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1.
Chembiochem ; : e202400037, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38688858

RESUMO

Our gut microbiota directly influences human physiology in health and disease. The myriad of surface glycoconjugates in both the bacterial cell envelope and our gut cells dominate the microbiota-host interface and play a critical role in host response and microbiota homeostasis. Among these, peptidoglycan is the basic glycan polymer offering the cell rigidity and a basis on which many other glycoconjugates are anchored. To directly study peptidoglycan in gut commensals and obtain the molecular insight required to understand their functional activities we need effective techniques like chemical probes to label peptidoglycan in live bacteria. Here we report a chemically guided approach to study peptidoglycan in a key mucin-degrading gut microbiota member of the Verrucomicrobia phylum, Akkermansia muciniphila. Two novel non-toxic tetrazine click-compatible peptidoglycan probes with either a cyclopropene or isonitrile handle allowed for the detection and imaging of peptidoglycan synthesis in this intestinal species.

2.
Lancet Glob Health ; 12(3): e445-e456, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38272044

RESUMO

BACKGROUND: Long-term immunity following yellow fever vaccination remains controversial. We aimed to summarise the literature regarding the long-term protection (≥10 years) conveyed by a single dose of yellow fever vaccination. METHODS: In this systematic review and meta-analysis, we searched 11 databases from database inception to Aug 24, 2023. We included cohort and cross-sectional studies reporting immunogenicity outcomes for children or adults who received a single dose of yellow fever vaccination 10 or more years ago. Case series and single case reports were excluded. Participants who received more than one dose of yellow fever vaccination before measurement of the outcome were excluded. Identified records were reviewed by two independent reviewers. The primary outcome of the meta-analysis was the pooled seroprotection rate. Risk of bias was assessed with the Risk Of Bias In Non-randomized Studies of Interventions tool, and the Joanna Briggs Institute tool for analytical cross-sectional studies. Studies of moderate or good quality that reported seroprotection were included for random-effects meta-analysis and stratified by endemicity and specific risk groups. The study was registered with PROSPERO, CRD42023384087. FINDINGS: Of the 7363 articles identified by our search, 39 were eligible for inclusion for systematic review. These studies comprised 2895 individuals vaccinated 10-60 years ago. 20 studies were included in the meta-analysis. Pooled seroprotection rates were 94% (95% CI 86-99) among healthy adults in a non-endemic setting (mostly travellers) and 76% (65-85) in an endemic setting (all Brazilian studies). The pooled seroprotection rate was 47% (35-60) in children (aged 9-23 months at time of vaccination) and 61% (38-82) in people living with HIV. Reported criteria for seroprotection were highly heterogeneous. INTERPRETATION: The gathered evidence suggests that a single dose of yellow fever vaccination provides lifelong protection in travellers. However, in people living with HIV and children (younger than 2 years), booster doses might still be required because lower proportions of vaccinees were seroprotected 10 or more years post-vaccination. Lower observed seroprotection rates among residents of endemic areas were partly explained by the use of a higher cutoff for seroprotection that was applied in Brazil. Studies from sub-Saharan Africa were scarce and of low quality; thus no conclusions could be drawn for this region. FUNDING: None.


Assuntos
Infecções por HIV , Febre Amarela , Criança , Adulto , Humanos , Febre Amarela/prevenção & controle , Estudos Transversais , Vacinação , Fatores de Tempo
3.
Trop Dis Travel Med Vaccines ; 10(1): 2, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38221606

RESUMO

For decades, immunoglobulin preparations have been used to prevent or treat infectious diseases. Since only a few years, monoclonal antibody applications (mAbs) are taking flight and are increasingly dominating this field. In 2014, only two mAbs were registered; end of October 2023, more than ten mAbs are registered or have been granted emergency use authorization, and many more are in (pre)clinical phases. Especially the COVID-19 pandemic has generated this surge in licensed monoclonal antibodies, although multiple phase 1 studies were already underway in 2019 for other infectious diseases such as malaria and yellow fever. Monoclonal antibodies could function as prophylaxis (i.e., for the prevention of malaria), or could be used to treat (tropical) infections (i.e., rabies, dengue fever, yellow fever). This review focuses on the discussion of the prospects of, and obstacles for, using mAbs in the prevention and treatment of (tropical) infectious diseases seen in the returning traveler; and provides an update on the mAbs currently being developed for infectious diseases, which could potentially be of interest for travelers.

