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Updated: Mar 12, 2026
Total Protein Extraction and 2-D Gel Electrophoresis Methods for Burkholderia Species
Published on: October 15, 2013
pH Alkalinization by Chloroquine Suppresses Pathogenic Burkholderia Type 6 Secretion System 1 and Multinucleated
Jennifer Chua1, Jeffrey L Senft2, Stephen J Lockett3
1Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA Jennifer.Chua.ctr@mail.mil Arthur.M.Friedlander.civ@mail.mil.
Abstract:
Burkholderia mallei and B. pseudomallei cause glanders and melioidosis, respectively, in humans and animals. A hallmark of pathogenesis is the formation of granulomas containing multinucleated giant cells (MNGCs) and cell death. These processes depend on type 6 secretion system 1 (T6SS-1), which is required for virulence in animals. We examined the cell biology of MNGC formation and cell death. We found that chloroquine diphosphate (CLQ), an antimalarial drug, inhibits Burkholderia growth, phagosomal escape, and subsequent MNGC formation. This depends on CLQ's ability to neutralize the acid pH because other alkalinizing compounds similarly inhibit escape and MNGC formation. CLQ inhibits bacterial virulence protein expression because T6SS-1 and some effectors of type 3 secretion system 3 (T3SS-3), which is also required for virulence, are expressed at acid pH. We show that acid pH upregulates the expression of Hcp1 of T6SS-1 and TssM, a protein coregulated with T6SS-1. Finally, we demonstrate that CLQ treatment of Burkholderia-infected Madagascar hissing cockroaches (HCs) increases their survival. This study highlights the multiple mechanisms by which CLQ inhibits growth and virulence and suggests that CLQ be further tested and considered, in conjunction with antibiotic use, for the treatment of diseases caused by Burkholderia.
Insights
Chloroquine diphosphate (CLQ) inhibits Burkholderia growth and virulence by neutralizing acidic environments essential for bacterial escape and protein expression. CLQ enhances survival in infected Madagascar hissing cockroaches, suggesting its potential as a therapeutic agent.
Area of Science:
- Microbiology
- Pathogenesis
- Drug Discovery
Background:
- * Burkholderia mallei and B. pseudomallei cause glanders and melioidosis, respectively.
- * Pathogenesis involves granuloma formation with multinucleated giant cells (MNGCs) and cell death, dependent on type 6 secretion system 1 (T6SS-1).
Purpose of the Study:
- * To investigate the cell biology of MNGC formation and cell death in Burkholderia infections.
- * To evaluate the effect of chloroquine diphosphate (CLQ) on Burkholderia growth, virulence, and host survival.
Main Methods:
- * Assessed the impact of CLQ and other alkalinizing compounds on bacterial growth, phagosomal escape, and MNGC formation.
- * Analyzed the expression of virulence factors, including T6SS-1 and type 3 secretion system 3 (T3SS-3) effectors, under varying pH conditions.
- * Evaluated CLQ's efficacy in a Madagascar hissing cockroach model of Burkholderia infection.
Main Results:
- * CLQ inhibits Burkholderia growth, phagosomal escape, and MNGC formation by neutralizing acidic pH.
- * CLQ suppresses the expression of T6SS-1 and T3SS-3 virulence proteins, which are upregulated at acidic pH.
- * CLQ treatment significantly increases survival rates in infected Madagascar hissing cockroaches.
Conclusions:
- * CLQ exhibits multifaceted inhibition of Burkholderia virulence through pH neutralization and suppression of key secretion systems.
- * CLQ demonstrates potential as an adjunctive therapy for glanders and melioidosis, warranting further clinical investigation.
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