-brain barrier (BBB) by Group B Streptococcus (GBS), the bacteria that causes meningitis in newborn infants.
The authors find a novel GBS gene, called iagA, which helps the bacteria invade the normally shield-like brain endothelial cells of the BBB. An iagA mutant showed decreased invasion through these cells and reduced the development of meningitis and lethality in vivo. Deletion of iagA did not affect other key steps in the pathogenesis of GBS meningitis, including bacterial survival. Thus iagA specifically promotes endothelial cell uptake of the pathogen. The iagA gene product seems to synthesize a glycolipid anchor that facilitates the bacteria's interaction with the host cell.
In an accompanying commentary, Miriam Baron and Dennis Kaspar write, "this work contributes to our understanding of the molecular pathogenesis of invasive GBS infection. Specifically, the identification of the iagA gene product as a major contributor to GBS invasion and virulence is an exciting development."
TITLE: Group B Streptococcus Blood-Brain Barrier Invasion Depends Upon Proper Cell Surface Anchoring of Lipoteichoic Acid
AUTHOR CONTACT:
Kelly Doran
University of California San Diego, San Diego, CA USA
Phone: 858-822-4260; E-mail: kdoran@ucsd.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23829
ACCOMPANYING COMMENTARY:
Title: Anchors away: contribution of a glycolipid anchor to bacterial invasion of host cells
AUTHOR CONTACT:
Dennis L. Kasper
Harvard Medical School, Boston, MA USA
Phone: 617-432-3636; Fax: 617-432-3639; E-mail: dennis_kasper@hms.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=26285
IMMUNOLOGY
NKT ANERGY OR ACTIVATION: QUESTIONS IN IMMUNOTHERAPY
Natural killer T cells (NKT) are a subset of T lymphocytes that mediate the host immune response. The glycolipid alpha-galactosylceramide potently and specifically activates these cells and has been used in cancer clinical trials to drive the immune response. But little is known about how multiple doses of this approach actually work. In a new study appearing in the September 1 print issue of The Journal of Clinical Investigation, Luc Van Kaer and colleagues from Vanderbilt University characterize the effects of multiple doses of glycolipid. The authors report the surprising finding that alpha-galactosylceramide induces anergy (a state of immune unresponsiveness) in NKT cells, and not activation as seen with a single dose. This anergy is long term, and lasts for at least one month in mice.
In a related commentary, Barbara Sullivan and Mitchell Kronenberg write, "This leads us to ask, should sequential administration of alpha-galactosylceramide still be used to activate NKT cells given the anergic state it has been shown here to induce? This intriguing article raises the issue of the avoidance of anergy induction in the design of treatment regimens that use alpha-galactosylceramide as a specific activator of NKT cells."
TITLE: Glycolipid antigen induces long-term natural killer T cell anergy in mice
AUTHOR CONTACT:
Luc Van Kaer
Vanderbilt University Medical Center, Nashville, TN USA
Phone: 615-343-2707; Fax: 615-343-2972; E-mail: luc.van.kaer@vanderbilt.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24762
ACCOMPANYING COMMENTARY:
Title: Activation or anergy: NKT cells are stunned by alpha-galactoceramide
AUTHOR CONTACT:
Mitchell Kronenberg
La Jolla Inst Allergy and Immunology, San Diego, CA USA
Phone: 858 678-4540; Fax: 858 678-4595; E-mail: mitch@liai.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=26297
PHYSIOLOGY
New ways to hone the bone and alleviate osteoporosis
A variety of therapies are used to treat osteoporosis. Most work by inhibiting bone absorbing osteoclast activity, but don't actually rebuild lost bone. Agents that rebuild bone are anabolics. The only bone anabolic clinically available is the 1-34 amino terminal fragment of parathyroid hormone (PTH 1-34). In a new study appearing in the September 1 print issue of The Journal of Clinical Investigation, Andrew Karaplis and colleagues from McGill University create mice lacking parathyroid hormone related protein (PTHrP) in osteoblasts – the cells that make bone. These mice have defective bone formation due to impaired bone marrow precursor cell recruitment and increased osteoblast cell death.
These experiments confirm the role of osteoblast-derived PTHrP in the process of bone formation. The authors show that osteoblast-derived PTHrP is a powerful endogenous bone anabolic agent that promotes the recruitment of osteogenic cells and prevents the death of osteoblasts. Also, the anabolic action of PTH 1-34 is amplified in these mice.
