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Immunization with an autotransporter protein of Orientia tsutsugamushi provides protective immunity against scrub typhus.

Ha NY, Sharma P, Kim G, Kim Y, Min CK, Choi MS, Kim IS, Cho NH - PLoS Negl Trop Dis (2015)

Bottom Line: Despite the wide range of preventative approaches that have been attempted in the past 70 years, all have failed to develop an effective prophylactic vaccine.Currently, the selection of the proper antigens is one of the critical barriers to generating cross-protective immunity against antigenically-variable strains of O. tsutsugamushi.Our findings demonstrate that ScaA functions as a bacterial adhesion factor, and anti-ScaA antibody significantly neutralizes bacterial infection of host cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.

ABSTRACT

Background: Scrub typhus is an acute febrile disease caused by Orientia tsutsugamushi infection. Recently, the rapid increase of scrub typhus incidence in several countries within the endemic region has become a serious public health issue. Despite the wide range of preventative approaches that have been attempted in the past 70 years, all have failed to develop an effective prophylactic vaccine. Currently, the selection of the proper antigens is one of the critical barriers to generating cross-protective immunity against antigenically-variable strains of O. tsutsugamushi.

Methodology/principal findings: We examined the potential role of ScaA protein, an autotransporter protein of O. tsutsugamushi, in bacterial pathogenesis and evaluated the protective attributes of ScaA immunization in lethal O. tsutsugamushi infection in mice. Our findings demonstrate that ScaA functions as a bacterial adhesion factor, and anti-ScaA antibody significantly neutralizes bacterial infection of host cells. In addition, immunization with ScaA not only provides protective immunity against lethal challenges with the homologous strain, but also confers significant protection against heterologous strains when combined with TSA56, a major outer membrane protein of O. tsutsugamushi.

Conclusions/significance: Immunization of ScaA proteins provides protective immunity in mice when challenged with the homologous strain and significantly enhanced protective immunity against infection with heterologous strains. To our knowledge, this is the most promising result of scrub typhus vaccination trials against infection of heterologous strains in mouse models thus far.

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Related in: MedlinePlus

Protective role of ScaA or combined immunization against heterologous strain infection.Mice (n = 5/group) were immunized with the indicated antigens and challenged intraperitoneally with 10 x LD50 (A) or 100 x LD50 (B) of O. tsutsugamushi. Mice were immunized with antigens from the Boryong strain and challenged with the indicated strains (BR: Boryong, KP: Karp, KT: Kato). p value and median survival are summarized in S3 Fig. *, p < 0.05; **, p < 0.01.
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pntd.0003585.g004: Protective role of ScaA or combined immunization against heterologous strain infection.Mice (n = 5/group) were immunized with the indicated antigens and challenged intraperitoneally with 10 x LD50 (A) or 100 x LD50 (B) of O. tsutsugamushi. Mice were immunized with antigens from the Boryong strain and challenged with the indicated strains (BR: Boryong, KP: Karp, KT: Kato). p value and median survival are summarized in S3 Fig. *, p < 0.05; **, p < 0.01.

Mentions: Next, we tested whether the candidate bacterial antigens could provide protective immunity against heterologous strain infection. Each group of mice were immunized with the indicated antigens derived from the O. tsutsugamushi Boryong strain and then challenged with a low (10 × LD50) or high (100 × LD50) dose of Boryong, Karp, or Kato strains (Fig. 4 and S3 Fig). We confirmed significant increases of both type 1 (IgG2C) [46] and type 2 (IgG1) antibodies against ScaA and/or TSA56 after third immunization (S4 Fig). Following infection with O. tsutsugamushi, mock-immunized mice began to lose body weight between 8–12 d after inoculation, depending on the bacterial doses and strains challenged, and lost 10–25% of body weight before they expired (S5 Fig). All the unimmunized mice had expired by 10–17 d after infection. The immunized mice survived after infection with O. tsutsugamushi maintained normal body weight during the experiment, but the expired ones rapidly lost their body weight from 4–8 d before death. All the mice immunized with ScaA or TSA56 were protected from the homologous Boryong strain regardless of infection dose, and were also protected against low dose (10 × LD50) Karp strain infection. When mice were challenged with high dose (100 × LD50) Karp strain infection, all the mice immunized with both ScaA and TSA56 survived and 80% of ScaA-immunized mice were protected. Although TSA56 immunization also provide significant protection (40% survival, p value = 0.017) compared to mock-immunized control group, the protection level was significantly (p value = 0.049) lower than that afforded by vaccination with both ScaA and TSA56 antigens. In the groups challenged with low dose Kato strain, groups immunized with both ScaA and TSA56 showed the best protective effect (60% survival) and TSA56 immunization provided only 20% survival. Immunization with ScaA also provided significant protection (40% survival). Although the level of protection afforded by ScaA (median survival = 22 d) was higher than that of TSA56 (median survival = 19 d), the difference was not statistically significant (p > 0.05). In contrast, ScaA vaccination (median survival = 18 d) significantly prolonged the survival of mice compared to TSA56 and mock-immunization (p < 0.01, median survival = 15 d in both groups) when mice were challenged with high dose of Kato strain. Immunization of TSA56 together with ScaA provided a similar level of protection as that observed in the ScaA immunization group even though all the challenged mice ultimately succumbed to pathogen infection.


