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Molecular characterization of Orientia tsutsugamushi causing scrub typhus among febrile patients in north-central Bangladesh.

ABSTRACT: Scrub typhus is a mite-borne rickettsial disease caused by Orientia tsutsugamushi, which is endemic in Asia Pacific region. In this study, infection rate and molecular epidemiologic traits of O. tsutsugamushi was investigated in Mymensingh, located in north-central Bangladesh. Among the blood samples from 453 febrile patients who visited Mymensingh medical college hospital in 2018, the 47 kDa protein gene of O. tsutsugamushi was detected in 78 samples (17.2%) by nested PCR. Phylogenetic analysis of the O. tsutsugamushi 56 kDa protein gene (18 samples) revealed a predominance of Karp-related genotype (89%), while the remaining belonged to Gilliam genotype. Samples of the Karp-related genotype mostly clustered with those of China, Taiwan, Thailand and India, etc., in emergent subgroups clades 2 and 4, which were distinct from clade 1, including prototype Karp strains. Among the 18 samples, three variable domains (VD) of 56 kDa type-specific antigen had different types of sequence diversity; VDI contained two or three repeats of eight amino acid units, while VDII and VDIII had amino acid substitution, deletion or insertion. The present study documented a potentially high prevalence of genetically diverse O. tsutsugamushi in north-central Bangladesh.

SUBMITTER: Al Amin MM

PROVIDER: S-EPMC6796758 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Molecular characterization of Orientia tsutsugamushi causing scrub typhus among febrile patients in north-central Bangladesh.

Al Amin M M MM Paul S K SK Aung M S MS Paul A A Aziz M A MA Khan N A NA Haque A K M F AKMF Ahamed F F Melan A A Sarker S R SR Hossain M A MA Ahmed S S Nasreen S A SA Haque N N Kobayashi N N

New microbes and new infections 20190827

Scrub typhus is a mite-borne rickettsial disease caused by Orientia tsutsugamushi, which is endemic in Asia Pacific region. In this study, infection rate and molecular epidemiologic traits of O. tsutsugamushi was investigated in Mymensingh, located in north-central Bangladesh. Among the blood samples from 453 febrile patients who visited Mymensingh medical college hospital in 2018, the 47 kDa protein gene of O. tsutsugamushi was detected in 78 samples (17.2%) by nested PCR. ...[more]

PMID: 31641512

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Project description:BackgroundScrub typhus, a bacterial infection caused by Orientia tsutsugamushi, is increasingly recognized as an important cause of fever in Asia, with an estimated one million infections occurring each year. Limited access to health care and the disease's non-specific symptoms mean that many patients are undiagnosed and untreated, but the mortality from untreated scrub typhus is unknown. This review systematically summarizes the literature on the untreated mortality from scrub typhus and disease outcomes.Methodology/principal findingsA literature search was performed to identify patient series containing untreated patients. Patients were included if they were symptomatic and had a clinical or laboratory diagnosis of scrub typhus and excluded if they were treated with antibiotics. The primary outcome was mortality from untreated scrub typhus and secondary outcomes were total days of fever, clinical symptoms, and laboratory results. A total of 76 studies containing 89 patient series and 19,644 patients were included in the final analysis. The median mortality of all patient series was 6.0% with a wide range (min-max) of 0-70%. Many studies used clinical diagnosis alone and had incomplete data on secondary outcomes. Mortality varied by location and increased with age and in patients with myocarditis, delirium, pneumonitis, or signs of hemorrhage, but not according to sex or the presence of an eschar or meningitis. Duration of fever was shown to be long (median 14.4 days Range (9-19)).ConclusionsResults show that the untreated mortality from scrub typhus appears lower than previously reported estimates. More data are required to clarify mortality according to location and host factors, clinical syndromes including myocarditis and central nervous system disease, and in vulnerable mother-child populations. Increased surveillance and improved access to diagnostic tests are required to accurately estimate the untreated mortality of scrub typhus. This information would facilitate reliable quantification of DALYs and guide empirical treatment strategies.