These findings demonstrate a previously unrecognized capacity of PTHrP produced within the skeletal microenvironment to regulate bone turnover, and to boost both bone formation and the anabolic properties of PTH 1-34. In a related commentary, T. John Martin writes that these findings have "implications for both our understanding of the pathogenesis of osteoporosis and its treatment."
TITLE: Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34
AUTHOR CONTACT:
Andrew Karaplis
McGill University, Montreal, Canada
Phone: 51 4340-8222; E-mail: akarapli@ldi.jgh.mcgill.ca
View the PDF of this article at: https://www.the-jci.org/article.php?id=24918
ACCOMPANYING COMMENTARY:
Title: Osteoblast-derived PTHrP is a physiological regulator of bone formation
AUTHOR CONTACT: T. John Martin St. Vincent's Institute of Medical Research, Melbourne, Australia Phone: 61-3-9288-2480; Fax: 61-3-9416-2676; E-mail: jmartin@svi.edu.au
View the PDF of this article at: https://www.the-jci.org/article.php?id=26239
PHYSIOLOGY
Vascular remodeling: getting the Ang of it
In a new study appearing in the September 1 print issue of The Journal of Clinical Investigation, Peter Oettgen and colleagues from Harvard define the role of the Ets-1 transcription factor in vascular inflammation and remodeling in response to angiotensin II.
While a role for Ets-1 as a transcriptional mediator of angiogenesis in endothelial cells had previously been shown, its role downstream of angiotensin II had not been defined. The authors show that Ets-1 deficient mice have decreased vascular inflammation and remodeling in response to angiotensin II, and they identify several target genes that are dependent upon Ets-1 for induction in the vasculature in response to angiotensin II. These results support a critical role for Ets-1 as a transcriptional mediator of angiotensin II-dependent vascular inflammation and remodeling.
In a related commentary, Victor Dzau and Marco Lopez-Ilasaca write, "Characterization of the critical transcription programs activated by angiotensin II in vivo and determination of the hierarchy of responses are vital to the understanding of the mechanism of vascular disease and to the development of therapies targeted at inhibiting the common transcription effectors of vascular physiology."
TITLE: Ets-1 is a critical regulator of Angiotensin II mediated vascular inflammation and remodeling
AUTHOR CONTACT:
Peter Oettgen
Harvard Institutes of Medicine, Boston, MA USA
Phone: 617-667-3390; E-mail: joettgen@bidmc.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24403
ACCOMPANYING COMMENTARY:
Title: Searching for transcriptional regulators of angiotensin II–induced vascular pathology
AUTHOR CONTACT:
Victor Dzau
Duke University, Durham, NC USA
Phone: 919-684-2255; Fax: 919-681-7020; E-mail: victor.dzau@duke.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=26384
PHYSIOLOGY
Growing lymph vessels with macrophages? Surprisingly, yes!
When the cornea is inflamed, blood and lymphatic vessels grow into it. But the cornea is typically an avascular area. In a new study appearing in the September 1 print issue of The Journal of Clinical Investigation, Joan Streilein and colleagues from the Schepens Eye Institute examine which cells generate these new lymphatic vessels in the cornea. The authors find that innate immune cells, in particular macrophages, contribute to this vessel formation during abnormal corneal conditions, and that bone marrow derived macrophages express lymphatic markers under conditions of corneal inflammation. These findings suggest a new mechanism of the formation of lymph vessels, where macrophages are responsible during inflammation.
In a related commentary, Dontscho Kerjaschki writes, "these findings add yet another facet to the plasticity of macrophages, which are already known to transform from naïve monocytes into VEGF-producing cells. Thus, macrophages support lymphangiogenesis in 2 different ways, either by transdifferentiating and directly incorporating into the endothelial layer or by stimulating division of preexistent local lymphatic endothelial cells."
TITLE: Inflammation induced lymphangiogenesis in the cornea arises fromCD11b-positive macrophages
AUTHOR CONTACT:
Joan Stein-Streilein
Schepens Eye Research Institute, Boston, MA USA
Phone: 617-912-7494; Fax: 617-912-0105; E-mail: jstein@vision.eri.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23874
ACCOMPANYING COMMENTARY:
Title: The crucial role of macrophages in lymphangiogenesis
AUTHOR CONTACT:
Dontscho Kerjaschki
University of Vienna, Vienna, Austria
Phone: 43-1-40400-5176; Fax: 43-1-40400-5193; E-mail: dontscho.kerjaschki@meduniwien.ac.at
View the PDF of this article at: https://www.the-jci.org/article.php?id=26354
Journal
Journal of Clinical Investigation