Improving human immunity to malaria
The deadlist form of malaria is caused the protozoan Plasmodium falciparum. During its life-cycle in human blood, the parasite P. falciparum expresses unique proteins on the surface on infected blood cells. Antibodies to these proteins are associated with protection from malaria, however, the identity of surface protein(s) that elicit the strongest immune response is unknown. Dr. James Beeson and colleagues at the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia have developed novel assays with transgenic P. falciparum expressing modified surface proteins, allowing the researchers to quantify serum antibodies to surface proteins among malaria-exposed children and adults. They found that most of the human antibody response to the surface proteins targets a parasite protein known as PfEMP1. Moreover, the showed that people with PfEMP1-specific antibodies had a reduced risk of malaria symptoms, whereas antibodies to other surface antigens were not associated with protective immunity. These findings suggest antibodies against PfEMP mediate human immunity to malaria and have implications for future malaria vaccine development.
TITLE:
Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity
AUTHOR CONTACT:
James Beeson
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, UNK, AUS
Phone: 613-9345-2555; Fax: 613-9347-0852; E-mail: beeson@wehi.edu.au
View this article at: http://www.jci.org/articles/view/62182?key=ed28073b9acd36ff3e6e
ONCOLOGY
Chemokine pathway suppresses colon cancer metastasis
Chemokines are signals in the body that act as beacons, calling out to migrating cells, such as white blood cells, guiding them to where they are needed. One chemokine in particular, chemokine 25 (CCL25), binds to chemokine Receptor 9 (CCR9), forming a signaling pathway that is important in the small intestine and colon, where it regulates immune response and decreases cell death. Drs. Steven Lipkin, Xiling Shen, and colleagues at Cornell University have discovered that the CCL25-CCR9 pathway also has an unexpected role— inhibiting colon cancer metastasis and invasion. They found that CCR9 was highly abundant in early stage colon cancer cells derived from human cancer but surprisingly lacking in invasive and metastatic cancer, suggesting a role for this receptor in reducing the spread of colon cancer. By blocking this pathway in early stage cancer cells, they showed that tumor formation within the small intestine/colon of mice was inhibited, but metastasis and invasion were increased. Furthermore, they found that activation of a second pathway called NOTCH, known to stimulate metastasis and invasion, promotes the degradation of CCR9, thus inhibiting the actions of its binding partner CCL25. This discovery sheds light on how colon cancer progresses and metastasizes.
TITLE:
Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis
AUTHOR CONTACT:
Steven Lipkin
Weill Cornell College of Medicine, New York, NY, USA
Phone: 2127747160; E-mail: stl2012@med.cornell.edu
View this article at: http://www.jci.org/articles/view/62110?key=ec3038b0ac205857d679
ENDOCRINOLOGY
Botulinum neurotoxin retooled to combat excess hormone production
In acromegaly, excess production of growth hormone triggers aberrant growth of body tissues . Researchers at the University of Geneva in Switzerland sought to develop new therapeutic approaches for treating acromegaly. Led by Dr. Emmanuel Somm, the team modified a Botulinum neurotoxin to specifically target pituitary somatotroph cells that secrete growth hormone. When given to rats, the recombinant protein reduced growth hormone synthesis and secretion. Reflecting this change, the body weight gain, body length, organ weight, and bone mass acquisition were all decreased in treated animals. These results provide promising preclinical data to support that engineered Botulinum neurotoxin to can be retargeted to non-neural cells to selectively inhibit hormone secretion.
TITLE:
A botulinum toxin-derived targeted secretion inhibitor downregulates the GH/IGF1 axis
AUTHOR CONTACT:
Emmanuel Somm
Department of Pediatrics, Faculty of Medecine, University of Geneva, Switze, GENEVA, UNK, CHE
Phone: 0041223824568; E-mail: emmanuel.somm@unige.ch
View this article at: http://www.jci.org/articles/view/63232?key=2524aed3b01dc0c147b8
IMMUNOLOGY
Gene deficiency increases risk for human papillomavirus infection
Epidermodysplasia verruciformis (EV) is a rare skin disorder caused by an increased susceptibility to a specific group of related human papillomaviruses. The majority of cases of this congenital disorder are associated with mutations either the gene EVER1 or EVER2. However, the underlying cause in the remaining patients is unclear. Dr. Emmanuelle Jouanguy and researchers at INSERM in Paris now report on two patients with an immune deficiency and various infectious diseases, including persistent EV-associated human papillomavirus infections. The Jouanguy team found that the patients both had loss-of-function of the RHOH gene, which encodes an atypical Rho GTPase that is primarily expressed in developing blood and immune cells. The patients lacked specific populations of T cells, and those T cell present had impaired T cell receptor signaling. The team went on to model the same genetic mutation in mice, which had similar T cell defects. Their findings uncover a new genetic risk factor for T cell deficiency and persistent EV-associated human papillomavirus infections in patients.
TITLE:
Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections
AUTHOR CONTACT:
Emmanuelle Jouanguy
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980, Paris, France
Phone: 33 1 40 61 55 40; E-mail: emmanuelle.jouanguy@inserm.fr
View this article at: http://www.jci.org/articles/view/62949?key=e8f5d52df7d9367c509f
ONCOLOGY
Micromanagement impacts cancer spread: miR34-a in cancer metastasis
Once a cancer has spread to other sites in the body, this aggressive, metastatic cancer is extremely refractory to most treatment options. Dr. Jonathan Kurie and coworkers at M.D. Anderson Cancer Center in Houston, Texas wanted to better understand the molecular pathways that underlie metastasis. They examined a known promoter of metastasis, a gene transcription factor known as ZEB1 that regulates the expression of multiple regulatory microRNAs. The team specifically studied which microRNAs regulated by ZEB1 contributed to its metastasis-promoting functions. They found that a major target of ZEB1 is microRNA-34a (miR34-a). Forced expression of miR-34a decreased tumor cell invasion and metastasis in mice, and expression patterns of miR-34a in human lung adenocarcinomas predicted clinical outcome. Their results suggest that pharmaceuticals targeting miR-34a may merit exploration as a therapeutic agent in lung cancer patients.
TITLE:
ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression
AUTHOR CONTACT:
Jonathan Kurie
M. D. Anderson Cancer Center, Houston, TX, USA
Phone: 713-745-6747; Fax: 713-792-1220; E-mail: jkurie@mdanderson.org
View this article at: http://www.jci.org/articles/view/63608?key=2741a2e21930025f7a44
INFORMATION:
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