Dataset Information

Origins, Importance and Genetic Stability of the Prototype Strains Gilliam, Karp and Kato of Orientia tsutsugamushi.

ABSTRACT: Scrub typhus, a chigger-borne febrile illness, occurs primarily in countries of the Asia-Pacific rim and islands of the Western Pacific. The etiologic agent is the obligate intracellular rickettsial bacterium Orientia tsutsugamushi. Research on O. tsutsugamushi has relied on the availability of several prototype strains, which were isolated from human cases of scrub typhus in the 1940s and 1950s. We review the history of the three original, and most important, prototype strains, Gilliam, Karp and Kato, including information on their isolation, their culture history, their clinical characteristics, their importance within the research literature on scrub typhus, and recent advances in elucidating their molecular genomics. The importance of these strains to the research and development of clinical tools related to scrub typhus is also considered. Finally, we examine whether the strains have been genetically stable since their isolation, and whether prototype strains maintained in separate laboratories are identical, based on pairwise comparisons of several sequences from four genes. By using genetic information archived in international DNA databases, we show that the prototype strains used by different laboratories are essentially identical, and that the strains have retained their genetic integrity at least since the 1950s. The three original prototype strains should remain a standard by which new diagnostic procedures are measured. Given their fundamental position in any comparative studies, they are likely to endure as a critical part of present and future research on scrub typhus and Orientia.

SUBMITTER: Kelly DJ

PROVIDER: S-EPMC6631653 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Origins, Importance and Genetic Stability of the Prototype Strains Gilliam, Karp and Kato of Orientia tsutsugamushi.

Kelly Daryl J DJ Fuerst Paul A PA Richards Allen L AL

Tropical medicine and infectious disease 20190430 2

Scrub typhus, a chigger-borne febrile illness, occurs primarily in countries of the Asia-Pacific rim and islands of the Western Pacific. The etiologic agent is the obligate intracellular rickettsial bacterium Orientia tsutsugamushi. Research on O. tsutsugamushi has relied on the availability of several prototype strains, which were isolated from human cases of scrub typhus in the 1940s and 1950s. We review the history of the three original, and most important, prototype strains, Gi ...[more]

PMID: 31052283

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Project description:Scrub typhus is a leading cause of febrile illness in endemic countries due to infection with Orientia tsutsugamushi (Ot), a seriously understudied intracellular bacterium. Pulmonary involvement associated with vascular parasitism in patients is common and can develop into life threatening interstitial pneumonia. The diverse antigenicity of Ot genotypes and inter-strain differences in genome content are connected to varied virulence and clinical outcomes; however, detailed studies of strain-related pulmonary immune responses in human patients or small animal models of infection are lacking. In this study, we have used two clinically prevalent bacterial strains (Karp and Gilliam) to reveal cellular immune responses in inflamed lungs and potential biomarkers of disease severity. The results demonstrate that outbred CD-1 mice are highly susceptible to both Karp and Gilliam strains; however, C57BL/6 (B6) mice were susceptible to Karp, but resistant to Gilliam (with self-limiting infection), corresponding to their tissue bacterial burdens and lung pathological changes. Multicolor flow cytometric analyses of perfused B6 mouse lungs revealed robust and sustained influx and activation of innate immune cells (macrophages, neutrophils, and NK cells), followed by CD4+ and CD8+ T cells, during Karp infection, but such responses were greatly attenuated during Gilliam infection. The robust cellular responses in Karp-infected B6 mice positively correlated with significantly early and high levels of serum cytokine/chemokine protein levels (CXCL1, CCL2/3/5, and G-CSF), as well as pulmonary gene expression (Cxcl1/2, Ccl2/3/4, and Ifng). In vitro infection of B6 mouse-derived primary macrophages also revealed bacterial strain-dependent immune gene expression profiles. This study provided the lines of evidence that highlighted differential tissue cellular responses against Karp vs. Gilliam infection, offering a framework for future investigation of Ot strain-related mechanisms of disease pathogenesis vs. infection control.