4.
Lancet Infect Dis ; 24(3): e189-e195, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37837983

RESUMO

Non-timely reporting, selective reporting, or non-reporting of clinical trial results are prevalent and serious issues. WHO mandates that summary results be available in registries within 12 months of study completion and published in full text within 24 months. However, only a limited number of clinical trials in infectious diseases, including those done during the COVID-19 pandemic, have their results posted on ClinicalTrials.gov. An analysis of 50 trials of eight antiviral drugs tested against COVID-19 with a completion date of at least 2 years ago revealed that only 18% had their results published in the registry, with 40% not publishing any results. Non-timely and non-reporting practices undermine patient participation and are ethically unacceptable. Strategies should include obligatory reporting of summary results within 12 months in clinical trial registries, with progress towards peer-reviewed publication within 24 months indicated. Timely publication of research papers should be encouraged through an automated flagging mechanism in clinical trial registries that draws attention to the status of results reporting, such as a green tick for trials that have reported summary results within 12 months and a red tick in case of failure to do so. We propose the inclusion of mandatory clinical trial reporting standards in the International Conference on Harmonization Good Clinical Practice guidelines, which should prohibit sponsor contract clauses that restrict reporting (referred to as gag clauses) and require timely reporting of results as part of the ethics committees' clearance process for clinical trial protocols.


Assuntos
COVID-19 , Doenças Transmissíveis , Humanos , Pandemias , Doenças Transmissíveis/tratamento farmacológico , Sistema de Registros , Viés
5.
Plant J ; 116(5): 1355-1369, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37647363

RESUMO

2,4-dichlorophenoxyacetic acid (2,4-D) is a synthetic analogue of the plant hormone auxin that is commonly used in many in vitro plant regeneration systems, such as somatic embryogenesis (SE). Its effectiveness in inducing SE, compared to the natural auxin indole-3-acetic acid (IAA), has been attributed to the stress triggered by this compound rather than its auxinic activity. However, this hypothesis has never been thoroughly tested. Here we used a library of forty 2,4-D analogues to test the structure-activity relationship with respect to the capacity to induce SE and auxinic activity in Arabidopsis thaliana. Four analogues induced SE as effectively as 2,4-D and 13 analogues induced SE but were less effective. Based on root growth inhibition and auxin response reporter expression, the 2,4-D analogues were classified into different groups, ranging from very active to not active auxin analogues. A halogen at the 4-position of the aromatic ring was important for auxinic activity, whereas a halogen at the 3-position resulted in reduced activity. Moreover, a small substitution at the carboxylate chain was tolerated, as was extending the carboxylate chain with an even number of carbons. The auxinic activity of most 2,4-D analogues was consistent with their simulated TIR1-Aux/IAA coreceptor binding characteristics. A strong correlation was observed between SE induction efficiency and auxinic activity, which is in line with our observation that 2,4-D-induced SE and stress both require TIR1/AFB auxin co-receptor function. Our data indicate that the stress-related effects triggered by 2,4-D and considered important for SE induction are downstream of auxin signalling.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Ácidos Indolacéticos/metabolismo , Ácido 2,4-Diclorofenoxiacético/farmacologia , Ácido 2,4-Diclorofenoxiacético/metabolismo , Relação Estrutura-Atividade , Halogênios/metabolismo , Halogênios/farmacologia , Regulação da Expressão Gênica de Plantas
6.
New Microbes New Infect ; 53: 101136, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37187799

RESUMO

Background: Earlier studies found characteristic haematological changes in African patients with active schistosomiasis. If consistently present, full blood counts (FBC) may be helpful to diagnose schistosomiasis also in migrants and returning travellers. Methods: A retrospective patient record review was conducted on data from seven European travel clinics, comparing FBC of Schistosoma egg-positive travellers and migrants to reference values. Sub-analyses were performed for children, returned travellers, migrants and different Schistosoma species. Results: Data analysis included 382 subjects (median age 21.0 years [range 2-73]). In returned travellers, decreases in means of haemoglobin particularly in females (ß = -0.82 g/dL, p = 0.005), MCV (ß = -1.6 fL, p = 0.009), basophils, neutrophils, lymphocytes and monocytes (ß = -0.07, p < 0.001; -0.57, p = 0.012; -0.57, p < 0.001 and -0.13 103/µL, p < 0.001, respectively) were observed. As expected, eosinophils were increased (ß = +0.45 103/µL, p < 0.001). In migrants, a similar FBC profile was observed, yet thrombocytes and leukocytes were significantly lower in migrants (ß = -48 103/µL p < 0.001 and ß = -2.35 103/µL, p < 0.001, respectively). Conclusions: Active egg-producing Schistosoma infections are associated with haematological alterations in returned travellers and migrants. However, these differences are discrete and seem to vary among disease stage and Schistosoma species. Therefore, the FBC is unsuitable as a surrogate diagnostic parameter to detect schistosomiasis.

