Scrub Typhus Vaccine Candidate Kp r56 Induces Humoral and Cellular Immune Responses in Cynomolgus Monkeys

Chattopadhyay, Suchismita; Jiang, Ju; Chan, Teik-Chye; Manetz, T. Scott; Chao, Chien‐Chung; Ching, Wei‐Mei; Richards, Allen L.

doi:10.1128/iai.73.8.5039-5047.2005

Cited by 53 publications

(58 citation statements)

References 52 publications

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“…Recent increases in the number of scrub typhus cases, coupled with observations of reduced effectiveness of antibiotic treatments (7)(8)(9)(10), have highlighted the need for effective vaccines. However, vaccine development has been hampered by a limited host immune response (11) and O. tsutsugamushi's ability to immunosuppress the host (12).…”

Section: Scrub Typhus Is Caused By the Obligate Intracellular Rickettsiamentioning

confidence: 99%

The Orientia tsutsugamushi genome reveals massive proliferation of conjugative type IV secretion system and host–cell interaction genes

Cho

Kim

Lee

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

216

259

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Scrub typhus is caused by the obligate intracellular rickettsiaOrientia tsutsugamushi (previously called Rickettsia tsutsugamushi). The bacterium is maternally inherited in trombicuid mites and transmitted to humans by feeding larvae. We report here the 2,127,051-bp genome of the Boryong strain, which represents the most highly repeated bacterial genome sequenced to date. The repeat density of the scrub typhus pathogen is 200-fold higher than that of its close relative Rickettsia prowazekii, the agent of epidemic typhus. A total of 359 tra genes for components of conjugative type IV secretion systems were identified at 79 sites in the genome. Associated with these are >200 genes for signaling and host-cell interaction proteins, such as histidine kinases, ankyrin-repeat proteins, and tetratrico peptide-repeat proteins. Additionally, the O. tsutsugamushi genome contains >400 transposases, 60 phage integrases, and 70 reverse transcriptases. Deletions and rearrangements have yielded unique gene combinations as well as frequent pseudogenization in the tra clusters. A comparative analysis of the tra clusters within the genome and across strains indicates sequence homogenization by gene conversion, whereas complexity, diversity, and pseudogenization are acquired by duplications, deletions, and transposon integrations into the amplified segments. The results suggest intragenomic duplications or multiple integrations of a massively proliferating conjugative transfer system. Diversifying selection on host-cell interaction genes along with repeated population bottlenecks may drive rare genome variants to fixation, thereby short-circuiting selection for low complexity in bacterial genomes.bacterial genome ͉ duplication ͉ repeats

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Section: Scrub Typhus Is Caused By the Obligate Intracellular Rickettsiamentioning

confidence: 99%

The Orientia tsutsugamushi genome reveals massive proliferation of conjugative type IV secretion system and host–cell interaction genes

Cho

Kim

Lee

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

216

259

View full text Add to dashboard Cite

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“…Symptoms may be triggered mostly through immune cells in the skin and in local lymph nodes, rather than resulting from immediate systemic distribution of bacteria. This would make it less likely that the infecting dose of O. tsutsugamushi influences measured bacteremia (2). The virulence of the infecting strain may also be an important contribution.…”

Section: Vol 47 2009mentioning

confidence: 99%

Orientia tsutsugamushiBacteremia and Cytokine Levels in Vietnamese Scrub Typhus Patients

Kramme

An²,

Khoa³

et al. 2009

J Clin Microbiol

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Scrub typhus, caused by the intracellular bacterium Orientia tsutsugamushi, is a major cause of febrile illness in the Asia/Pacific region. Here, we implemented a novel real-time PCR and determined the relation of DNA target gene concentration with serum cytokine levels. The limit of detection of the novel real-time PCR was 1,062 DNA copies per ml of EDTA whole blood. Specificity was excellent as determined on a panel of blood-and skin-borne bacteria, including Rickettsia spp. as well as healthy Vietnamese blood donors. Bacterial DNA concentrations after 9 to 12 days from symptoms onset were significantly higher than in earlier or later periods (P < 0.05). Significantly higher concentrations of gamma interferon (IFN-␥) and interleukin-10 (IL-10) occurred during the acute phase of disease (<10 days from onset) as opposed to the convalescent phase (P < 0.05). No significant differences were observed between the acute and the convalescent phases for tumor necrosis factor alpha (TNF-␣) and IL-1␤ concentrations. Regression analysis of DNA concentrations and cytokine levels identified a significant positive relationship for IL-10 (P < 0.0182) but not for IFN-␥, TNF-␣, and IL-1␤. In conclusion, proinflammatory cytokines and IL-10 were differentially related to human bacteremia. They may thus be induced by different constituents of O. tsutsugamushi. As a future prospect in a clinical diagnostic laboratory, quantitative real-time PCR may serve as a reliable tool to monitor therapy and to detect treatment failure.