Project description:Scrub typhus also known as bush typhus is a disease with symptoms similar to Chikungunya infection. It is caused by a gram-negative bacterium Orientia tsutsugamushi which resides in its vertebrate host, Mites. The genome of Orientia tsutsugamushi str. Karp encodes for 1,563 proteins, of which 344 are characterized as hypothetical ones. In the present study, we tried to identify the probable functions of these 344 hypothetical proteins (HPs). All the characterized hypothetical proteins (HPs) belong to the various protein classes like enzymes, transporters, binding proteins, metabolic process and catalytic activity and kinase activity. These hypothetical proteins (HPs) were further analyzed for virulence factors with 62 proteins identified as the most virulent proteins among these hypothetical proteins (HPs). In addition, we studied the protein sequence similarity network for visualizing functional trends across protein superfamilies from the context of sequence similarity and it shows great potential for generating testable hypotheses about protein structure-function relationships. Furthermore, we calculated toplogical properties of the network and found them to obey network power law distributions showing a fractal nature. We also identifed two highly interconnected modules in the main network which contained five hub proteins (KJV55465, KJV56211, KJV57212, KJV57203 and KJV57216) having 1.0 clustering coefficient. The structural modeling (2D and 3D structure) of these five hub proteins was carried out and the catalytic site essential for its functioning was analyzed. The outcome of the present study may facilitate a better understanding of the mechanism of virulence, pathogenesis, adaptability to host and up-to-date annotations will make unknown genes easy to identify and target for experimentation. The information on the functional attributes and virulence characteristic of these hypothetical proteins (HPs) are envisaged to facilitate effective development of novel antibacterial drug targets of Orientia tsutsugamushi.

Project description:BackgroundScrub typhus is a vector-borne febrile illness caused by Orientia tsutsugamushi transmitted by the bite of Trombiculid mites. O. tsutsugamushi has a high genetic diversity and is increasingly recognized to have a wider global distribution than previously assumed.Methodology/principle findingsWe evaluated the clinical outcomes and host immune responses of the two most relevant human pathogenic strains of O. tsutsugamushi; Karp (n = 4) and Gilliam (n = 4) in a time-course study over 80 days post infection (dpi) in a standardized scrub typhus non-human primate rhesus macaque model. We observed distinct features in clinical progression and immune response between the two strains; Gilliam-infected macaques developed more pronounced systemic infection characterized by an earlier onset of bacteremia, lymph node enlargement, eschar lesions and higher inflammatory markers during the acute phase of infection, when compared to the Karp strain. C-reactive protein (CRP) plasma levels, interferon gamma (IFN-γ, interleukin-1 receptor antagonist (IL-1ra), IL-15 serum concentrations, CRP/IL10- and IFN-γ/IL-10 ratios correlated positively with bacterial load in blood, implying activation of the innate immune response and preferential development of a T helper-type 1 immune response. The O. tsutsugamushi-specific immune memory responses in cells isolated from skin and lymph nodes at 80 dpi were more markedly elevated in the Gilliam-infected macaques than in the Karp-infected group. The comparative cytokine response dynamics of both strains revealed significant up-regulation of IFN-γ, tumor necrosis factor (TNF), IL-15, IL-6, IL-18, regulatory IL-1ra, IL-10, IL-8 and granulocyte-colony-stimulating factor (G-CSF). These data suggest that the clinical outcomes and host immune responses to scrub typhus could be associated with counter balancing effects of pro- and anti-inflammatory cytokine-mediated responses. Currently, no data on characterized time-course comparisons of O. tsutsugamushi strains regarding measures of disease severity and immune response is available. Our study provides evidence for the strain-specificity of host responses in scrub typhus, which supports our understanding of processes at the initial inoculation site (eschar), systemic disease progression, protective and/or pathogenic host immune mechanisms and cellular immune memory function.Conclusions/significanceThis study characterised an improved intradermal rhesus macaque challenge model for scrub typhus, whereby the Gilliam strain infection associated with higher disease severity in the rhesus macaque model than the previous Karp strain infection. Difficulties associated with inoculum quantitation for obligate-intracellular bacteria were overcome by using functional inoculum titrations in outbred mice. The Gilliam-based rhesus macaque model provides improved endpoint measurements and contributes towards the identification of correlates of protection for future vaccine development.

Dataset Information

Origins, Importance and Genetic Stability of the Prototype Strains Gilliam, Karp and Kato of Orientia tsutsugamushi.

Publications

Origins, Importance and Genetic Stability of the Prototype Strains Gilliam, Karp and Kato of <i>Orientia tsutsugamushi</i>.

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