Induction of Protective Immunity Against Scrub Typhus With a 56-Kilodalton Recombinant Antigen Fused With a 47-Kilodalton Antigen of Orientia Tsutsugamushi Karp

Wen, Bin; Wen, Bin; Niu, Dongsheng; Chen, Mei‐Ling; Qiu, Ling

doi:10.4269/ajtmh.2005.72.458

Cited by 39 publications

(52 citation statements)

References 34 publications

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“…MLD50. Thus, Balb/c mice were infected with diluted doses of an immunofocus assay-quantified inoculum in order to determine the MLD50 by probit analysis as reported previously [29] (Fig. 1D, right panel).…”

Section: Resultsmentioning

confidence: 99%

Dissemination of Orientia tsutsugamushi and Inflammatory Responses in a Murine Model of Scrub Typhus

et al. 2014

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Central aspects in the pathogenesis of scrub typhus, an infection caused by Orientia (O.) tsutsugamushi, have remained obscure. Its organ and cellular tropism are poorly understood.The purpose of this study was to analyze the kinetics of bacterial dissemination and associated inflammatory responses in infected tissues in an experimental scrub typhus mouse model, following infection with the human pathogenic strain Karp. We provide a thorough analysis of O. tsutsugamushi infection in inbred Balb/c mice using footpad inoculation, which is close to the natural way of infection. By a novel, highly sensitive qPCR targeting the multi copy traD genes, we quantitatively monitored the spread of O. tsutsugamushi Karp from the skin inoculation site via the regional lymph node to the internal target organs. The highest bacterial loads were measured in the lung. Using confocal imaging, we also detected O. tsutsugamushi at the single cell level in the lung and found a predominant macrophage rather than endothelial localization. Immunohistochemical analysis of infiltrates in lung and brain revealed differently composed lesions with specific localizations: iNOS-expressing macrophages were frequent in infiltrative parenchymal noduli, but uncommon in perivascular lesions within these organs. Quantitative analysis of the macrophage response by immunohistochemistry in liver, heart, lung and brain demonstrated an early onset of macrophage activation in the liver. Serum levels of interferon (IFN)-γ were increased during the acute infection, and we showed that IFN-γ contributed to iNOS-dependent bacterial growth control.Our data show that upon inoculation to the skin, O. tsutsugamushi spreads systemically to a large number of organs and gives rise to organ-specific inflammation patterns. The findings suggest an essential role for the lung in the pathogenesis of scrub typhus. The model will allow detailed studies on host-pathogen interaction and provide further insight into the pathogenesis of O. tsutsugamushi infection.

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Section: Resultsmentioning

confidence: 99%

Dissemination of Orientia tsutsugamushi and Inflammatory Responses in a Murine Model of Scrub Typhus

et al. 2014

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“…This protein is a member of the HtrA protein family, which is characterized by serine protease and chaperone activities. The 47-kD HtrA gene and gene product of the Karp strain have been used to develop DNA (Niu et al 2003, Xu et al 2005) and recombinant protein (Niu et al 2003, Yu et al 2005) vaccine candidates displaying immunogenicity and efficacy in mouse scrub typhus models. Recent evaluations in our laboratory have shown not only that the pKarp47 DNA vaccine candidate is highly effective in protecting CD-1 outbred mice from homologous challenge, but also in protecting them from heterologous challenge from 4 of 17 disparate isolates using a single immunization (A.L.R., unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Diversity of the 47-kD HtrA Nucleic Acid and Translated Amino Acid Sequences from 17 Recent Human Isolates ofOrientia

Jiang

Paris

Blacksell

et al. 2013

Vector-Borne and Zoonotic Diseases

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Orientia tsutsugamushi, the etiologic agent of potentially fatal scrub typhus, is characterized by a high antigenic diversity, which complicates the development of a broadly protective vaccine. Efficacy studies in murine and nonhuman primate models demonstrated the DNA vaccine candidate pKarp47, based upon the O. tsutsugamushi Karp 47-kD HtrA protein gene, to be a successful immunoprophylactic against scrub typhus. To characterize 47-kD HtrA protein diversity among human isolates of Orientia, we sequenced the full open reading frame (ORF) of the 47-kD HtrA gene and analyzed the translated amino acid sequences of 17 patient isolates from Thailand (n=13), Laos (n=2), Australia (n=1), and the United Arab Emirates (UAE) (n=1) and 9 reference strains: Karp (New Guinea), Kato (Japan), Ikeda (Japan), Gilliam (Burma), Boryong (Korea), TA763, TH1811 and TH1817 (Thailand), and MAK243 (China). The percentage identity (similarity) of translated amino acid sequences between 16 new isolates and 9 reference strains of O. tsutsugamushi ranged from 96.4% to 100% (97.4% to 100%). However, inclusion of the recently identified Orientia chuto sp. nov. reduced identity (similarity) values to 82.2% to 83.3% (90.4% to 91.4%). These results demonstrate the diversity of Orientia 47-kD HtrA among isolates encountered by humans and therefore provide support for the necessity of developing a broadly protective scrub typhus vaccine that takes this diversity into account.

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“…These developments are presently driving renewed efforts to develop a vaccine, particularly by the US Department of Defense. Modern technologies such as DNA vaccines [67][68][69], recombinant proteins [70][71][72], and combination DNA-protein vaccines appear to be promising strategies for disease prevention, as was recently suggested elsewhere [38].…”

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confidence: 99%

Scrub Typhus: The Geographic Distribution of Phenotypic and Genotypic Variants ofOrientia tsutsugamushi

et al. 2009

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Orientia tsutsugamushi is the etiological agent of scrub typhus, an acute, mite-borne, febrile illness that occurs in the Asia-Pacific region. Historically, strain characterization used serological analysis and revealed dramatic antigenic diversity. Eyeing a recommendation of potential vaccine candidates for broad protection, we review geographic diversity and serological and DNA prevalences. DNA analysis together with immunological analysis suggest that the prototype Karp strain and closely related strains are the most common throughout the region of endemicity. According to serological analysis, approximately 50% of isolates are seroreactive to Karp antisera, and approximately one-quarter of isolates are seroreactive to antisera against the prototype Gilliam strain. Molecular methods reveal greater diversity. By molecular methods, strains phylogenetically similar to Karp make up approximately 40% of all genotyped isolates, followed by the JG genotype group (Japan strains serotypically similar to the Gilliam strain but genetically non-Gilliam; 18% of all genotyped isolates). Three other genotype groups (Kato-related, Kawasaki-like, and TA763-like) each represent approximately 10% of genotyped isolates. Strains genetically similar to the Gilliam strain make up only 5% of isolates. Strains from these groups should be included in any potential vaccine.

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Induction of Protective Immunity Against Scrub Typhus With a 56-Kilodalton Recombinant Antigen Fused With a 47-Kilodalton Antigen of Orientia Tsutsugamushi Karp

Cited by 39 publications

References 34 publications

Dissemination of Orientia tsutsugamushi and Inflammatory Responses in a Murine Model of Scrub Typhus

Dissemination of Orientia tsutsugamushi and Inflammatory Responses in a Murine Model of Scrub Typhus

Diversity of the 47-kD HtrA Nucleic Acid and Translated Amino Acid Sequences from 17 Recent Human Isolates ofOrientia

Scrub Typhus: The Geographic Distribution of Phenotypic and Genotypic Variants ofOrientia tsutsugamushi

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