Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
312
result(s) for
"Mayo, Mark"
Sort by:
Burkholderia pseudomallei Sequence Type 46 Transmission from Asia to Australia
Melioidosis is caused by the environmental pathogen Burkholderia pseudomallei. Among 1,331 patients with melioidosis during 1989-2023 in the Darwin Prospective Melioidosis Study in Australia, we identified 6 locally acquired cases caused by B. pseudomallei sequence type 46. Because of global transmission and expansion of endemicity, clinicians should increase awareness of melioidosis.
Journal Article
Raising the Stakes: Loss of Efflux Pump Regulation Decreases Meropenem Susceptibility in Burkholderia pseudomallei
Burkholderia pseudomallei is resistant to most antibiotics. Decreased susceptibility to the reserve antibiotic meropenem would dramatically decrease treatment options. We document the first cases of decreased meropenem susceptibility and identify its molecular basis. Decreased susceptibility was associated with poorer outcomes.
Abstract
Background
Burkholderia pseudomallei, the causative agent of the high-mortality disease melioidosis, is a gram-negative bacterium that is naturally resistant to many antibiotics. There is no vaccine for melioidosis, and effective eradication is reliant on biphasic and prolonged antibiotic administration. The carbapenem drug meropenem is the current gold standard option for treating severe melioidosis. Intrinsic B. pseudomallei resistance toward meropenem has not yet been documented; however, resistance could conceivably develop over the course of infection, leading to prolonged sepsis and treatment failure.
Methods
We examined our 30-year clinical collection of melioidosis cases to identify B. pseudomallei isolates with reduced meropenem susceptibility. Isolates were subjected to minimum inhibitory concentration (MIC) testing toward meropenem. Paired isolates from patients who had evolved decreased susceptibility were subjected to whole-genome sequencing. Select agent-compliant genetic manipulation was carried out to confirm the molecular mechanisms conferring resistance.
Results
We identified 11 melioidosis cases where B. pseudomallei isolates developed decreased susceptibility toward meropenem during treatment, including 2 cases not treated with this antibiotic. Meropenem MICs increased from 0.5-0.75 µg/mL to 3-8 µg/mL. Comparative genomics identified multiple mutations affecting multidrug resistance-nodulation-division (RND) efflux pump regulators, with concomitant overexpression of their corresponding pumps. All cases were refractory to treatment despite aggressive, targeted therapy, and 2 were associated with a fatal outcome.
Conclusions
This study confirms the role of RND efflux pumps in decreased meropenem susceptibility in B. pseudomallei. These findings have important ramifications for the diagnosis, treatment, and management of life-threatening melioidosis cases.
Journal Article
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.
Journal Article
Emergence of Burkholderia pseudomallei Sequence Type 562, Northern Australia
Since 2005, the range of Burkholderia pseudomallei sequence type 562 (ST562) has expanded in northern Australia. During 2005-2019, ST562 caused melioidosis in 61 humans and 3 animals. Cases initially occurred in suburbs surrounding a creek before spreading across urban Darwin, Australia and a nearby island community. In urban Darwin, ST562 caused 12% (53/440) of melioidosis cases, a proportion that increased during the study period. We analyzed 2 clusters of cases with epidemiologic links and used genomic analysis to identify previously unassociated cases. We found that ST562 isolates from Hainan Province, China, and Pingtung County, Taiwan, were distantly related to ST562 strains from Australia. Temporal genomic analysis suggested a single ST562 introduction into the Darwin region in ≈1988. The origin and transmission mode of ST562 into Australia remain uncertain.
Journal Article
CXCR3 is associated with T-cell-induced heart damage in acute rheumatic fever
The pathogenesis of acute rheumatic fever (ARF) is poorly understood, limiting the development of immune-modulating therapies to treat disease and prevent progressive heart damage. Here, participants with definite ARF were compared to other severe acute paediatric conditions and matched healthy controls by profiling circulating immune molecules and cells to inform disease mechanisms and potential druggable pathways. ARF shared immunological similarities with other inflammatory conditions, including elevated serum IL-6 and an increased frequency of circulating CD4
+
T cells. However, elevation of the chemokine CCL5 and immunoglobulin IgG3, along with reduced expression of the chemokine receptor CXCR3 in the T cell compartment distinguished ARF from all other groups. Immunofluorescence imaging of rheumatic valve tissue confirmed a role for CXCR3-mediated T cell tissue homing during inflammatory disease. Together with a reduced frequency of circulating regulatory T cells, these data underscore a perturbed T cell compartment and provide a rationale for exploring currently available immune-modulating therapies to treat ARF.
Acute rheumatic fever (ARF) is a serious sequela of Strep A infection, for which a diagnostic biomarker is still lacking. Here, the authors demonstrate that CXCR3 directs T cells to heart valves in patients with ARF, linking inflammation to tissue damage.
