Neurotropic Threat Characterization of Burkholderia pseudomallei Strains - Volume 21, Number 1—January 2015 - Emerging Infectious Disease journal - CDC

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Neurotropic Threat Characterization of Burkholderia pseudomallei Strains - Volume 21, Number 1—January 2015 - Emerging Infectious Disease journal - CDC

Volume 21, Number 1—January 2015

Research

Neurotropic Threat Characterization of Burkholderia pseudomallei Strains

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• Results
• Discussion
• Suggested Citation

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• Figure 1
• Figure 2

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• Table 1
• Table 2

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Jodie Morris , Anne Fane, Catherine Rush, Brenda Govan, Mark Mayo, Bart J. Currie, and Natkunam Ketheesan

Author affiliations: James Cook University, Townsville, Queensland, Australia (J. Morris, A. Fane, C. Rush, B. Govan, N. Ketheesan); Menzies School of Health Research, Darwin, Northern Territory, Australia (M. Mayo, B.J. Currie); Royal Darwin Hospital, Darwin (B.J. Currie)

Suggested citation for this article

Abstract

The death rate for neurologic melioidosis is high. Whether certain Burkholderia pseudomallei strains are more likely than other strains to cause central nervous system infection and whether route of infection influences the neurotropic threat remain unclear. Therefore, we compared the virulence and dissemination of Australian clinical isolates collected during October 1989–October 2012 from patients with neurologic and nonneurologic melioidosis after intranasal and subcutaneous infection of mice in an experimental model. We did not observe neurotropism as a unique characteristic of isolates from patients with neurologic melioidosis. Rather, a distinct subset of B. pseudomallei strains appear to have heightened pathogenic potential for rapid dissemination to multiple tissues, including the central nervous system, irrespective of the infection route. This finding has valuable public health ramifications for initiating appropriate and timely therapy after exposure to systemically invasive B. pseudomallei strains. Increasing understanding of B. pseudomallei pathology and its influencing factors will further reduce illness and death from this disease.

Melioidosis is caused by the gram-negative bacterium Burkholderia pseudomallei. It incorporates a wide spectrum of clinical disease that ranges from severe, rapidly fatal, invasive disease to asymptomatic latent infection; thus, diagnosis is immensely challenging (1). No vaccine against melioidosis is currently available. The ability of B. pseudomallei to cause severe, rapidly fatal, invasive infections and to persist in the environment for extended periods, plus its intrinsic resistance to many antibacterial drugs, make B. pseudomallei a desirable candidate for use as a bioterrorism agent (1). Furthermore, B. pseudomallei can invade host cells, including macrophages, neutrophils, and other cells of the immune system, and persist within them (2,3). Without appropriate drug therapy, the death rate for melioidosis can exceed 90% (4,5).

Neurologic abnormalities occur in 3%–5% of melioidosis cases, and more than one quarter of those are fatal (5–8). Many similarities have been described regarding the clinical features of neurologic melioidosis in naturally infected animals and humans and in animal models infected with B. pseudomallei(6,9–15). Cranial nerve palsies and unilateral limb weakness are frequently described in patients with neurologic melioidosis (6,7,9,13,14). Flaccid paraparesis, commonly documented in animals with B. pseudomallei infection, also has been reported in humans (6,10,15). Often, microscopic and macroscopic abscesses are evident, and a predilection of B. pseudomallei for the brainstem and spinal cord has been suggested (9,12–14).

In contrast to patients with other forms of melioidosis, those with melioidosis with central nervous system (CNS) involvement are less likely to have predisposing risk factors, such as diabetes and chronic lung disease (6,8,9). Relatively little is known about the potential for different B. pseudomalleistrains to cause severe disease, including whether particular strains are more likely to cause neurologic sequelae or whether CNS involvement is a consequence of the mode of delivery of B. pseudomallei. Neurologic melioidosis can result from direct invasion or through hematogenous spread (3,6,11,16,17). Initial suggestions that neurologic melioidosis might result from damage from immune or toxin-mediated mechanisms (6,12) has been supplanted by the recognition that direct invasion of brain and spinal cord by bacteria is evident on histologic examination of samples from case-patients who died (16). Furthermore, direct invasion of the brain by B. pseudomallei was recently demonstrated in an experimental model of melioidosis meningitis after delivery of intracellular bacteria by CNS-infiltrating CD11b+ immune cells (3).

Given the high rate of death from neurologic melioidosis, interest is increasing in improving understanding of its pathogenesis, particularly the potential for different B. pseudomallei isolates to cause neurologic melioidosis and the influence of the route of transmission on entry into and dissemination within the CNS. Therefore, using a well-characterized animal model of melioidosis (18) and clinical isolates of B. pseudomallei collected in the Northern Territory, Australia, during October 1989–October 2012 (7), we sought to determine whether strains isolated from patients with neurologic melioidosis (neurologic isolates) showed higher virulence levels and neurotropism than isolates from patients with nonneurologic melioidosis (nonneurologic isolates) after respiratory and percutaneous exposure.

Dr Morris is a postdoctoral researcher in the Australian Institute of Tropical Health and Medicine. Her research interests include the immunopathogenesis of B. pseudomallei infection.

Acknowledgments

We thank Christopher Davis and Ifor Beacham for their helpful discussions and contribution to the work described in this article.

This research was financially supported in part by the Commonwealth of Australia through the National Security Science and Technology Centre within the Defence Science and Technology Organisation and the US Department of Homeland Security. This support does not represent an endorsement of the contents or conclusions of the research. The authors have no financial interests in the results of this study.

References

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14. Howe PW, Holland HM, Burrow JCN, Currie BJ. Neurological melioidosis (Burkholderia pseudomallei) mimicking Guillain-Barré syndrome. Anaesth Intensive Care. 1997;25:166–7 .PubMed
15. Haran MJ, Jenney AW, Keenan RJ, Flavell HD, Anstey NM, Currie BJ. Paraplegia secondary to Burkholderia pseudomallei myelitis: a case report.Arch Phys Med Rehabil. 2001;82:1630–2. DOIPubMed
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Figures

• Figure 1. Comparison of survival after intranasal and subcutaneous infection of BALB/c mice with equivalent doses of the neurologic Burkholderia pseudomallei isolates MSHR435 (5 × 102 CFU) (A) and MSHR1153 (4.5...
• Figure 2. Comparison of Burkholderia pseudomallei loads in organs of BALB/c mice at days 1 (A, B), 3 (C, D) and 7 (E, F) after intranasal (white bars) and subcutaneous (black...

Tables

• Table 1. Clinical features of Burkholderia pseudomallei strains isolated from patients with neurologic and nonneurologic melioidosis and their virulence in C57BL/6 and BALB/c mice, Northern Territory, Australia, October 1989–October 2012
• Table 2. Development of signs of neurologic involvement in C57BL/6 mice after intranasal infection with Burkholderia pseudomallei strains isolated from patients with neurologic and non-neurologic melioidosis, Northern Territory, Australia, October 1989–October 2012

Suggested citation for this article: Morris J, Fane A, Rush C, Govan B, Mayo M, Currie et al. Neurotropic threat characterization of Burkholderia pseudomallei strains. Emerg Infect Dis [Internet]. 2015 Jan [date cited]. http://dx.doi.org/10.3201/eid2101.131570

DOI: 10.3201/eid2101.131570