7.
Travel Med Infect Dis ; 52: 102520, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36526126

RESUMO

According to current guidelines, atovaquone-proguanil (AP) malaria chemoprophylaxis should be taken once daily starting one day before travel and continued for seven days post-exposure. However, drug-sparing regimens, including discontinuing AP after leaving malaria-endemic areas are cost-saving and probably more attractive to travelers, and may thus enhance adherence. AP has causal prophylactic effects, killing malaria parasites during the hepatic stage. If early hepatic stages were already targeted by AP, AP could possibly be discontinued upon return. Pharmacokinetic data and studies on drug-sparing AP regimens suggest this to be the case. Nevertheless, the evidence is weak and considered insufficient to modify current recommendations. Field trials require large numbers of travelers and inherently suffer from the lack of a control group. Safely-designed controlled human malaria infection trials could significantly reduce study participant numbers and safely establish an effective AP abbreviated regimen which we propose as the optimal trial design to test this concept.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Humanos , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Proguanil/farmacologia , Proguanil/uso terapêutico , Atovaquona/farmacologia , Atovaquona/uso terapêutico , Malária/tratamento farmacológico , Malária/prevenção & controle , Combinação de Medicamentos , Viagem , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle
8.
Chembiochem ; 23(19): e202200340, 2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-35877976

RESUMO

The interactions between bacteria and their host often rely on recognition processes that involve host or bacterial glycans. Glycoengineering techniques make it possible to modify and study the glycans on the host's eukaryotic cells, but only a few are available for the study of bacterial glycans. Here, we have adapted selective exoenzymatic labeling (SEEL), a chemical reporter strategy, to label the lipooligosaccharides of the bacterial pathogen Neisseria gonorrhoeae, using the recombinant glycosyltransferase ST6Gal1, and three synthetic CMP-sialic acid derivatives. We show that SEEL treatment does not affect cell viability and can introduce an α2,6-linked sialic acid with a reporter group on the lipooligosaccharides by Western blot, flow cytometry and fluorescent microscopy. This new bacterial glycoengineering technique allows for the precise modification, here with α2,6-sialoside derivatives, and direct detection of specific surface glycans on live bacteria, which will aid in further unravelling the precise biological functions of bacterial glycans.


Assuntos
Ácido N-Acetilneuramínico do Monofosfato de Citidina , Neisseria gonorrhoeae , Ácido N-Acetilneuramínico do Monofosfato de Citidina/metabolismo , Glicosiltransferases/metabolismo , Lipopolissacarídeos , Ácido N-Acetilneuramínico , Polissacarídeos Bacterianos/metabolismo , Ácidos Siálicos/metabolismo
9.
Travel Med Infect Dis ; 49: 102365, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35661741

RESUMO

BACKGROUND: Atovaquone/proguanil (AP) is a highly effective malaria chemoprophylaxis combination. According to current guidelines, AP is taken once daily during, and continued for seven days post exposure. A systematic review by Savelkoel et al. summarised data up to 2017 on abbreviated AP regimens, and concluded that discontinuing AP upon return may be effective, although the available data was insufficient to modify current recommendations. The same applies to other studies evaluating during-travel dose-sparing regimens. METHODS: A literature search in Pubmed and Embase was performed including search terms related to AP prophylaxis and pharmacokinetics to search for recent studies on abbreviated AP regimens published since 2017. RESULTS: Since the 2017 review, no new studies assessing discontinuing AP ad-hoc post-exposure prophylaxis have been published. Two new studies were identified assessing other abbreviated AP regimens; one investigated a twice-weekly AP regimen in 32 travellers, and one a three-day AP course in therapeutic dose (1000/400 mg) prior to exposure in 215 travellers. No malaria cases were detected in the study participants adhering to these regimens. CONCLUSIONS: Further research would be needed if the research question is considered of sufficient importance to facilitate evidence-based decision-making to modify current guidelines, as efficacy studies in travellers are fraught with confounders. We recommend human challenge trials to study abbreviated AP regimens pertaining to malaria chemoprophylaxis as they allow for rational, subject number, time- and cost-saving trial designs.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Combinação de Medicamentos , Humanos , Malária/tratamento farmacológico , Malária/prevenção & controle , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Proguanil/uso terapêutico , Viagem
10.
Glycobiology ; 32(1): 11-22, 2022 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-34939094

