Human Immune Responses to Melioidosis and Cross-Reactivity to Low-Virulence <i>Burkholderia</i> Species, Thailand1

Rongkard, Patpong; Kronsteiner, Barbara; Hantrakun, Viriya; Jenjaroen, Kemajittra; Sumonwiriya, Manutsanun; Chaichana, Panjaporn; Chumseng, Suchintana; Chantratita, Narisara; Wuthiekanun, Vanaporn; Fletcher, Helen A.; Teparrukkul, Prapit; Limmathurotsakul, Direk; Npj., Day; Dunachie, Susanna

doi:10.3201/eid2603.190206

Cited by 16 publications

(16 citation statements)

References 36 publications

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“…This includes the indirect hemagglutination assay (IHA), which is the serological standard test for melioidosis in many endemic regions, whose sensitivity might be as low as 56%, and is commonly positive in the endemic population [27][28][29]. There is known cross-reactivity of antibody and cellular responses to B. pseudomallei and environmental Burkholderia species of low pathogenicity in both melioidosis patients and endemic controls [30], so the development of a diagnostic test for acute melioidosis with high specificity is highly desirable.…”

Section: Introductionmentioning

confidence: 99%

Melioidosis DS rapid test: A standardized serological dipstick assay with increased sensitivity and reliability due to multiplex detection

et al. 2020

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Background Melioidosis, caused by Burkholderia pseudomallei , is a severe infectious disease with high mortality rates, but is under-recognized worldwide. In endemic areas, there is a great need for simple, low-cost and rapid diagnostic tools. In a previous study we showed, that a protein multiplex array with 20 B . pseudomallei -specific antigens detects antibodies in melioidosis patients with high sensitivity and specificity. In a subsequent study the high potential of anti- B . pseudomallei antibody detection was confirmed using a rapid Hcp1 single protein-based assay. Our protein array also showed that the antibody profile varies between patients, possibly due to a combination of host factors but also antigen variations in the infecting B . pseudomallei strains. The aim of this study was to develop a rapid test, combining Hcp1 and the best performing antigens BPSL2096, BPSL2697 and BPSS0477 from our previous study, to take advantage of simultaneous antibody detection. Methods and principal findings The 4-plex dipstick was validated with sera from 75 patients on admission plus control groups, achieving 92% sensitivity and 97–100% specificity. We then re-evaluated melioidosis sera with the 4-plex assay that were previously misclassified by the monoplex Hcp1 rapid test. 12 out of 55 (21.8%) false-negative samples were positive in our new dipstick assay. Among those, 4 sera (7.3%) were Hcp1 positive, whereas 8 (14.5%) sera remained Hcp1 negative but gave a positive reaction with our additional antigens. Conclusions Our dipstick rapid test represents an inexpensive, standardized and simple diagnostic tool with an improved serodiagnostic performance due to multiplex detection. Each additional band on the test strip makes a false-positive result more unlikely, contributing to its reliability. Future prospective studies will seek to validate the gain in sensitivity and specificity of our multiplex rapid test approach in different melioidosis patient cohorts.

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Section: Introductionmentioning

confidence: 99%

Melioidosis DS rapid test: A standardized serological dipstick assay with increased sensitivity and reliability due to multiplex detection

et al. 2020

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“…6% of healthy controls exhibited strong cellular responses to Hcp1 and TssM. This may be a result of repeated environmental exposure to B. pseudomallei or successful clearance of B. pseudomallei after exposure (37,38). In previous studies, there was no difference in IFN-g production by PBMC from melioidosis patients versus healthy controls upon stimulation with cytomegalovirus, Epstein-Barr virus and influenza virus (CEF) peptide pool which is a positive control for CD8 + T cell functionality (26,39).…”

Section: Discussionmentioning

confidence: 93%

“…It has been previously reported that CD4 + , CD8 + and NK cells from melioidosis patients are sources of IFN-g production following stimulation with B. pseudomallei proteins such as LolC, OppA and PotF or whole bacteria (27,37,39). Similar to our study, Rongkard et al reported that acute melioidosis patients predominantly exhibited IFN-g production from CD4 + T cells when stimulated with culture filtrate antigens from B. pseudomallei (37). CD4 + T cells, but not CD8 + T cells have also previously been shown to be important in mediating immunity against B. pseudomallei infections using depletion studies in a murine model (41).…”

Section: Discussionmentioning

confidence: 99%

Melioidosis Patient Survival Correlates With Strong IFN-γ Secreting T Cell Responses Against Hcp1 and TssM

Sengyee

Yarasai

Janon³

et al. 2021

Front. Immunol.

