Melioidosis: insights into the pathogenicity of Burkholderia pseudomallei

Abstract

Burkholderia pseudomallei is a potential bioterror agent and the causative agent of melioidosis, a severe disease that is endemic in areas of Southeast Asia and Northern Australia. Infection is often associated with bacterial dissemination to distant sites, and there are many possible disease manifestations, with melioidosis septic shock being the most severe. Eradication of the organism following infection is difficult, with a slow fever-clearance time, the need for prolonged antibiotic therapy and a high rate of relapse if therapy is not completed. Mortality from melioidosis septic shock remains high despite appropriate antimicrobial therapy. Prevention of disease and a reduction in mortality and the rate of relapse are priority areas for future research efforts. Studying how the disease is acquired and the host–pathogen interactions involved will underpin these efforts; this review presents an overview of current knowledge in these areas, highlighting key topics for evaluation.

Key Points

  • Melioidosis is caused by the aerobic, Gram-negative soil-dwelling bacillus Burkholderia pseudomallei and is an important cause of severe sepsis in Southeast Asia and Northern Australia. The high associated mortality rate, wide availability in the environment in endemic areas, intrinsic resistance to many antibiotics and the potential for aerosol spread has made this organism a potential bioterror agent.

  • The genome of B. pseudomallei consists of a large chromosome (4.07 Mb) carrying genes mainly associated with cell growth and metabolism, and a smaller chromosome (3.17 Mb) which has a greater proportion of genes encoding accessory functions such as adaptation and survival in different environments. Approximately 6% of the genome is made up of genomic islands that have probably been acquired by horizontal gene transfer.

  • Factors associated with disease acquisition in endemic regions include adverse weather conditions, the route and size of the inoculum and the integrity of the host immune system. The geographical incidence of B. pseudomallei and typical clinical features of the disease are reviewed.

  • No single B. pseudomallei determinant has been shown to have a role in virulence during human disease, persistence or latency. However, putative virulence factors include quorum sensing, a type III secretion system, capsular polysaccharide and, with less conclusive evidence, lipopolysaccharide and flagella.

  • B. pseudomallei is an intracellular pathogen that multiplies within macrophages. Recent data have shed light on the mechanisms that this bacterium uses to adapt to, and exploit, the intracellular environment. IFN-γ and TNF-α have an important role in early resistance against B. pseudomallei infection. Although more is becoming known about the pathogenesis of this bacterium in disease, the host–pathogen interactions are still ill-defined.

  • Potential new therapies that warrant further clinical evaluation include granulocyte colony-stimulating factor and CpG (bacterial DNA). Development of an effective human melioidosis vaccine is a research priority.

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Figure 1: Selected clinical features of melioidosis, the 'great mimicker'.
Figure 2: Clinical isolates of Burkholderia pseudomallei.
Figure 3: The phylogeny of the Burkholderia genus.
Figure 4: The intracellular lifestyle of Burkholderia pseudomallei.
Figure 5: Host–pathogen interactions in Burkholderia pseudomallei infection: bacterial virulence meets innate immunity.

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Acknowledgements

We thank members of the Wellcome Trust–Oxford University–Mahidol University Tropical Medicine Research Programme for their support, in particular V. Wuthiekanun and W. Chierakul. We thank the staff of Sappasithiprasong Hospital for many years of fruitful collaboration; special thanks go to W. Chaowagul. W.J.W. is supported by the Dutch Foundation for Tropical Research (WOTRO). S.J.P. is supported by a Wellcome Trust Career Development Award in Clinical Tropical Medicine.

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Correspondence to W. Joost Wiersinga.

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DATABASES

Entrez Genome Project

Burkholderia mallei

Burkholderia pseudomallei

Burkholderia thailandensis

Escherichia coli

Ralstonia solanacearum

Salmonella enterica serovar Typhimurium

Shigella flexneri

FURTHER INFORMATION

Wellcome Trust South-East Asia Programme in Thailand

B. pseudomallei genome sequence

The Institute for Genomic Research (TIGR)

CDC list of bioterrorism agents

BICHAT, the European Commission's Task Force on biological and chemical threats

Glossary

Genomic islands

Clusters of genes that have been imported from unrelated bacterial taxa through horizontal gene transfer, and which might help the bacterium to acquire a new (possibly pathogenic) lifestyle.

Shotgun sequencing

A genomic sequencing strategy that involves random fragmentation of large DNA segments. The fragments are sequenced, and programs with highly refined algorithms are used to reassemble the original DNA sequence.

Multilocus sequence typing

(MLST). A method for the genotypic characterization of prokaryotes at the infraspecific level, using the allelic mismatches of a small number of housekeeping genes. Designed as a tool in molecular epidemiology and used for recognizing distinct strains within named species.

Subtractive hybridization

A technique used to identify differentially expressed genes. The DNA species present in one sample are specifically enriched by hybridization with nucleic acids from another sample and by removing the associated double-stranded molecules.

Quorum sensing

A system by which bacteria communicate. Signalling molecules — chemicals similar to pheromones that are produced by an individual bacterium — can affect the behaviour of surrounding bacteria.

Complement

A part of the innate immune system comprising serum proteins that can protect against infection.

Limulus amoebocytelysate assay

A chromogenic assay used to monitor endotoxin production.

Natural killer (NK) cells

Lymphocytes that do not express the T-cell receptor or B-cell receptor and that mediate natural killing against prototypical NK-cell-sensitive targets.

Human leukocyte antigen

(HLA). Also known as major histocompatibility complex (MHC), a glycoprotein that is found on the surface of antigen-presenting cells that presents antigen for recognition by TH cells.

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