RESUMO

All bacteria display surface-exposed glycans that can play an important role in their interaction with the host and in select cases mimic the glycans found on host cells, an event called molecular or glycan mimicry. In this review, we highlight the key bacteria that display human glycan mimicry and provide an overview of the involved glycan structures. We also discuss the general trends and outstanding questions associated with human glycan mimicry by bacteria. Finally, we provide an overview of several techniques that have emerged from the discipline of chemical glycobiology, which can aid in the study of the composition, variability, interaction and functional role of these mimicking glycans.


Assuntos
Mimetismo Molecular , Polissacarídeos , Bactérias , Glicômica , Humanos , Polissacarídeos/química , Polissacarídeos Bacterianos
13.
Open Forum Infect Dis ; 7(7): ofaa251, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32715018

RESUMO

BACKGROUND: Experimental murine models and human challenge studies of Salmonella Typhi infection have suggested that the gut microbiome plays an important protective role against the development of typhoid fever. Anaerobic bacterial communities have been hypothesized to mediate colonization resistance against Salmonella species by producing short-chain fatty acids, yet the composition and function of the intestinal microbiota in human patients with typhoid fever remain ill defined. METHODS: We prospectively collected fecal samples from 60 febrile patients admitted to Chittagong Medical College Hospital, Bangladesh, with typhoid fever or nontyphoidal febrile illness and from 36 healthy age-matched controls. The collected fecal samples were subjected to 16s rRNA sequencing followed by targeted metabolomics analysis. RESULTS: Patients with typhoid fever displayed compositional and functional disruption of the gut microbiota compared with patients with nontyphoidal febrile illness and healthy controls. Specifically, typhoid fever patients had lower microbiota richness and alpha diversity and a higher prevalence of potentially pathogenic bacterial taxa. In addition, a lower abundance of short-chain fatty acid-producing taxa was seen in typhoid fever patients. The differences between typhoid fever and nontyphoidal febrile illness could not be explained by a loss of colonization resistance after antibiotic treatment, as antibiotic exposure in both groups was similar. CONCLUSIONS: his first report on the composition and function of the gut microbiota in patients with typhoid fever suggests that the restoration of these intestinal commensal microorganisms could be targeted using adjunctive, preventive, or therapeutic strategies.

14.
Infect Immun ; 87(8)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31109950

RESUMO

The Gram-negative intracellular pathogen Burkholderia pseudomallei is the causative agent of melioidosis, an important cause of sepsis in Southeast Asia. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is essential for an appropriate immune response during pathogen invasion. In patients with melioidosis, TLR5 is the most abundantly expressed TLR, and a hypofunctional TLR5 variant has been associated with improved survival. Here, we studied the functional role of TLR5 and its ligand flagellin in experimental melioidosis. First, we observed differential TLR5 expression in the pulmonary and hepatic compartments upon infection with B. pseudomallei Next, we found that B. pseudomallei-challenged TLR5-deficient (Tlr5-/- ) mice were more susceptible to infection than wild-type (WT) mice, as demonstrated by higher systemic bacterial loads, increased organ injury, and impaired survival. Lung bacterial loads were not different between the two groups. The phenotype was flagellin independent; no difference in in vivo virulence was observed for the flagellin-lacking mutant MM36 compared to the wild-type B. pseudomallei strain 1026b. Tlr5-/- mice showed a similar impaired antibacterial defense when infected with MM36 or 1026b. Ex vivo experiments showed that TLR5-deficient macrophages display markedly impaired phagocytosis of B. pseudomallei In conclusion, these data suggest that TLR5 deficiency has a detrimental flagellin-independent effect on the host response against pulmonary B. pseudomallei infection.