Project description:BACKGROUND:Scrub typhus, a febrile illness of substantial incidence and mortality, is caused by infection with the obligately intracellular bacterium Orientia tsutsugamushi. It is estimated that there are more than one million cases annually transmitted by the parasitic larval stage of trombiculid mites in the Asia-Pacific region. The antigenic and genetic diversity of the multiple strains of O. tsutsugamushi hinders the advancement of laboratory diagnosis, development of long-lasting vaccine-induced protection, and interpretation of clinical infection. Despite the life-threatening severity of the illness in hundreds of thousands of cases annually, 85-93% of patients survive, often without anti-rickettsial treatment. To more completely understand the disease caused by Orientia infection, animal models which closely correlate with the clinical manifestations, target cells, organ involvement, and histopathologic lesions of human cases of scrub typhus should be employed. Previously, our laboratory has extensively characterized two relevant C57BL/6 mouse models using O. tsutsugamushi Karp strain: a route-specific intradermal model of infection and persistence and a hematogenously disseminated dose-dependent lethal model. PRINCIPAL FINDINGS:To complement the lethal model, here we illustrate a sublethal model in the same mouse strain using the O. tsutsugamushi Gilliam strain, which resulted in dose-dependent severity of illness, weight loss, and systemic dissemination to endothelial cells of the microcirculation and mononuclear phagocytic cells. Histopathologic lesions included expansion of the pulmonary interstitium by inflammatory cell infiltrates and multifocal hepatic lesions with mononuclear cellular infiltrates, renal interstitial lymphohistiocytic inflammation, mild meningoencephalitis, and characteristic typhus nodules. SIGNIFICANCE:These models parallel characteristics of human cases of scrub typhus, and will be used in concert to understand differences in severity which lead to lethality or host control of the infection and to address the explanation for short duration of heterologous immunity in Orientia infection.

Project description:Orientia tsutsugamushi (Ots) is an obligate, intracellular, mite-transmitted human pathogen which causes scrub typhus. Understanding the diversity of Ots antigens is essential for designing specific diagnostic assays and efficient vaccines. The protective immunodominant type-specific 56 kDa antigen (TSA) of Ots varies locally and across its geographic distribution. TSA contains four hypervariable domains. We bioinformatically analyzed 345 partial sequences of TSA available from India, most of which contain only the three variable domains (VDI-III) and three spacer conserved domains (SVDI, SVDII/III, SVDIII). The total number (152) of antigenic types (amino acid variants) varied from 14-36 in the six domains of TSA that we studied. Notably, 55% (787/1435) of the predicted CD4 T-cell epitopes (TCEs) from all the six domains had high binding affinities (HBA) to at least one of the prevalent Indian human leukocyte antigen (HLA) alleles. A surprisingly high proportion (61%) of such TCEs were from spacer domains; indeed 100% of the CD4 TCEs in the SVDI were HBA. TSA sequences from India had more antigenic types (AT) than TSA from Korea. Overall, >90% of predicted CD4 TCEs from spacer domains were predicted to have HBA against one or more prevalent HLA types from Indian, Korean, Asia-Pacific region or global population data sets, while only <50% of CD4 TCEs in variable domains exhibited such HBA. The phylogenetically and immunologically important amino acids in the conserved spacer domains were identified. Our results suggest that the conserved spacer domains are predicted to be functionally more important than previously appreciated in immune responses to Ots infections. Changes occurring at the TCE level of TSA may contribute to the wide range of pathogenicity of Ots in humans and mouse models. CD4 T-cell functional experiments are needed to assess the immunological significance of these HBA spacer domains and their role in clearance of Ots from Indian patients.

Dataset Information

Molecular characterization of Orientia tsutsugamushi causing scrub typhus among febrile patients in north-central Bangladesh.

Publications

Molecular characterization of <i>Orientia tsutsugamushi</i> causing scrub typhus among febrile patients in north-central Bangladesh.

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