Melioidosis: molecular aspects of pathogenesis

Stone, Joshua K.; DeShazer, David; Brett, Paul J.; Burtnick, Mary N.

doi:10.1586/14787210.2014.970634

Cited by 63 publications

(65 citation statements)

References 121 publications

(195 reference statements)

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“…Infection typically occurs via the respiratory route or through punctured skin, and the most common presentations are life-threatening pneumonia and bacteremia (2,3,10,11,18). A key aspect of pathogenesis by both B. mallei and B. pseudomallei that complicates treatment is their ability to invade and to survive and replicate within host cells, including professional phagocytes (5,7,42,43). The organisms use type 3 and type 6 secretion systems to inject effector proteins inside host cells and to subvert eukaryotic cellular functions.…”

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confidence: 99%

Antibodies against In Vivo -Expressed Antigens Are Sufficient To Protect against Lethal Aerosol Infection with Burkholderia mallei and Burkholderia pseudomallei

et al. 2017

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Burkholderia mallei, a facultative intracellular bacterium and tier 1 biothreat, causes the fatal zoonotic disease glanders. The organism possesses multiple genes encoding autotransporter proteins, which represent important virulence factors and targets for developing countermeasures in pathogenic Gram-negative bacteria. In the present study, we investigated one of these autotransporters, BatA, and demonstrate that it displays lipolytic activity, aids in intracellular survival, is expressed in vivo, elicits production of antibodies during infection, and contributes to pathogenicity in a mouse aerosol challenge model. A mutation in the batA gene of wild-type strain ATCC 23344 was found to be particularly attenuating, as BALB/c mice infected with the equivalent of 80 median lethal doses cleared the organism. This finding prompted us to test the hypothesis that vaccination with the batA mutant strain elicits protective immunity against subsequent infection with wild-type bacteria. We discovered that not only does vaccination provide high levels of protection against lethal aerosol challenge with B. mallei ATCC 23344, it also protects against infection with multiple isolates of the closely related organism and causative agent of melioidosis, Burkholderia pseudomallei. Passive-transfer experiments also revealed that the protective immunity afforded by vaccination with the batA mutant strain is predominantly mediated by IgG antibodies binding to antigens expressed exclusively in vivo. Collectively, our data demonstrate that BatA is a target for developing medical countermeasures and that vaccination with a mutant lacking expression of the protein provides a platform to gain insights regarding mechanisms of protective immunity against B. mallei and B. pseudomallei, including antigen discovery.

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Antibodies against In Vivo -Expressed Antigens Are Sufficient To Protect against Lethal Aerosol Infection with Burkholderia mallei and Burkholderia pseudomallei

et al. 2017

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“…B. pseudomallei possesses numerous virulence factors, including surface polysaccharides, such as capsular polysaccharide (CPS) and lipopolysaccharide (LPS), which are involved in inhibition of opsonophagocytosis and resistance to complement-mediated killing [7,8]. phospholipases), motility proteins and secondary metabolites [9]. Additional virulence factors include various secreted proteins (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Additional virulence factors include various secreted proteins (e.g. phospholipases), motility proteins and secondary metabolites [9]. B. pseudomallei is also intrinsically resistant to many commonly used antibiotics, including aminoglycosides, penicillins, rifamycins and third-generation cephalosporins [10][11][12].…”

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confidence: 99%

Novel multi-component vaccine approaches for Burkholderia pseudomallei

Morici

Torres

Titball

2019

Clinical and Experimental Immunology

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Burkholderia pseudomallei is the causative agent of melioidosis. Historically believed to be a relatively rare human disease in tropical countries, a recent study estimated that, worldwide, there are approximately 165 000 human melioidosis cases per year, more than half of whom die. The bacterium is inherently resistant to many antibiotics and treatment of the disease is often protracted and ineffective. There is no licensed vaccine against melioidosis, but a vaccine is predicted to be of value if used in high-risk populations. There has been progress over the last decade in the pursuit of an effective vaccine against melioidosis. Animal models of disease including mouse and non-human primates have been developed, and these models show that antibody responses play a key role in protection against melioidosis. Surprisingly, although B. pseudomallei is an intracellular pathogen there is limited evidence that CD8 + T cells play a role in protection. It is evident that a multi-component vaccine, incorporating one or more protective antigens, will probably be essential for protection because of the pathogen's sophisticated virulence mechanisms as well as strain heterogeneity. Multi-component vaccines in development include glycoconjugates, multivalent subunit preparations, outer membrane vesicles and other nano/microparticle platforms and live-attenuated or inactivated bacteria. A consistent finding with vaccine candidates tested in mice is the ability to induce sterilizing immunity at low challenge doses and extended time to death at higher challenge doses. Further research to identify ways of eliciting more potent immune responses might provide a path for licensing an effective vaccine.