Assuntos
Melioidose/etiologia , Receptor 5 Toll-Like/fisiologia , Animais , Burkholderia pseudomallei/fisiologia , Feminino , Flagelina/metabolismo , Humanos , Pulmão/patologia , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/fisiologia
15.
J Am Chem Soc ; 140(36): 11424-11437, 2018 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-30107725

RESUMO

The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human ß2 and ß5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial drugs.


Assuntos
Artemisininas/farmacologia , Plasmodium falciparum/enzimologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Artemisininas/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Inibidores de Proteassoma/química , Relação Estrutura-Atividade
16.
J Infect ; 77(1): 60-67, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29746945

RESUMO

OBJECTIVES: Typhoid fever caused by Salmonella Typhi remains a major burden worldwide. Gastrointestinal bleeding can be seen in up to 10 percent of patients and may be fatal. The coagulopathy, which may be the driver of this severe complication in patients with typhoid fever, however is ill defined. The aim of this study was to evaluate the activation of coagulation, anticoagulation, and fibrinolysis in patients with acute typhoid fever. METHODS: Parameters of coagulation and fibrinolysis were measured in 28 hospitalized patients with culture-confirmed or PCR-confirmed typhoid fever and compared to 38 age- and sex-matched healthy volunteers. RESULTS: Patients demonstrated activation of the coagulation system, as reflected by elevated in vitro thrombin generation and high plasma levels of fibrinogen, D-dimer and prothrombin fragment F1 + 2 in concert with consumption of coagulation factors resulting in a prolonged prothrombin-time and activated-partial-thromboplastin-time. Concurrently, the anticoagulant proteins, protein C and antithrombin, were significantly lower in comparison to healthy controls. Patients also demonstrated evidence of activation and inhibition of fibrinolysis and a marked activation of endothelial cells. The extent of coagulation activation was associated with the course of the disease, repeated testing during convalescence showed a return toward normal values. CONCLUSIONS: Activation of coagulation is an important clinical feature of typhoid fever and is associated with severity of disease.


Assuntos
Coagulação Sanguínea , Endotélio/patologia , Fibrinólise , Febre Tifoide/sangue , Febre Tifoide/complicações , Adulto , Anticoagulantes , Bangladesh , Células Endoteliais/microbiologia , Células Endoteliais/patologia , Endotélio/citologia , Endotélio/microbiologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Reação em Cadeia da Polimerase , Estudos Prospectivos , Protrombina , Salmonella typhi/genética , Salmonella typhi/isolamento & purificação , Índice de Gravidade de Doença , Trombocitopenia , Febre Tifoide/patologia , Adulto Jovem
17.
Int J Infect Dis ; 72: 63-68, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29778583

RESUMO

Intravesical bacillus Calmette-Guérin (BCG) is widely used for high-risk, non-muscle-invasive bladder cancer. This report describes four cases that illustrate the spectrum of BCG-induced complications, varying from granulomatous prostatitis to sepsis. There is considerable debate regarding whether inflammation or infection is the predominant mechanism in the pathogenesis of BCG disease. In two patients with a systemic illness, the symptoms first resolved after adding prednisone, indicating a principal role for inflammation in systemic disease. In vitro testing of T-cell responses and a mycobacterial growth inhibition assay were performed for these patients with systemic disease. The patient with mild symptoms showed more effective in vitro growth reduction of BCG, while the patient with sepsis and organ involvement had high T-cell responses but ineffective killing. While these findings are preliminary, it is believed that immunological assays, as described in this report, may provide a better insight into the pathogenesis of BCG disease in individual patients, justifying further research.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Antineoplásicos/uso terapêutico , Vacina BCG/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Idoso , Terapia Combinada , Humanos , Masculino , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Resultado do Tratamento , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/patologia
18.
PLoS Negl Trop Dis ; 11(7): e0005823, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28749963

