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Research Highlights

Feed a bacterium, kill a tumor

Researchers have exploited the nutritional needs of a salmonella strain to target and kill tumor cells. Hoffman and colleagues selected strains of Salmonella typhimurium that are dependent on the presence of the amino acids leucine and arginine for growth. These amino acids are only in sufficient supply inside tumor cells, allowing growth of the bacterium and accumulation of the bacterial toxic lipid-A, which provokes nuclear destruction and eventual regression of the tumor. In contrast, S. typhimurium introduced intravenously into tumor-free mice is rapidly cleared without detrimental effects to the animals. The authors applied their approach to treating prostate cancer in mice and observed tumor regression after intravenous or intratumoral administration. Visualization of the S. typhimurium cells inside the animals further showed their high concentration in tumor tissue and a lack of growth in other organs, such as liver, lung, kidney or spleen. In contrast to previously developed bacterial-based tumor eradication strategies where the bacteria grow only on necrotic tissue, the S. typhimurium strain described here shows enhanced growth throughout a tumor cell's lifetime, which may explain the high rate of success observed. (Proc. Natl. Acad. Sci. USA 102, 755–760, 2005) GTO

Sweet spots

Carbohydrate-cell interactions are ubiquitous in nature and figure in numerous developmental and pathogenic events. Bacteria are thought to gain entrance to susceptible hosts, for example, by binding to surface carbohydrates. However, methods for rapidly characterizing such interactions have been lacking. Now Disney and Seeberger describe carbohydrate arrays that can be used to probe carbohydrate-cell interactions. Using arrays of five simple sugars, they were able to demonstrate binding of normal Escherichia coli strains only to mannose sugars, whereas mutant E. coli with reduced affinity to mannose, failed to bind. Although bacteria bind best to simple sugars rather than to those with complex linkages, multivalent binding provides a stronger signal, as one particular surface with a three-dimensional scaffold gave the highest signal-to-noise ratio. The authors use their microarrays to screen for molecules that interfere with bacteria-carbohydrate interactions, which might prove to have therapeutic value. They also show that bacteria can be isolated from complex mixtures and that viable cells can be recovered and tested further for antibiotic sensitivity. These features of carbohydrate arrays make them potentially useful for quick isolation and characterization of human pathogens. (Chem. Biol. 11, 1701–1707, 2004) LD

Tuning up dendritic cells

Induction of CD40-receptor expression in dendritic cells is a key step in their activation of cytotoxic T lymphoctes in epitope-specific immunotherapy. However, endogenous CD40 regulatory mechanisms often lead to transient dendritic cell activation. What's more, systemic, nontargeted CD40 stimulation can produce negative side effects because of the receptor's ubiquitous expression on many cell types. To get around this, Spencer and colleagues have engineered dendritic cells to express a recombinant CD40 receptor fused to a drug-inducible protein, with a membrane targeting sequence that is shielded from ectodomain-dependent inhibitory mechanisms. Dendritic cells in which the recombinant CD40 receptor has been activated ex vivo using a lipid-permeable, high-affinity dimerizer drug show CD8+ T-cell effector responses superior to those of control dendritic cells expressing natural CD40 receptor. Furthermore, in vivo activation of recombinant dendritic cells, through systemic injection of the CD40-inducing drug in mouse tumor models, resulted in enhanced antigen-specific T-cell responses and decreased tumor volume when compared with injection of either in vitro–stimulated dendritic cells or a CD40-specific monoclonal antibody. (Nat. Med. 11, 130–137, 2005) NC

Taking aim at ALS

The glutamate transporter GLT1 regulates synaptic levels of glutamate, the primary neurotransmitter in the brain. Loss of GLT1 function is associated with several neurological disorders, among them the incurable neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Yet despite the likely therapeutic importance of glutamate transporters, a pharmaceutical means of targeting them is not available. In an effort to discover such drugs, Rothstein et al. screened over 1,000 compounds approved by the US Food and Drug Administration in rat spinal-cord cultures for increased GLT1 levels. The most effective compounds were several β-lactam antibiotics—revealing a new activity of this widely used antibiotic class. In vitro and in vivo studies with one of the hits, ceftriaxone, showed that it stimulated GLT1 expression and glutamate transport and could protect neurons from ischemic injury. When tested in a mouse model of ALS, the drug delayed the degeneration of motor neurons and muscles and prolonged the animals' survival (Nature 433, 73–77, 2005). KA

Unwinding salt intolerance

Researchers have found that plants transformed with a pea DNA helicase gene (PDH45) grow normally under high-salt and other stressful conditions. The PDH45 gene is upregulated in pea plants stressed by high salinity, dehydration, wounding or low temperature. Under high-salt conditions, PDH45 mRNA levels in pea plants are more than three times those of unstressed wild-type plants. When transformed with PDH45—a gene homologous to the eukaryotic initiation factor eIF-4A, which has both DNA and RNA helicase activities—salt-stressed tobacco plants were comparable to unstressed wild-type plants in several parameters, including height, fresh weight of leaves and seeds, and time to flowering. The researchers speculate that the mechanism by which PDH45 confers stress tolerance, though not completely understood, likely involves regulation of translation initiation, a known function of eIF-4A, or of transcription regulation, through its RNA helicase function. Stress tolerance in the transgenic tobacco plants described in this paper suggests a new pathway to engineer to maximize crop yield in sub-optimal conditions. (Proc. Natl. Acad. Sci. USA 102, 509–514, 2005) TM

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Research Highlights. Nat Biotechnol 23, 189 (2005).

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