Melioidosis: molecular aspects of pathogenesis

Abstract

Burkholderia pseudomallei is a gram-negative bacterium that causes melioidosis, a multifaceted disease that is highly endemic in southeast Asia and northern Australia. This facultative intracellular pathogen possesses a large genome that encodes a wide array of virulence factors that promote survival in vivo by manipulating host cell processes and disarming elements of the host immune system. Antigens and systems that play key roles in B. pseudomallei virulence include capsular polysaccharide, lipopolysaccharide, adhesins, specialized secretion systems, actin-based motility and various secreted factors. This review provides an overview of the current and steadily expanding knowledge regarding the molecular mechanisms used by this organism to survive within a host and their contribution to the pathogenesis of melioidosis.

Keywords::

• Burkholderia pseudomallei
• capsule
• facultative intracellular pathogen
• lipopolysaccharide
• melioidosis
• pathogenesis
• secretion systems
• virulence factors

Financial & competing interests disclosure

The authors are funded by the NIH-National Institute of Allergy and Infectious Diseases and DOD-Defense Threat Reduction Agency. MN Burtnick and PJ Brett declare NIH-NIAID award numbers AI065359 and AIO91783. D Deshazer declares DTRA/JSTO-CBD proposal number CBCALL12-LSI-2-0070. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Melioidosis is an emerging infectious disease that can be difficult to treat due to the intrinsic resistance of Burkholderia pseudomallei to many commonly used antibiotics.

• Diagnosis of melioidosis can be challenging and no vaccines are currently available for prevention of B. pseudomallei infections.

• The complex intracellular lifestyle of B. pseudomallei involves numerous factors and is only beginning to be understood at a molecular level.

• B. pseudomallei expresses several major virulence determinants that are required for survival of the organism in animal models of melioidosis.

• Surface polysaccharides (capsular polysaccharide and lipopolysaccharide) are important for evasion of host innate immune defenses, are protective antigens and represent promising vaccine candidates.

• Adherence of B. pseudomallei to host cells is multifactorial and the contribution of various autotransporter proteins in this process is only beginning to be explored.

• Virulence-associated type III and type VI secretion systems play major roles in the intracellular behavior of B. pseudomallei. Research aimed at determining how these systems function at a molecular level and how they are regulated will provide important insights into the pathogenesis of melioidosis.

• The mechanistic details regarding intracellular actin-based motility and B. pseudomallei-induced multinucleated giant cell formation are poorly understood; the role of multinucleated giant cells in disease is unclear.

• A better understanding of the molecular mechanisms underlying B. pseudomallei pathogenesis may lead to the identification of new therapeutic targets, diagnostic antigens and vaccine candidates.