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“…The accumulation of coding region sequences in the pan-genome [17] is largely associated with the horizontal acquisition of sequences, including genomic islands from genetic near neighbors [18]. The virulence of B. pseudomallei has been attributed to multiple genomic loci, including type III and type VI secretion systems, lipopolysaccharides, actin-based motility factors, toxins, adhesins, and capsular polysaccharide clusters [16, 19]. The large accessory genome likely contributes to the observed clinical diversity [20] and results in the ability to rapidly adapt to dynamic and hostile environments.…”

Section: Introductionmentioning

confidence: 99%

Pathogen to commensal: longitudinal within-host population dynamics, evolution, and adaptation during a chronic >16-year Burkholderia pseudomallei infection

Pearson

Sahl

Hepp

et al. 2019

Preprint

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Although acute melioidosis is the most common outcome of Burkholderia pseudomallei infection, we have documented a case, P314, where the disease severity lessened with time, and the pathogen evolved towards a commensal relationship with the host. In the current study, we used whole-genome sequencing to monitor this chronic infection to better understand B. pseudomallei persistence in P314’s sputum despite intense and repeated therapeutic regimens. We collected and sequenced 118 B. pseudomallei isolates from P314’s airways over a >16-year period, and also sampled the patient’s home environment, recovering six closely related B. pseudomallei isolates from water. Using comparative genomics, we identified 126 SNPs in the core genome of the 124 isolates or 162 SNPs/indels when the accessory genome was included. The core SNPs were used to construct a phylogenetic tree, which demonstrated a close relationship between environmental and clinical isolates and detailed within-host evolutionary patterns. The phylogeny had little homoplasy, consistent with a single clonal population. Repeated sampling revealed evidence of genetic diversification, but frequent extinctions left only one successful lineage through the first four years and two lineages after that, resulting in a highly linear topology. Although these extinctions and persistence could be explained by genetic drift, we observe phenotypic changes consistent with in situ adaptation. Using a mouse model, P314 isolates caused greatly reduced morbidity and mortality compared to the environmental isolates. Additionally, potentially adaptive phenotypes changed with time and included differences in the O-antigen, capsular polysaccharide, motility, and colony morphology. The >13-year co-existence of two long-lived lineages presents interesting hypotheses that can be tested in future studies to provide additional insights into selective pressures, niche differentiation, and microbial adaptation. This unusual melioidosis case presents a rare example of the evolutionary progression to commensalism by a highly virulent pathogen within a single human host. Author summary Pathogens frequently jump between different hosts and associated adaptation may lead to the emergence of new infectious agents. Such host-jumping evolution is witnessed through endpoint analyses but these cannot capture genetic changes in lineages that have gone extinct. In this study, we have identified and monitored an example of the adaptive evolution of a bacterium often deadly to its mammalian host, in an unprecedented case whereby disease lessened through time and the pathogen adapted to become a part of the commensal human flora. We used genomic analyses to characterize more than 16 years of this evolutionary process and the stepwise mutations that control dictate pathogen interactions with the patient. Soon after infection, mutational changes occurred that allowed the bacterium to remain in the airways without causing disease. This shift towards avirulence was determined based on clinical data ...

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Melioidosis: molecular aspects of pathogenesis

Cited by 63 publications

References 121 publications

Antibodies against In Vivo -Expressed Antigens Are Sufficient To Protect against Lethal Aerosol Infection with Burkholderia mallei and Burkholderia pseudomallei

Antibodies against In Vivo -Expressed Antigens Are Sufficient To Protect against Lethal Aerosol Infection with Burkholderia mallei and Burkholderia pseudomallei

Novel multi-component vaccine approaches for Burkholderia pseudomallei

Pathogen to commensal: longitudinal within-host population dynamics, evolution, and adaptation during a chronic >16-year Burkholderia pseudomallei infection

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