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ABSTRACT: Group A streptococci (GAS) may engage different sets of virulence strategies, depending on the site of infection and host context. We previously isolated 2 phenotypic variants of a globally disseminated M1T1 GAS clone: a virulent wild-type (WT) strain, characterized by a SpeB(+)/SpeA(-)/Sda1(low) phenotype, and a hypervirulent animal-passaged (AP) strain, better adapted to survive in vivo, with a SpeB(-)/SpeA(+)/Sda1(high) phenotype. This AP strain arises in vivo due to the selection of bacteria with mutations in covS, the sensor part of a key 2-component regulatory system, CovR/S. To determine whether covS mutations explain the hypervirulence of the AP strain, we deleted covS from WT bacteria (DeltaCovS) and were able to simulate the hypervirulence and gene expression phenotype of naturally selected AP bacteria. Correction of the covS mutation in AP bacteria reverted them back to the WT phenotype. Our data confirm that covS plays a direct role in regulating GAS virulence.
The Journal of Infectious Diseases 02/2010; 201(6):855-65. · 6.41 Impact Factor
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BMC Bioinformatics. 01/2010;
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Adrianus C M Boon,
Jennifer deBeauchamp,
Anna Hollmann,
Jennifer Luke,
Malak Kotb, Sarah Rowe,
David Finkelstein,
Geoffrey Neale,
Lu Lu,
Robert W Williams,
Richard J Webby
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ABSTRACT: Despite the prevalence of H5N1 influenza viruses in global avian populations, comparatively few cases have been diagnosed in humans. Although viral factors almost certainly play a role in limiting human infection and disease, host genetics most likely contribute substantially. To model host factors in the context of influenza virus infection, we determined the lethal dose of a highly pathogenic H5N1 virus (A/Hong Kong/213/03) in C57BL/6J and DBA/2J mice and identified genetic elements associated with survival after infection. The lethal dose in these hosts varied by 4 logs and was associated with differences in replication kinetics and increased production of proinflammatory cytokines CCL2 and tumor necrosis factor alpha in susceptible DBA/2J mice. Gene mapping with recombinant inbred BXD strains revealed five loci or Qivr (quantitative trait loci for influenza virus resistance) located on chromosomes 2, 7, 11, 15, and 17 associated with resistance to H5N1 virus. In conjunction with gene expression profiling, we identified a number of candidate susceptibility genes. One of the validated genes, the hemolytic complement gene, affected virus titer 7 days after infection. We conclude that H5N1 influenza virus-induced pathology is affected by a complex and multigenic host component.
Journal of Virology 09/2009; 83(20):10417-26. · 5.40 Impact Factor
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ABSTRACT: We exploited the fact that leukemic cells utilize significantly higher levels of S-adenosylmethionine (SAMe) than normal lymphocytes and developed tools that selectively diminished their survival under physiologic conditions. Using RNA interference gene silencing technology, we modulated the kinetics of methionine adenosyltransferase-II (MAT-II), which catalyzes SAMe synthesis from ATP and l-Met. Specifically, we silenced the expression of the regulatory MAT-IIbeta subunit in Jurkat cells and accordingly shifted the K(m L-Met) of the enzyme 10-15-fold above the physiologic levels of l-Met, thereby reducing enzyme activity and SAMe pools, inducing excessive apoptosis and diminishing leukemic cell growth in vitro and in vivo. These effects were reversed at unphysiologically high l-Met (>50 microm), indicating that diminished leukemic cell growth at physiologic l-Met levels was a direct result of the increase in MAT-II K(m L-Met) due to MAT-IIbeta ablation and the consequent reduction in SAMe synthesis. In our NOD/Scid IL-2Rgamma(null) humanized mouse model of leukemia, control shRNA-transduced Jurkat cells exhibited heightened engraftment, whereas cells lacking MAT-IIbeta failed to engraft for up to 5 weeks post-transplant. These stark differences in malignant cell survival, effected by MAT-IIbeta ablation, suggest that it may be possible to use this approach to disadvantage leukemic cell survival in vivo with little to no harm to normal cells.
Journal of Biological Chemistry 09/2008; 283(45):30788-95. · 4.77 Impact Factor
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ABSTRACT: Like most human diseases, infectious diseases are effected by complex genetic traits and multiple, interactive environmental and inherent host factors. By linking specific genotypes to disease susceptibility phenotypes we can identify the genetic basis for inter-individual differences in disease susceptibility as well as gain insight into how gene-environment interactions influence infection outcomes. Our research has focused on delineating interactive pathways and molecular events modulating host resistance or susceptibility to specific pathogens. Our model system has been that of Group A Streptococcus infections that can manifest in starkly different ways and cause distinct diseases in genetically distinct individuals. We have extended our work to other pathogens, including those with a potential of causing major, global biological threats. In as much as it is quite difficult to conduct certain infectious disease studies in humans, there has been a critical need for small animal models for infectious diseases. Appreciating the limitations of existing models, we developed several novel and complementary mouse models that are ideal for use in systems genetics studies of complex diseases. These models not only allow biological validation of known genetic associations, but importantly they afford an unbiased tool for discovering novel genes and pathways contributing to disease outcomes, under different environments.
Novartis Foundation symposium 02/2008; 293:156-65; discussion 165-7, 181-3.
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Nourtan Abdeltawab,
Rita Kansal, Sarah Rowe,
Lidia Gardner,
Charity Brannen,
Mohammed Nooh,
Santhosh Mukundan,
Hossam Abdelsamed,
Ramy Attia,
William Taylor,
Lu Lu,
Robert Williams,
Malak Kotb
BMC Bioinformatics. 01/2008;
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12/2007: pages 13-17;