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“…Serological analyses show that the antigenicity of the 56-kDa protein is diverse and includes variants such as the representative Karp-, Gilliam-, and Kato-type strains and other isolates (2,8,18). The immune responses to the 56-kDa protein provide protection against Scrub typhus, suggesting that it is a potential candidate for vaccine development (3,16,33). No commercially licensed vaccine for scrub typhus is currently available.…”

mentioning

confidence: 99%

Genetic Typing, Based on the 56-Kilodalton Type-Specific Antigen Gene, of Orientia tsutsugamushi Strains Isolated from Chiggers Collected from Wild-Caught Rodents in Taiwan

Lin

Tsai

Tsui

et al. 2011

Appl Environ Microbiol

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Orientia tsutsugamushi is the etiological agent of scrub typhus, a mite-borne, febrile illness that occurs in the Asia-Pacific region. We conducted strain characterization of O. tsutsugamushi isolates from chiggers obtained from rodents based the nucleotide sequence of the 56-kDa outer membrane protein gene. With the use of PCR, a total of 68 DNA sequences of 56-kDa antigen genes were amplified. Phylogenetic analysis revealed that there were at least six definable clusters among the 68 isolates: 37% Karp-related strains (25/68), 27% TA763 strains (18/68), 12% JG-related strains (8/68), 19% Kato-related strains (13/68), 4% divergent strains (3/68), and 1% representing a Gilliam prototype strain (1/68). Overall, the O. tsutsugamushi genotypes exhibited a high degree of diversity, similar to that seen in strains from the rest of the areas where scrub typhus is endemic. Orientia tsutsugamushi is an obligate intracellular, Gramnegative bacterium that causes scrub typhus, an acute febrile illness characterized by a typical primary lesion (eschar), lymphadenopathy, and nonspecific symptoms such as chills, headache, and malaise (10, 24). The disease is endemic in Asian countries, including Japan, South Korea, China, Thailand, and Taiwan (6, 13). An estimated 1 million cases occur annually (22). However, the precise incidence of this disease is unknown, as the available diagnostic facilities in most of the region of endemicity are limited (32). In nature, the bacterial agent is maintained within a life cycle involving wild mammals and a mite vector, primarily of the Leptotrombidium genus (14). Humans are accidentally infected by the bites of a larval mite, known as a chigger, during feeding (30).The 56-kDa type-specific antigen (TSA) gene encodes a dominant membrane protein, which accounts for 10% to 15% of the total protein of O. tsutsugamushi (17). The deduced size of the 56-kDa protein varies from 516 to 541 amino acids, according to gene sequences deposited in the GenBank (11). It is highly immunogenic, and the sera of most patients with scrub typhus are reactive. Serological analyses show that the antigenicity of the 56-kDa protein is diverse and includes variants such as the representative Karp-, Gilliam-, and Kato-type strains and other isolates (2,8,18). The immune responses to the 56-kDa protein provide protection against Scrub typhus, suggesting that it is a potential candidate for vaccine development (3,16,33). No commercially licensed vaccine for scrub typhus is currently available.In the present study, we cloned and sequenced the 56-kDa TSA gene of O. tsutsugamushi isolated from the chigger mite obtained from a rodent in order to understand the genetic types as well as the relationships with other known strains. Our results demonstrated that the genotypes of O. tsutsugamushi isolates appeared highly diverse and widely and geographically distributed in Taiwan. MATERIALS AND METHODSStudy site and arthropod collection. All the arthropods used in this study were collected from rodents captured by randomly settin...

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Scrub Typhus Vaccine Candidate Kp r56 Induces Humoral and Cellular Immune Responses in Cynomolgus Monkeys

Cited by 53 publications

References 52 publications

The Orientia tsutsugamushi genome reveals massive proliferation of conjugative type IV secretion system and host–cell interaction genes

The Orientia tsutsugamushi genome reveals massive proliferation of conjugative type IV secretion system and host–cell interaction genes

Orientia tsutsugamushiBacteremia and Cytokine Levels in Vietnamese Scrub Typhus Patients

Genetic Typing, Based on the 56-Kilodalton Type-Specific Antigen Gene, of Orientia tsutsugamushi Strains Isolated from Chiggers Collected from Wild-Caught Rodents in Taiwan

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