Dataset Information

Targeting imperfect vaccines against drug-resistance determinants: a strategy for countering the rise of drug resistance.

ABSTRACT: The growing prevalence of antimicrobial resistance in major pathogens is outpacing discovery of new antimicrobial classes. Vaccines mitigate the effect of antimicrobial resistance by reducing the need for treatment, but vaccines for many drug-resistant pathogens remain undiscovered or have limited efficacy, in part because some vaccines selectively favor pathogen strains that escape vaccine-induced immunity. A strain with even a modest advantage in vaccinated hosts can have high fitness in a population with high vaccine coverage, which can offset a strong selection pressure such as antimicrobial use that occurs in a small fraction of hosts. We propose a strategy to target vaccines against drug-resistant pathogens, by using resistance-conferring proteins as antigens in multicomponent vaccines. Resistance determinants may be weakly immunogenic, offering only modest specific protection against resistant strains. Therefore, we assess here how varying the specific efficacy of the vaccine against resistant strains would affect the proportion of drug-resistant vs. -sensitive strains population-wide for three pathogens--Streptococcus pneumoniae, Staphylococcus aureus, and influenza virus--in which drug resistance is a problem. Notably, if such vaccines confer even slightly higher protection (additional efficacy between 1% and 8%) against resistant variants than sensitive ones, they may be an effective tool in controlling the rise of resistant strains, given current levels of use for many antimicrobial agents. We show that the population-wide impact of such vaccines depends on the additional effect on resistant strains and on the overall effect (against all strains). Resistance-conferring accessory gene products or resistant alleles of essential genes could be valuable as components of vaccines even if their specific protective effect is weak.

SUBMITTER: Joice R

PROVIDER: S-EPMC3723804 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting imperfect vaccines against drug-resistance determinants: a strategy for countering the rise of drug resistance.

Joice Regina R Lipsitch Marc M

PloS one 20130725 7

The growing prevalence of antimicrobial resistance in major pathogens is outpacing discovery of new antimicrobial classes. Vaccines mitigate the effect of antimicrobial resistance by reducing the need for treatment, but vaccines for many drug-resistant pathogens remain undiscovered or have limited efficacy, in part because some vaccines selectively favor pathogen strains that escape vaccine-induced immunity. A strain with even a modest advantage in vaccinated hosts can have high fitness in a pop ...[more]

PMID: 23935910

Similar Datasets

Project description:Hypoxia is a predominant feature in glioblastoma (GBM) and contributes greatly to its drug resistance. However, the molecular mechanisms which are responsible for the development of the resistant phenotype of GBM under hypoxic conditions remain unclear. To analyze the key pathways promoting therapy resistance in hypoxic GBM, we utilized the U87-MG cell line as a human GBM cell model and the human brain HEB cell line as a non-neoplastic brain cell model. These cell lines were cultured in the presence of 21, 5, and 1% O2 for 24 h. We detected the changes in transcriptional profiling and analyzed the biological processes and functional interactions for the genes with different expression levels under different hypoxia conditions. The results indicated that those alterations of U87-MG cells presented specific transcriptional signature in response to diverse hypoxia levels. Gene ontology analysis revealed that the genes related to the DNA replication and cell cycle were suppressed, while the genes involved in tissue and system development to promote cancer development were activated following hypoxia. Moreover, functional interaction analysis suggested that the epigenetic regulator HDAC3 and the transcriptional factors CEBPB and JUN played a central role in organ and system developmental process pathway. Previous studies reported the global alterations caused by activation of HDAC3, CEBPB, and JUN could form the molecular basis of the resistance to chemotherapy and radiation therapy of hypoxic GBM. In our study, the significant growth inhibitory effect of temozolomide on hypoxic GBM cells could be promoted under downregulation of these genes. The experiment suggested that HDAC3, CEBPB, and JUN were closely involved in the drug-resistance phenotype of hypoxic GBM. In summary, we profiled the hypoxia-dependent changes in the transcriptome of the U87-MG cell line and the human brain cell line HEB to identify the transcriptional signatures of U87-MG cells and elucidate the role of hypoxia in the drug-resistant phenotype of GBM. Furthermore, we identified three key genes and explored their important roles in the drug resistance of hypoxic GBM.

Dataset Information

Targeting imperfect vaccines against drug-resistance determinants: a strategy for countering the rise of drug resistance.

Publications

Targeting imperfect vaccines against drug-resistance determinants: a strategy for countering the rise of drug resistance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets