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Melioidosis: Review Article
Melioidosis: Review Article
review article
Medical Progress
Melioidosis
W. Joost Wiersinga, M.D., Ph.D., Bart J. Currie, F.R.A.C.P.,
and Sharon J. Peacock, Ph.D.
M
elioidosis, caused by the environmental gram-negative bacil- From the Department of Medicine, Divi-
lus Burkholderia pseudomallei, is classically characterized by pneumonia and sion of Infectious Diseases, and the
Center for Experimental and Molecular
multiple abscesses, with a mortality rate of up to 40%. It is an important Medicine, Academic Medical Center, Am-
cause of community-acquired sepsis in Southeast Asia and northern Australia. Its sterdam (W.J.W.); the Infectious Diseases
known global distribution is expanding, a reflection of improvements in diagnostic Department and Northern Territory Medi-
cal Program, Royal Darwin Hospital, and
microbiology and increasing numbers of cases in travelers and returning military the Global and Tropical Health Division,
personnel (Fig. 1).1,2 A locally acquired case of melioidosis was recently described in Menzies School of Health Research, Dar-
the United States.3 B. pseudomallei has been classified by the Centers for Disease Con- win, NT, Australia (B.J.C.); the Faculty of
Tropical Medicine, Mahidol University,
trol and Prevention as a category B bioterrorism agent, resulting in increased research Bangkok, Thailand (S.J.P.); and the De-
and understanding of melioidosis. This review considers recent developments in partment of Medicine, University of
pathogenesis, diagnostics, and treatment. Cambridge, Addenbrooke’s Hospital,
Cambridge, United Kingdom (S.J.P.). Ad-
dress reprint requests to Dr. Wiersinga at
THE B AC TER IUM the Department of Medicine, Division of
Infectious Diseases, Academic Medical
Center, Meibergdreef 9, Rm. G2-132, 1105
B. pseudomallei belongs to the burkholderia genus, which contains over 40 species. AZ Amsterdam, the Netherlands, or at
Other pathogenic members include B. mallei, which causes glanders in horses and w.j.wiersinga@amc.uva.nl.
other solipeds and is highly virulent in humans, and B. cenocepacia, which is an im- N Engl J Med 2012;367:1035-44.
portant cause of opportunistic infection in patients with cystic fibrosis. The genus DOI: 10.1056/NEJMra1204699
also includes B. thailandensis, which coexists with B. pseudomallei in the soil in Thai- Copyright © 2012 Massachusetts Medical Society.
land and Australia, and B. oklahomensis, which is sporadically found in the midwest-
ern United States; these two species rarely, if ever, cause disease and are much less
virulent (by a factor of >100,000) than B. pseudomallei in hamsters and mice.3,4
Endemic disease
08/11/12
B. pseudomallei and prevent bacterial escape from and enable the bacteriumAuthor to move
Wiersingainside the cell,
endocytic vacuoles.7 The B. pseudomallei genome with the subsequent formation
Fig #
Title
1 of cell-membrane
encodes six type VI secretion systems, which are protrusions and directMEcell-to-cell bacterial spread
implicated in bacterial virulence, intracellular sur- (Fig. 2).17 B. pseudomallei
DE can also induce multinu-
JIngelfinger
Artist JMuller
vival, and competition within bacterial communi- cleated giant-cell formation. 19,20
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
ties.14,15 Capsular polysaccharide, lipopolysaccha- Please check carefully
(O-PS; types III O-PS and IV O-PS) are additional AND THE IMMUNE RESPONSE
putative virulence factors.7 Flagella may be of im- Pattern-recognition receptors — especially the
portance for B. pseudomallei motility and invasion toll-like receptors (TLRs) and nucleotide-binding
of host cells, although their importance as a viru- oligomerization domain (NOD)–like receptors
lence factor in human disease is debated. Burk- (NLRs) — are the first to detect host invasion by
holderia lethal factor 1 is similar to Escherichia coli pathogens, initiate immune responses, and form
cytotoxic necrotizing factor 1 and interferes with the crucial link between innate and adaptive im-
the initiation of translation, leading to alteration munity.21 Pattern-recognition receptors recognize
conserved motifs on pathogens termed “pathogen- tween infection with the human immunodeficien-
associated molecular patterns” (PAMPs). B. pseudo cy virus (HIV) and the risk of melioidosis.34 The
mallei expresses various PAMPs, including lipopoly- proinflammatory cytokines tumor necrosis factor
saccharide, peptidoglycan, flagella, TTSS, and α and interleukin-6 — both of which are up-
DNA, which are recognized by various TLRs, and regulated during melioidosis — activate the co-
related molecules such as CD14 and MD2, which agulation system in severe melioidosis. All three
can be up-regulated in patients with melioidosis.22 of the major pathways are implicated, with the
TLR4-region genetic variants in humans are associ- concurrent enhancement of procoagulant mech-
ated with susceptibility to melioidosis.23 Whether anisms and impairment of anticoagulant and fi-
the lipopolysaccharide of B. pseudomallei signals brinolytic mechanisms.35 The complement system,
by means of TLR2, like the lipopolysaccharide of responsible for restoring host cellular homeosta-
Legionella pneumophila and Leptospira interrogans,22,24 sis and opsonization and elimination of bacteria,
or by means of TLR4,21,25 which is regarded as the becomes rapidly activated and consumed during
receptor for lipopolysaccharide, remains the sub- B. pseudomallei infection.7
ject of intense study. Surprisingly, CD14-deficient
and TLR2-deficient mice with experimentally in- THE SPEC T RUM OF HUM A N DISE A SE
duced melioidosis have a markedly improved host
defense, as reflected by a strong survival advan- EPIDEMIOLOGY
tage, whereas TLR4-deficient mice are indistin- Among the major regions where melioidosis is
guishable from wild-type mice with respect to bac- endemic, the Top End of the Northern Territory in
terial outgrowth and survival.22,26 Australia and northeast Thailand represent hot
B. pseudomallei can also activate the cytosolic spots, with annual incidence rates of up to 50 cases
inflammasome, a large, multiprotein complex per 100,000 people (Fig. 1).36,37 Melioidosis is the
formed, among others, by the NLRs NLRC4 and third most common cause of death from infec-
NLRP3, the assembly of which leads to the acti- tious disease in northeast Thailand, exceeded only
vation of caspase 1 and promotes the maturation by HIV infection and tuberculosis.36 Malaysia,
of the proinflammatory cytokines interleukin-1β Singapore, Vietnam, Cambodia, and Laos are also
and interleukin-18.21 Interleukin-18 plays a pro- regions of endemic disease.2,38 Reports have ex-
tective role during melioidosis through induction panded the endemic zone to areas of the Indian
of interferon-γ, a key cytokine that contributes subcontinent, southern China, Hong Kong, Tai-
to protection against melioidosis.27-29 By compari- wan, various Pacific and Indian Ocean islands,
son, interleukin-1β may play a deleterious role by and parts of the Americas.39 Sporadic cases have
causing excessive neutrophil recruitment and been reported in Nigeria, Gambia, Kenya, and
tissue damage and by inhibiting the activation of Uganda, but the extent of the disease in Africa
interferon-γ production (Fig. 2).28 B. pseudomallei– remains uncertain.39-41
induced activation of caspase 1 through NLRC4, The magnitude of melioidosis in the Americas
a receptor for the TTSS3 component BsaK,30 remains to be elucidated. Two cases reported in
leads to rapid macrophage cell death — a pro- the United States were thought to have been ac-
cess known as pyroptosis, which serves as a host quired in Honduras.42 Severe melioidosis in Puerto
defense mechanism to restrict intracellular bac- Rico has been described in a patient with chronic
terial growth.28,31 granulomatous disease and in a person with dia-
The immune response initiated by pattern- betes, both of whom became ill during the rainy
recognition receptors leads to the recruitment of season.43,44 Sporadic cases of melioidosis have
neutrophils, macrophages, and lymphocytes to- been reported in Ecuador, Guadeloupe, and Aruba,
ward the site of infection. Although disproportion- and the emergence of melioidosis in Brazil is an
ate neutrophil recruitment may be detrimental,28 example of increasing recognition in areas where
activated neutrophils play a critical role in early the disease has become manifest as a result of
bacterial containment.32 Murine cell-depletion enhanced awareness and diagnostic tests.45 Aru-
studies have shown that T cells — in particular, ba was the location of an outbreak in sheep,
CD4+ T cells — are important in both innate and goats, and pigs in the 1950s46 and may have
adaptive immunity against B. pseudomallei infec- been the location for an infection acquired by a
tion,29,33 although there is no association be- child with cystic fibrosis who recently presented
TREM-1
Burkholderia pseudomallei
Macrophage TLR2 Phagocytosis
CD14
MyD88 TLR4
TLR5
MyD88
IRAK-M MyD88
Endocytic
vesicle
Inflammasome
Pyroptosis
Pro–interleukin-1β Interleukin-1β
Pro–interleukin-18 Interleukin-18
Cytokine release
Neutrophil
recruitment
Interferon-γ
Antigen
presentation
Bacterial
restriction
Neutrophil
TNF-α
Interleukin-6
T-cell
Cell-mediated recruitment Immunosuppression
immunity and apoptosis
Humoral Complement
immunity T cell activation
B-cell
antibody Activation of
production coagulation
B cell
COLOR FIGURE
Version 6 08/27/12
1038 n engl j med 367;11 nejm.org september 13, 2012 Author Wiersinga
Fig # 2
Title
The New England Journal of Medicine
ME
Downloaded from nejm.org at TUFTS UNIVERSITY on August 15, 2020. For personal use only. No other DE
usesJIngelfinger
without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved. Artist JMuller
AUTHOR PLEASE NOTE:
medical progress
A D
Percutaneous
Ingestion
inoculation
Local
Gastrointestinal Skin lesions
ulcer
tract mucosal in disseminated
ulceration or
E
disease
lymphadenopathy
Asymptomatic
infection
B
Inhalation Bacteremia
F
Any organ
(e.g., spleen,
Severe sepsis
Pneumonia prostate,
or latent disease
kidney, liver)
C
G
Reactivation of
latent focus
Version 6 08/14/12
Author Wiersinga
A notable difference in presentation between to reinfection, with the remainder
Fig # 3 due to relapse
Title
patients in tropical Australia and those in South- from a persistent focus of infection.54 Mortality
ME
east Asia is suppurative parotitis, which accounts rates for melioidosis DE
are approximately
JIngelfinger 40% in
Artist JMuller 36
for up to 40% of cases of melioidosis in children northeast Thailand (35% in children)
AUTHOR PLEASE NOTE: and 14%
in Thailand and Cambodia but is extremely rare in Australia.37 Figure has been redrawn and type has been reset
Please check carefully
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