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Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a serious infectious disease with diverse clinical manifestations. The morbidity and mortality of melioidosis is high in Southeast Asia and no licensed vaccines currently exist. This study was aimed at evaluating human cellular and humoral immune responses in Thai adults against four melioidosis vaccine candidate antigens. Blood samples from 91 melioidosis patients and 100 healthy donors from northeast Thailand were examined for immune responses against B. pseudomallei Hcp1, AhpC, TssM and LolC using a variety of cellular and humoral immune assays including IFN-γ ELISpot assays, flow cytometry and ELISA. PHA and a CPI peptide pool were also used as control stimuli in the ELISpot assays. Hcp1 and TssM stimulated strong IFN-γ secreting T cell responses in acute melioidosis patients which correlated with survival. High IFN-γ secreting CD4+ T cell responses were observed during acute melioidosis. Interestingly, while T cell responses of melioidosis patients against the CPI peptide pool were low at the time of enrollment, the levels increased to the same as in healthy donors by day 28. Although high IgG levels against Hcp1 and AhpC were detected in acute melioidosis patients, no significant differences between survivors and non-survivors were observed. Collectively, these studies help to further our understanding of immunity against disease following natural exposure of humans to B. pseudomallei as well as provide important insights for the selection of candidate antigens for use in the development of safe and effective melioidosis subunit vaccines.

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“…In particular, elevated interferon gamma (IFN-γ) responses associated with CD4 + and CD8 + T cells are important to combat the disease ( 15 ). Moreover, IFN-γ-producing natural killer (NK) and natural killer T (NKT) cells also participate in the response against melioidosis in mice ( 17 ) and humans ( 18 , 19 ). Finally, humoral immunity also contributes to the elimination of B. pseudomallei in mice, and protective antibody responses have been described in human observational studies ( 20 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

BpOmpW Antigen Stimulates the Necessary Protective T-Cell Responses Against Melioidosis

Tomás-Cortázar

Bossi²,

Quinn

et al. 2021

Front. Immunol.

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Melioidosis is a potentially fatal bacterial disease caused by Burkholderia pseudomallei and is estimated to cause 89,000 deaths per year in endemic areas of Southeast Asia and Northern Australia. People with diabetes mellitus are most at risk of melioidosis, with a 12-fold increased susceptibility for severe disease. Interferon gamma (IFN-γ) responses from CD4 and CD8 T cells, but also from natural killer (NK) and natural killer T (NKT) cells, are necessary to eliminate the pathogen. We previously reported that immunization with B. pseudomallei OmpW (BpOmpW antigen) protected mice from lethal B. pseudomallei challenge for up to 81 days. Elucidating the immune correlates of protection of the protective BpOmpW vaccine is an essential step prior to clinical trials. Thus, we immunized either non-insulin-resistant C57BL/6J mice or an insulin-resistant C57BL/6J mouse model of type 2 diabetes (T2D) with a single dose of BpOmpW. BpOmpW induced strong antibody responses, stimulated effector CD4+ and CD8+ T cells and CD4+ CD25+ Foxp3+ regulatory T cells, and produced higher IFN-γ responses in CD4+, CD8+, NK, and NKT cells in non-insulin-resistant mice. The T-cell responses of insulin-resistant mice to BpOmpW were comparable to those of non-insulin-resistant mice. In addition, as a precursor to its evaluation in human studies, humanized HLA-DR and HLA-DQ (human leukocyte antigen DR and DQ isotypes, respectively) transgenic mice elicited IFN-γ recall responses in an enzyme-linked immune absorbent spot (ELISpot)-based study. Moreover, human donor peripheral blood mononuclear cells (PBMCs) exposed to BpOmpW for 7 days showed T-cell proliferation. Finally, plasma from melioidosis survivors with diabetes recognized our BpOmpW vaccine antigen. Overall, the range of approaches used strongly indicated that BpOmpW elicits the necessary immune responses to combat melioidosis and bring this vaccine closer to clinical trials.

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Human Immune Responses to Melioidosis and Cross-Reactivity to Low-Virulence Burkholderia Species, Thailand1

Cited by 16 publications

References 36 publications

Melioidosis DS rapid test: A standardized serological dipstick assay with increased sensitivity and reliability due to multiplex detection

Melioidosis DS rapid test: A standardized serological dipstick assay with increased sensitivity and reliability due to multiplex detection

Melioidosis Patient Survival Correlates With Strong IFN-γ Secreting T Cell Responses Against Hcp1 and TssM

BpOmpW Antigen Stimulates the Necessary Protective T-Cell Responses Against Melioidosis

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