Research Article: Sequence- and Structure-Based Immunoreactive Epitope Discovery for Burkholderia pseudomallei Flagellin

Date Published: July 29, 2015

Publisher: Public Library of Science

Author(s): Arnone Nithichanon, Darawan Rinchai, Alessandro Gori, Patricia Lassaux, Claudio Peri, Oscar Conchillio-Solé, Mario Ferrer-Navarro, Louise J. Gourlay, Marco Nardini, Jordi Vila, Xavier Daura, Giorgio Colombo, Martino Bolognesi, Ganjana Lertmemonkolchai, Bart J Currie.

Abstract: Burkholderia pseudomallei is a Gram-negative bacterium responsible for melioidosis, a serious and often fatal infectious disease that is poorly controlled by existing treatments. Due to its inherent resistance to the major antibiotic classes and its facultative intracellular pathogenicity, an effective vaccine would be extremely desirable, along with appropriate prevention and therapeutic management. One of the main subunit vaccine candidates is flagellin of Burkholderia pseudomallei (FliCBp). Here, we present the high resolution crystal structure of FliCBp and report the synthesis and characterization of three peptides predicted to be both B and T cell FliCBp epitopes, by both structure-based in silico methods, and sequence-based epitope prediction tools. All three epitopes were shown to be immunoreactive against human IgG antibodies and to elicit cytokine production from human peripheral blood mononuclear cells. Furthermore, two of the peptides (F51-69 and F270-288) were found to be dominant immunoreactive epitopes, and their antibodies enhanced the bactericidal activities of purified human neutrophils. The epitopes derived from this study may represent potential melioidosis vaccine components.

Partial Text: Burkholderia pseudomallei, a pathogenic Gram-negative bacterium present in soil and water, is responsible for melioidosis, an often fatal infectious disease that is most frequently reported in tropical regions of the world, especially in Thailand and northern Australia, where the disease is endemic [1]. Diagnosis and treatment of melioidosis are far from adequate, as symptoms lack a specific signature necessary for rapid diagnosis, and the bacterium is inherently resistant to many commercially available classes of antibiotics. In addition, due to the intrinsically polymorphic nature of the pathogen, infections can occur in acute and chronic forms, with a plethora of different clinical manifestations [2]. Over the last few years, the study of melioidosis has become increasingly relevant, not only as a public health concern, but also due to bioterrorism implications, since B. pseudomallei is classified as a category B infective agent.

In the melioidosis vaccine development field, several protein antigens have been tested for their ability to trigger a protective immune response in animal models of disease, however, protection has proven to be limited in all cases [7]. In addition to the adaptive immune response, innate immunity also plays an important role in resistance to B. pseudomallei infection [3,56]. Neutrophils are one of the key players in cellular immunity that stimulate bacterial killing, both directly or indirectly via cytokine production [57,58]. Therefore, it is likely that a future melioidosis vaccine should comprise antigens/epitopes that trigger both arms of the immune system.



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