Immunization with an autotransporter protein of Orientia tsutsugamushi provides protective immunity against scrub typhus.

Ha NY, Sharma P, Kim G, Kim Y, Min CK, Choi MS, Kim IS, Cho NH - PLoS Negl Trop Dis (2015)

Protective role of ScaA or combined immunization against heterologous strain infection.Mice (n = 5/group) were immunized with the indicated antigens and challenged intraperitoneally with 10 x LD50 (A) or 100 x LD50 (B) of O. tsutsugamushi. Mice were immunized with antigens from the Boryong strain and challenged with the indicated strains (BR: Boryong, KP: Karp, KT: Kato). p value and median survival are summarized in S3 Fig. *, p < 0.05; **, p < 0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359152&req=5

pntd.0003585.g004: Protective role of ScaA or combined immunization against heterologous strain infection.Mice (n = 5/group) were immunized with the indicated antigens and challenged intraperitoneally with 10 x LD50 (A) or 100 x LD50 (B) of O. tsutsugamushi. Mice were immunized with antigens from the Boryong strain and challenged with the indicated strains (BR: Boryong, KP: Karp, KT: Kato). p value and median survival are summarized in S3 Fig. *, p < 0.05; **, p < 0.01.
Mentions: Next, we tested whether the candidate bacterial antigens could provide protective immunity against heterologous strain infection. Each group of mice were immunized with the indicated antigens derived from the O. tsutsugamushi Boryong strain and then challenged with a low (10 × LD50) or high (100 × LD50) dose of Boryong, Karp, or Kato strains (Fig. 4 and S3 Fig). We confirmed significant increases of both type 1 (IgG2C) [46] and type 2 (IgG1) antibodies against ScaA and/or TSA56 after third immunization (S4 Fig). Following infection with O. tsutsugamushi, mock-immunized mice began to lose body weight between 8–12 d after inoculation, depending on the bacterial doses and strains challenged, and lost 10–25% of body weight before they expired (S5 Fig). All the unimmunized mice had expired by 10–17 d after infection. The immunized mice survived after infection with O. tsutsugamushi maintained normal body weight during the experiment, but the expired ones rapidly lost their body weight from 4–8 d before death. All the mice immunized with ScaA or TSA56 were protected from the homologous Boryong strain regardless of infection dose, and were also protected against low dose (10 × LD50) Karp strain infection. When mice were challenged with high dose (100 × LD50) Karp strain infection, all the mice immunized with both ScaA and TSA56 survived and 80% of ScaA-immunized mice were protected. Although TSA56 immunization also provide significant protection (40% survival, p value = 0.017) compared to mock-immunized control group, the protection level was significantly (p value = 0.049) lower than that afforded by vaccination with both ScaA and TSA56 antigens. In the groups challenged with low dose Kato strain, groups immunized with both ScaA and TSA56 showed the best protective effect (60% survival) and TSA56 immunization provided only 20% survival. Immunization with ScaA also provided significant protection (40% survival). Although the level of protection afforded by ScaA (median survival = 22 d) was higher than that of TSA56 (median survival = 19 d), the difference was not statistically significant (p > 0.05). In contrast, ScaA vaccination (median survival = 18 d) significantly prolonged the survival of mice compared to TSA56 and mock-immunization (p < 0.01, median survival = 15 d in both groups) when mice were challenged with high dose of Kato strain. Immunization of TSA56 together with ScaA provided a similar level of protection as that observed in the ScaA immunization group even though all the challenged mice ultimately succumbed to pathogen infection.

Bottom Line: Despite the wide range of preventative approaches that have been attempted in the past 70 years, all have failed to develop an effective prophylactic vaccine.Currently, the selection of the proper antigens is one of the critical barriers to generating cross-protective immunity against antigenically-variable strains of O. tsutsugamushi.Our findings demonstrate that ScaA functions as a bacterial adhesion factor, and anti-ScaA antibody significantly neutralizes bacterial infection of host cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.

ABSTRACT

Background: Scrub typhus is an acute febrile disease caused by Orientia tsutsugamushi infection. Recently, the rapid increase of scrub typhus incidence in several countries within the endemic region has become a serious public health issue. Despite the wide range of preventative approaches that have been attempted in the past 70 years, all have failed to develop an effective prophylactic vaccine. Currently, the selection of the proper antigens is one of the critical barriers to generating cross-protective immunity against antigenically-variable strains of O. tsutsugamushi.

Methodology/principal findings: We examined the potential role of ScaA protein, an autotransporter protein of O. tsutsugamushi, in bacterial pathogenesis and evaluated the protective attributes of ScaA immunization in lethal O. tsutsugamushi infection in mice. Our findings demonstrate that ScaA functions as a bacterial adhesion factor, and anti-ScaA antibody significantly neutralizes bacterial infection of host cells. In addition, immunization with ScaA not only provides protective immunity against lethal challenges with the homologous strain, but also confers significant protection against heterologous strains when combined with TSA56, a major outer membrane protein of O. tsutsugamushi.

Conclusions/significance: Immunization of ScaA proteins provides protective immunity in mice when challenged with the homologous strain and significantly enhanced protective immunity against infection with heterologous strains. To our knowledge, this is the most promising result of scrub typhus vaccination trials against infection of heterologous strains in mouse models thus far.

Show MeSH
Related in: MedlinePlus