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      Increased Neurotropic Threat from Burkholderia pseudomallei Strains with a B. mallei–like Variation in the bimA Motility Gene, Australia

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          Abstract

          These strains have heightened pathogenic potential for rapid dissemination to multiple tissues, including the central nervous system.

          Abstract

          Neurologic melioidosis is a serious, potentially fatal form of Burkholderia pseudomallei infection. Recently, we reported that a subset of clinical isolates of B. pseudomallei from Australia have heightened virulence and potential for dissemination to the central nervous system. In this study, we demonstrate that this subset has a B. mallei–like sequence variation of the actin-based motility gene, bimA. Compared with B. pseudomallei isolates having typical bimA alleles, isolates that contain the B. mallei–like variation demonstrate increased persistence in phagocytic cells and increased virulence with rapid systemic dissemination and replication within multiple tissues, including the brain and spinal cord, in an experimental model. These findings highlight the implications of bimA variation on disease progression of B. pseudomallei infection and have considerable clinical and public health implications with respect to the degree of neurotropic threat posed to human health.

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          Most cited references32

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          Type VI secretion is a major virulence determinant in Burkholderia mallei.

          Burkholderia mallei is a host-adapted pathogen and a category B biothreat agent. Although the B. mallei VirAG two-component regulatory system is required for virulence in hamsters, the virulence genes it regulates are unknown. Here we show with expression profiling that overexpression of virAG resulted in transcriptional activation of approximately 60 genes, including some involved in capsule production, actin-based intracellular motility, and type VI secretion (T6S). The 15 genes encoding the major sugar component of the homopolymeric capsule were up-expressed > 2.5-fold, but capsule was still produced in the absence of virAG. Actin tail formation required virAG as well as bimB, bimC and bimE, three previously uncharacterized genes that were activated four- to 15-fold when VirAG was overproduced. Surprisingly, actin polymerization was found to be dispensable for virulence in hamsters. In contrast, genes encoding a T6S system were up-expressed as much as 30-fold and mutations in this T6S gene cluster resulted in strains that were avirulent in hamsters. SDS-PAGE and mass spectrometry demonstrated that BMAA0742 was secreted by the T6S system when virAG was overexpressed. Purified His-tagged BMAA0742 was recognized by glanders antiserum from a horse, a human and mice, indicating that this Hcp-family protein is produced in vivo during infection.
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            Is Open Access

            Variable Virulence Factors in Burkholderia pseudomallei (Melioidosis) Associated with Human Disease

            Burkholderia pseudomallei is a Gram-negative environmental bacterium that causes melioidosis, a potentially life-threatening infectious disease affecting mammals, including humans. Melioidosis symptoms are both protean and diverse, ranging from mild, localized skin infections to more severe and often fatal presentations including pneumonia, septic shock with multiple internal abscesses and occasionally neurological involvement. Several ubiquitous virulence determinants in B. pseudomallei have already been discovered. However, the molecular basis for differential pathogenesis has, until now, remained elusive. Using clinical data from 556 Australian melioidosis cases spanning more than 20 years, we identified a Burkholderia mallei-like actin polymerization bimA Bm gene that is strongly associated with neurological disease. We also report that a filamentous hemagglutinin gene, fhaB3, is associated with positive blood cultures but is negatively correlated with localized skin lesions without sepsis. We show, for the first time, that variably present virulence factors play an important role in the pathogenesis of melioidosis. Collectively, our study provides a framework for assessing other non-ubiquitous bacterial virulence factors and their association with disease, such as candidate loci identified from large-scale microbial genome-wide association studies.
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              Actin-dependent movement of bacterial pathogens.

              Listeria, Rickettsia, Burkholderia, Shigella and Mycobacterium species subvert cellular actin dynamics to facilitate their movement within the host cytosol and to infect neighbouring cells while evading host immune surveillance and promoting their intracellular survival. 'Attaching and effacing' Escherichia coli do not enter host cells but attach intimately to the cell surface, inducing motile actin-rich pedestals, the function of which is currently unclear. The molecular basis of actin-based motility of these bacterial pathogens reveals novel insights about bacterial pathogenesis and fundamental host-cell pathways.
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                Author and article information

                Journal
                Emerg Infect Dis
                Emerging Infect. Dis
                EID
                Emerging Infectious Diseases
                Centers for Disease Control and Prevention
                1080-6040
                1080-6059
                May 2017
                : 23
                : 5
                : 740-749
                Affiliations
                [1]James Cook University, Townsville, Queensland, Australia (J.L. Morris, A. Fane, C.M. Rush, B.L. Govan, E. Parker, N. Ketheesan);
                [2]Menzies School of Health Research, Darwin, Northern Territory, Australia (D.S. Sarovich, E.P. Price, M. Mayo, B.J. Currie);
                [3]Royal Darwin Hospital, Darwin (B.J. Currie)
                Author notes
                Address for correspondence: Jodie L. Morris, James Cook University, Australian Institute of Tropical Health and Medicine, DB094-206, Solander Dr, Townsville, QLD 4811, Australia; email: jodie.morris1@ 123456jcu.edu.au
                Article
                15-1417
                10.3201/eid2305.151417
                5403032
                28418830
                9c132f6f-a953-46c7-8cd9-e3f30cdf1dc2
                History
                Categories
                Research
                Research
                Increased Neurotropic Threat from Burkholderia pseudomallei Strains with a B. mallei–like Variation in the bimA Motility Gene, Australia

                Infectious disease & Microbiology
                melioidosis,burkholderia pseudomallei,virulence,neurologic,neurotropism,route of infection,actin-based motility,intracellular,bima,bacteria,bacterial infection

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