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A Detailed Look At How AAV Infects
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| Barlett |
While adeno-associated viruses (AAV) may yet prove the perfect vectors to ferry genes into cells during gene therapy, many trials have not worked as ideally as hoped. Challenged by their inability to use AAV for cystic fibrosis therapy, Jeffrey Bartlett of Children's Research Institute and Ohio State University in Columbus and his colleagues have characterized in depth AAV's entry pathway in cells permissive to infection to determine where potential hindrances might lie.
The researchers used fluorescent labeling to track viruses and reveal the key steps in viral entry, infection, and nuclear translocation. ``This study lays the groundwork,'' Bartlett says. ``Our plan is to use this study as a template of what happens in permissive cell types to compare instances where AAV doesn't infect cells and determine the differences in the infectious pathway. This will allow us to define the blocks. Once we've identified the blocks, hopefully we can find means to get around them.''
(J. S. Bartlett, R. Wilcher, and R. J. Samulski. 2000. Infectious entry pathway of adeno-associated virus and adeno-associated virus vectors. J. Virol. 74:2777-2785.) Abstract | Full Text
Fever Boosts Host's Defenses, but Has No Effect on Bacteria
Fever as a response to infection has persisted for 400-500 million years, but the mechanisms by which it contributes to infection clearance are still poorly understood. To explore these mechanisms, Qinqqi Jiang of the University of Maryland School of Medicine and colleagues infected mice with Klebsiella peritonitis and adjusted the animals' body temperatures to 36.5-37șC (afebrile) or 39-39.5șC (febrile).
In the febrile animals, survival improved to 50% and the bacterial load was reduced by 100,000-fold compared with afebrile mice, all of which died. When the Klebsiella cells were cultured in vitro, ``the bacteria grew equally well in 37șC and 39.5șC cultures,'' says coauthor Jeffrey Hasday. ``This suggests that the improved survival in the warmer mice was caused by effects on host defenses rather than on the bacteria.'' The researchers speculate that fever may enhance an antimicrobial effector.
(Q. Jiang, A. S. Cross, I. S. Singh, T. T. Chen, R. M. Viscardi, and J. D. Hasday. 2000. Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect. Immun. 68:1265-1270.) Abstract | Full Text
Biopesticide May Contribute to Vancomycin Resistance
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| Patel |
Paenibacillus popilliae has been used as a biopesticide for more than five decades, but researchers at the Mayo Clinic in Rochester, Minn., and the Virginia Polytechnic Institute, Blacksburg, caution that it may contribute to the spread of vancomycin resistance.
The team found a vancomycin resistance gene cluster in P. popilliae in which the spatial arrangement of the genes suggests a common ancestry with resistance genes in vancomycin-resistant enterococci (VRE). ``This group of genes is more similar [to those in VRE] than the gene clusters found in glycopeptide-producing organisms that have been postulated as the original source of these genes,'' says lead author Robin Patel. ``We can't say [the P. popillae cluster] is the direct source of vancomycin resistance in human enterococci,'' she adds, but says the team's findings do suggest that continued use of the biopesticide may not be prudent.
(R. Patel, K. Piper, F. R. Cockerill III, J. M. Steckelberg, and A. A. Yousten. 2000. The biopesticide Paenibacillus popilliae has a vancomycin resistance gene cluster homologous to the enterococcal VanA vancomycin resistance gene cluster. Antimicrob. Agents Chemother. 44:705-709.) Abstract | Full Text
Single Neonatal DNA Vaccination Achieves Long-Lasting Immunity
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| L-R: Whitton, Zhang, Slifka, Hassett |
Scientists at the Scripps Research Institute of La Jolla, Calif., have elicited protective immunity via a single DNA plasmid inoculation in newborn mice that proved effective even a full year after vaccination. Moreover, the researchers were able to detect long-lived, viral-specific immune responses directly ex vivo without any secondary stimulation.
The quality of the DNA-generated immune responses proved comparable to those elicited by conventional vaccine, coauthor Lindsay Whitton says. ``The T cells induced by DNA vaccination are similar in several functional attributes to those induced by live-virus vaccination.'' The DNA vaccine lagged only in the quantity of virus-specific T cells elicited, which was 10- to 40-fold lower than the number generated by live virus in adult mice. However, Whitton added, to achieve 1 in 100 CD8+ cells specific for the virus a year after a single inoculation was ``pretty impressive.''
(D. E. Hassett, J. Zhang, M. Slifka, and J. L. Whitton. 2000. Immune responses following neonatal DNA vaccination are long-lived, abundant, and qualitatively similar to those induced by conventional immunization. J. Virol. 74:2620-2627.) Abstract | Full Text
Possible Role for MsrA in Infective Endocarditis
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| Vriesema |
As oral streptococci are important agents of infective endocarditis (IE), they must be able to adapt to different environmental circumstances, including the increase in pH that they encounter upon moving from the mouth to the neutral conditions of the bloodstream. Researchers at the Academic Medical Center in Amsterdam, the Netherlands, have determined that this pH shift activates expression of the msrA gene, which may play a crucial role in facilitating IE.
Previously, an msrA promoter was found to be activated in a rabbit model of IE, lead author Aldwin Vriesema notes. ``In addition to this finding, we have now shown that an increase in pH might be a stimulus for the induction of this gene,'' he says. ``As MsrA is involved in protection against oxidative stressactivation of this gene might contribute to bacterial survival in the bloodstream or at the heart valves and thus to the development of IE.'' In addition, the researchers determined that MsrA is essential for optimal bacterial growth, a key virulence trait and possibly another crucial element in the development of IE.
(A. J. M. Vriesema, J. Dankert, and S. A. J. Zaat. 2000. A shift from oral to blood pH is a stimulus for adaptive gene expression of Streptococcus gordonii CH1 and induces protection against oxidative stress and enhanced bacterial growth by expression of msrA. Infect. Immun. 68:1061-1068.) Abstract | Full Text
Pyrazinamide Resistance Does Not Reduce M. tuberculosis Virulence
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| Zhang |
A research team bolstering conclusions that mutations in the Mycobacterium tuberculosis pncA gene are the major, if not sole, mechanism of resistance to the drug pyrazinamide (PZA) has found several PZA-monoresistant stains in Quebec whose fitness does not appear to be attenuated.
PZA-monoresistant strains are rare since the drug is used in combination, notes coauthor Ying Zhang of Johns Hopkins University, Baltimore, Md. Usually when bacteria acquire drug resistance, they lose some fitness and therefore some virulence, he says. ``Although these strains lost the pyrazinamide enzyme [coded for by pncA], their ability to cause disease was not reduced. This was somewhat surprising.''
Confirming the paramount role of pncA in PZA resistance could lead to better PZA susceptibility testing, which are currently subject to false resistance detection, Zhang adds.
(S.-J. Cheng, L. Thibert, T. Sanchez, L. Heifets, and Y. Zhang. 2000. pncA mutations as a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis: spread of a monoresistant strain in Quebec, Canada. Antimicrob. Agents Chemother. 44:528-532.) Abstract | Full Text
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