RESUMO

BACKGROUND: Typhoid fever, caused by the intracellular pathogen Salmonella (S.) enterica serovar Typhi, remains a major cause of morbidity and mortality worldwide. Granzymes are serine proteases promoting cytotoxic lymphocytes mediated eradication of intracellular pathogens via the induction of cell death and which can also play a role in inflammation. We aimed to characterize the expression of extracellular and intracellular granzymes in patients with typhoid fever and whether the extracellular levels of granzyme correlated with IFN-γ release. METHODS AND PRINCIPAL FINDINGS: We analyzed soluble protein levels of extracellular granzyme A and B in healthy volunteers and patients with confirmed S. Typhi infection on admission and day of discharge, and investigated whether this correlated with interferon (IFN)-γ release, a cytokine significantly expressed in typhoid fever. The intracellular expression of granzyme A, B and K in subsets of lymphocytic cells was determined using flow cytometry. Patients demonstrated a marked increase of extracellular granzyme A and B in acute phase plasma and a correlation of both granzymes with IFN-γ release. In patients, lower plasma levels of granzyme B, but not granzyme A, were found at day of discharge compared to admission, indicating an association of granzyme B with stage of disease. Peripheral blood mononuclear cells of typhoid fever patients had a higher percentage of lymphocytic cells expressing intracellular granzyme A and granzyme B, but not granzyme K, compared to controls. CONCLUSION: The marked increase observed in extra- and intracellular levels of granzyme expression in patients with typhoid fever, and the correlation with stage of disease, suggests a role for granzymes in the host response to this disease.


Assuntos
Granzimas/sangue , Interferon gama/sangue , Febre Tifoide/sangue , Adulto , Bangladesh , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Salmonella typhi/isolamento & purificação , Linfócitos T/imunologia , Febre Tifoide/diagnóstico , Adulto Jovem
19.
J Infect ; 75(2): 104-114, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28551371

RESUMO

OBJECTIVES: The diagnosis of typhoid fever is a challenge. Aiming to develop a typhoid diagnostic we measured antibody responses against Salmonella Typhi (S. Typhi) protein antigens and the Vi polysaccharide in a cohort of Bangladeshi febrile patients. METHODS: IgM against 12 purified antigens and the Vi polysaccharide was measured by ELISA in plasma from patients with confirmed typhoid fever (n = 32), other confirmed infections (n = 17), and healthy controls (n = 40). ELISAs with the most specific antigens were performed on plasma from 243 patients with undiagnosed febrile disease. RESULTS: IgM against the S. Typhi protein antigens correlated with each other (rho > 0.8), but not against Vi (rho < 0.6). Typhoid patients exhibited higher IgM against 11/12 protein antigens and Vi than healthy controls and those with other infections. Vi, PilL, and CdtB exhibited the greatest sensitivity and specificity. Specificity and sensitivity was improved when Vi was combined with a protein antigen, generating sensitivities and specificities of 0.80 and >0.85, respectively. Applying a dynamic cut-off to patients with undiagnosed febrile disease suggested that 34-58% had an IgM response indicative of typhoid. CONCLUSIONS: We evaluated the diagnostic potential of several S. Typhi antigens; our assays give good sensitivity and specificity, but require further assessment in differing patient populations.


Assuntos
Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Técnicas Bacteriológicas/métodos , Salmonella typhi/imunologia , Febre Tifoide/diagnóstico , Bangladesh , Humanos , Imunoglobulina M/sangue , Polissacarídeos Bacterianos/imunologia , Febre Tifoide/imunologia
20.
Elife ; 62017 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-28483042

RESUMO

Salmonella Typhi is the causative agent of typhoid. Typhoid is diagnosed by blood culture, a method that lacks sensitivity, portability and speed. We have previously shown that specific metabolomic profiles can be detected in the blood of typhoid patients from Nepal (Näsström et al., 2014). Here, we performed mass spectrometry on plasma from Bangladeshi and Senegalese patients with culture confirmed typhoid fever, clinically suspected typhoid, and other febrile diseases including malaria. After applying supervised pattern recognition modelling, we could significantly distinguish metabolite profiles in plasma from the culture confirmed typhoid patients. After comparing the direction of change and degree of multivariate significance, we identified 24 metabolites that were consistently up- or down regulated in a further Bangladeshi/Senegalese validation cohort, and the Nepali cohort from our previous work. We have identified and validated a metabolite panel that can distinguish typhoid from other febrile diseases, providing a new approach for typhoid diagnostics.


Assuntos
Metabolômica/métodos , Plasma/química , Salmonella typhi/crescimento & desenvolvimento , Salmonella typhi/metabolismo , Febre Tifoide/diagnóstico , Febre Tifoide/patologia , Bangladesh , Humanos , Espectrometria de Massas , Senegal
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