Journal Article
An outer membrane vesicle vaccine prevents lung pathology in a macaque model of pneumonic melioidosis
Melioidosis is an emerging infectious disease caused by the intracellular bacterial pathogen,
Burkholderia pseudomallei
. Infection of humans and animals can occur through multiple routes of bacterial entry resulting in life-threatening pneumonia and/or bacteremia.
B. pseudomallei
is inherently resistant to multiple antibiotics and mortality rates are high despite therapeutic intervention. Development of an effective vaccine could protect at-risk individuals, such as those who reside in highly endemic areas, military personnel, diabetics, and travelers. Despite decades of pursuit, no candidate vaccine for melioidosis has advanced beyond pre-clinical testing in rodent models. Here, we demonstrate that an outer membrane vesicle (OMV) vaccine prevents pulmonary disease in non human primates (NHP) using survivability, biotelemetry, and clinical pathology assessments. Using two independent serologic assays, we demonstrate that vaccination in rhesus macaques is associated with systemic and mucosal IgG and IgA to OMV surface proteins and polysaccharides. We also show that NHP immune sera promotes opsonophagocytosis by macrophages and that human sera responses to several key OMV antigens are associated with survival in melioidosis. Collectively, these results attest to the potential efficacy of the OMV vaccine and lay the groundwork for its advancement to human phase 1 clinical trials.
Currently, there is no licensed vaccine for
Burkholderia pseudomallei
, the causative agent of melioidosis. Here, the authors evaluate the efficacy and safety of an outer-membrane vesicle vaccine in macaques and demonstrate that it prevents lung pathology.
Journal Article
Melioidosis in the remote Katherine region of northern Australia
Melioidosis is endemic in the remote Katherine region of northern Australia. In a population with high rates of chronic disease, social inequities, and extreme remoteness, the impact of melioidosis is exacerbated by severe weather events and disproportionately affects First Nations Australians. All culture-confirmed melioidosis cases in the Katherine region of the Australian Top End between 1989–2021 were included in the study, and the clinical features and epidemiology were described. The diversity of Burkholderia pseudomallei strains in the region was investigated using genomic sequencing. From 1989–2021 there were 128 patients with melioidosis in the Katherine region. 96/128 (75%) patients were First Nations Australians, 72/128 (56%) were from a very remote region, 68/128 (53%) had diabetes, 57/128 (44%) had a history of hazardous alcohol consumption, and 11/128 (9%) died from melioidosis. There were 9 melioidosis cases attributable to the flooding of the Katherine River in January 1998; 7/9 flood-associated cases had cutaneous melioidosis, five of whom recalled an inoculating event injury sustained wading through flood waters or cleaning up after the flood. The 126 first-episode clinical B . pseudomallei isolates that underwent genomic sequencing belonged to 107 different sequence types and were highly diverse, reflecting the vast geographic area of the study region. In conclusion, melioidosis in the Katherine region disproportionately affects First Nations Australians with risk factors and is exacerbated by severe weather events. Diabetes management, public health intervention for hazardous alcohol consumption, provision of housing to address homelessness, and patient education on melioidosis prevention in First Nations languages should be prioritised.
Journal Article
Development of a Prototype Lateral Flow Immunoassay (LFI) for the Rapid Diagnosis of Melioidosis
Burkholderia pseudomallei is a soil-dwelling bacterium and the causative agent of melioidosis. Isolation of B. pseudomallei from clinical samples is the \"gold standard\" for the diagnosis of melioidosis; results can take 3-7 days to produce. Alternatively, antibody-based tests have low specificity due to a high percentage of seropositive individuals in endemic areas. There is a clear need to develop a rapid point-of-care antigen detection assay for the diagnosis of melioidosis. Previously, we employed In vivo Microbial Antigen Discovery (InMAD) to identify potential B. pseudomallei diagnostic biomarkers. The B. pseudomallei capsular polysaccharide (CPS) and numerous protein antigens were identified as potential candidates. Here, we describe the development of a diagnostic immunoassay based on the detection of CPS. Following production of a CPS-specific monoclonal antibody (mAb), an antigen-capture immunoassay was developed to determine the concentration of CPS within a panel of melioidosis patient serum and urine samples. The same mAb was used to produce a prototype Active Melioidosis Detect Lateral Flow Immunoassay (AMD LFI); the limit of detection of the LFI for CPS is comparable to the antigen-capture immunoassay (∼0.2 ng/ml). The analytical reactivity (inclusivity) of the AMD LFI was 98.7% (76/77) when tested against a large panel of B. pseudomallei isolates. Analytical specificity (cross-reactivity) testing determined that 97.2% of B. pseudomallei near neighbor species (35/36) were not reactive. The non-reactive B. pseudomallei strain and the reactive near neighbor strain can be explained through genetic sequence analysis. Importantly, we show the AMD LFI is capable of detecting CPS in a variety of patient samples. The LFI is currently being evaluated in Thailand and Australia; the focus is to optimize and validate testing procedures on melioidosis patient samples prior to initiation of a large, multisite pre-clinical evaluation.
Journal Article