An Alternative Splicing Variant of the Mixed-Lineage Leukemia 5 Protein Is a Cellular Adhesion Receptor for ScaA of Orientia tsutsugamushi

Nguyen, Yen Thi Hai; Kim, Chaewon; Kim, Hong-Il; Kim, Yuri; Lee, Sang-Eun; Chang, Sunghoe; Ha, Na-Young; Cho, Nam Hyuk

doi:10.1128/mbio.01543-22

Cited by 3 publications

(4 citation statements)

References 43 publications

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“…Since the final submission of this a valuable article has been published includes valid assay for neutralizing antibodies to O. tsutsugamushi 57 .…”

Section: Addendummentioning

confidence: 99%

A scrub typhus vaccine presents a challenging unmet need

Walker

Mendell

2023

npj Vaccines

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Scrub typhus caused by the obligately intracellular bacterium, Orientia tsutsugamushi, is a major cause of life-threatening acute undifferentiated febrile illness in eastern Asia and the islands of the Western Pacific and Indian oceans. Since the estimation of an incidence of 1 million cases annually two decades ago, the number of cases has increased substantially in endemic regions, reappeared where the disease was forgotten, and spread northward. Trombiculid mites are both reservoir and vector. Despite 80 years of efforts to develop a vaccine, there is none. Protective immunity is mediated by antibodies and CD8 and CD4 T cells. Previous efforts have failed because of gaps in understanding immunity to O. tsutsugamushi, particularly the requirements for vaccine-induced immunity, lack of knowledge regarding immune memory in scrub typhus, and lack of attention to addressing the issue of cross-protection between strains. There are numerous strains of O. tsutsugamushi, and modestly durable immunity is strain-specific. Antibodies to the strain that caused infection are protective against challenges with the homologous strain but, despite reactivity with other immunodominant antigens, the immune serum does not protect against heterologous strains. Among the antigens detected by western immunoblot in immune sera (22-, 47-, 56-, 58-, and 110 kDa proteins), only the 56 kDa protein stimulates strong protection. This protein contains four hypervariable regions which are likely, on the basis of limited data, to be the targets of neutralizing antibodies. However, a method that definitively detects neutralizing antibody has yet to be developed. Only one study has used genomic data to pursue the discovery of protective antigens. Three conserved autotransporters were identified, and only immunization with ScaA provided protection against the homologous strain, but only 40% of animals were protected against challenge with a heterologous strain. A multiplex vaccine containing conformational antigens of the hypervariable regions of the 56 kDa protein of the strains of the greatest clinical and epidemiological importance, as well as conserved regions of the 56 kDa protein, ScaA, and other protective antigens identified by future genomic and bioinformatics methods should be developed and tested.

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“…Since the final submission of this a valuable article has been published includes valid assay for neutralizing antibodies to O. tsutsugamushi 57 .…”

Section: Addendummentioning

confidence: 99%

A scrub typhus vaccine presents a challenging unmet need

Walker

Mendell

2023

npj Vaccines

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“…The translocation mechanism of TSA56 has not been described, but it possesses an N-terminal signal peptide that appears to be cleaved [ 10 ]. ScaA requires a conserved block (CB2, Boryong aa 843 to 875) and involves its flanking regions (fragments F4 and F5, Boryong aa 607 to 994 and 867 to 1241) for attachment, with F5 exhibiting the highest immunogenicity (i.e., anti-ScaA IgG titer) [ 42 ]. TSA56 primarily binds fibronectin at its surface-exposed antigen domain III and adjacent C-terminal region (Boryong aa 312 to 341) [ 11 ], which is relatively conserved [ 74 ] and may work in concert with ScaC [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…TA686 and Karp also possessed similar ScaC, and whether ScaF is also involved in adherence in these strains should be determined. Most studies on adherence have been conducted using nonphagocytic cells [ 11 , 42 , 43 , 86 ], but O. tsutsugamushi also infects monocytes and antigen-presenting cells at the site of inoculation [ 88 ]. It has yet to be determined whether variation in core Sca proteins or the presence of accessory Sca proteins control cellular tropism, which could explain variation in strain-level virulence among mice strains and nonhuman primates [ 89 ].…”

Section: Discussionmentioning

confidence: 99%

“…Intact genes encoding ScaA, ScaC, ScaD, and ScaE are present in all complete O. tsutsugamushi genomes sequenced to date (i.e., core genes), while genes encoding ScaB and ScaF are only present in a subset of strains (i.e., accessory genes). Among core Sca proteins, only ScaA and ScaC are of known function and are involved in cellular attachment, binding to an isoform of the mixed-lineage leukemia 5 protein [ 42 ] and fibronectin [ 43 ], respectively. Like TSA56, Sca proteins (particularly ScaA) are immunogenic [ 44 ] yet reveal different phylogenetic relationships [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

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Concatenated ScaA and TSA56 Surface Antigen Sequences Reflect Genome-Scale Phylogeny of Orientia tsutsugamushi: An Analysis Including Two Genomes from Taiwan

Minahan,

Yen,

Guo

et al. 2024

Pathogens

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Orientia tsutsugamushi is an obligate intracellular bacterium associated with trombiculid mites and is the causative agent of scrub typhus, a life-threatening febrile disease. Strain typing of O. tsutsugamushi is based on its immunodominant surface antigen, 56-kDa type-specific antigen (TSA56). However, TSA56 gene sequence-based phylogenetic analysis is only partially congruent with core genome-based phylogenetic analysis. Thus, this study investigated whether concatenated surface antigen sequences, including surface cell antigen (Sca) proteins, can reflect the genome-scale phylogeny of O. tsutsugamushi. Complete genomes were obtained for two common O. tsutsugamushi strains in Taiwan, TW-1 and TW-22, and the core genome/proteome was identified for 11 O. tsutsugamushi strains. Phylogenetic analysis was performed using maximum likelihood (ML) and neighbor-joining (NJ) methods, and the congruence between trees was assessed using a quartet similarity measure. Phylogenetic analysis based on 691 concatenated core protein sequences produced identical tree topologies with ML and NJ methods. Among TSA56 and core Sca proteins (ScaA, ScaC, ScaD, and ScaE), TSA56 trees were most similar to the core protein tree, and ScaA trees were the least similar. However, concatenated ScaA and TSA56 sequences produced trees that were highly similar to the core protein tree, the NJ tree being more similar. Strain-level characterization of O. tsutsugamushi may be improved by coanalyzing ScaA and TSA56 sequences, which are also important targets for their combined immunogenicity.

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An atlas of human vector-borne microbe interactions reveals pathogenicity mechanisms

Hart,

Sonnert,

Tang

et al. 2024

Cell

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An Alternative Splicing Variant of the Mixed-Lineage Leukemia 5 Protein Is a Cellular Adhesion Receptor for ScaA of Orientia tsutsugamushi

Abstract: O. tsutsugamushi is a mite-borne pathogen that causes scrub typhus. As an obligately intracellular pathogen, its adhesion to and invasion of host cells are critical steps for bacterial growth.

Cited by 3 publications

References 43 publications

A scrub typhus vaccine presents a challenging unmet need

A scrub typhus vaccine presents a challenging unmet need

Concatenated ScaA and TSA56 Surface Antigen Sequences Reflect Genome-Scale Phylogeny of Orientia tsutsugamushi: An Analysis Including Two Genomes from Taiwan

An atlas of human vector-borne microbe interactions reveals pathogenicity mechanisms

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