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Intranasal immunization with recombinant Toxoplasma gondii actin depolymerizing factor confers protective efficacy against toxoplasmosis in mice.

ABSTRACT: Toxoplasma gondii is an opportunistic protozoan closely associated with AIDS and vertical transmission. T. gondii actin depolymerizing factor (TgADF) plays an important role in actin cytoskeleton remodeling, and it is required to invade host cells. TgADF was a promising vaccine candidate. To observe the immunological changes and protective efficacy of recombinant TgADF protein (rTgADF) against T. gondii infection, we optimized the intranasal immunization dose of rTgADF and analyzed the survival rate and tachyzoite loads in mouse tissues after oral challenge with T. gondii tachyzoites.rTgADF was prepared, purified, and combined with mouse anti-His antibody and rabbit anti-T. gondii serum. After intranasal immunization with 10 ?g, 20 ?g, 30 ?g, or 40 ?g of rTgADF, the 30-?g group elicited high levels of secretory IgA (sIgA) in nasal, intestinal, and vesical washes, raised IgG titres in the sera, strong proliferation of splenocytes, and increased secretion of IL-2 and IFN-? when compared with the control group. When the mice were orally challenged with T. gondii, an increase in the survival rate (36.36 %) and a decrease in the tachyzoite loads in the liver (67.77 %) and brain (51.01 %) were observed.Our findings demonstrate that intranasal immunization with rTgADF can simultaneously trigger mucosal and systemic immune responses and protect the mice against T. gondii infection.

SUBMITTER: Liu Z

PROVIDER: S-EPMC5053087 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Intranasal immunization with recombinant Toxoplasma gondii actin depolymerizing factor confers protective efficacy against toxoplasmosis in mice.

Liu Zhuanzhuan Z Yin Litian L Li Yaqing Y Yuan Fei F Zhang Xiaofan X Ma Jiazhi J Liu Hongmei H Wang Yanjuan Y Zheng Kuiyang K Cao Jianping J

BMC immunology 20161006 1

<h4>Background</h4>Toxoplasma gondii is an opportunistic protozoan closely associated with AIDS and vertical transmission. T. gondii actin depolymerizing factor (TgADF) plays an important role in actin cytoskeleton remodeling, and it is required to invade host cells. TgADF was a promising vaccine candidate. To observe the immunological changes and protective efficacy of recombinant TgADF protein (rTgADF) against T. gondii infection, we optimized the intranasal immunization dose of rTgADF and ana ...[more]

PMID: 27716047

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Project description:Toxoplasma gondii is a ubiquitous protozoan intracellular parasite, the causative agent of toxoplasmosis, and a worldwide zoonosis for which an effective vaccine is needed. Actin is a highly conserved microfilament protein that plays an important role in the invasion of host cells by T. gondii. This study investigated the immune responses elicited by BALB/c mice after nasal immunisation with a recombinant T. gondii actin (rTgACT) and the subsequent protection against chronic and lethal T. gondii infections. We evaluated the systemic response by proliferation, cytokine and antibody measurements, and we assessed the mucosal response by examining the levels of TgACT-specific secretory IgA (SIgA) in nasal, vaginal and intestinal washes. Parasite load was assessed in the liver and brain, and the survival of mice challenged with a virulent strain was determined. The results showed that the mice immunised with rTgACT developed high levels of specific anti-rTgACT IgG titres and a mixed IgG1/IgG2a response with a predominance of IgG2a. The systemic immune response was associated with increased production of Th1 (IFN-? and IL-2), Th2 (IL-4) and Treg (IL-10) cytokines, indicating that not only Th1-type response was induced, but also Th2- and Treg-types responses were induced, and the splenocyte stimulation index (SI) was increased in the mice immunised with rTgACT. Nasal immunisation with rTgACT led to strong mucosal immune responses, as seen by the increased secretion of SIgA in nasal, vaginal and intestinal washes. The vaccinated mice displayed significant protection against lethal infection with the virulent RH strain (survival increased by 50%), while the mice chronically infected with RH exhibited lower liver and brain parasite loads (60.05% and 49.75%, respectively) than the controls. Our data demonstrate, for the first time, that actin triggers a strong systemic and mucosal response against T. gondii. Therefore, actin may be a promising vaccine candidate against toxoplasmosis.

Project description:Streptococcus pneumoniae is a bacterial pathogen that causes various diseases of public health concern worldwide. Current pneumococcal vaccines target the capsular polysaccharide surrounding the cells. However, only up to 13 of more than 90 pneumococcal capsular serotypes are represented in the current conjugate vaccines. In this study, we used two experimental approaches to evaluate the potential of Streptococcus mitis, a commensal that exhibits immune cross-reactivity with S. pneumoniae, to confer protective immunity to S. pneumoniae lung infection in mice. First, we assessed the immune response and protective effect of wild-type S. mitis against lung infection by S. pneumoniae strains D39 (serotype 2) and TIGR4 (serotype 4). Second, we examined the ability of an S. mitis mutant expressing the S. pneumoniae type 4 capsule (S. mitis TIGR4cps) to elicit focused protection against S. pneumoniae TIGR4. Our results showed that intranasal immunization of mice with S. mitis produced significantly higher levels of serum IgG and IgA antibodies reactive to both S. mitis and S. pneumoniae, as well as enhanced production of interleukin 17A (IL-17A), but not gamma interferon (IFN-γ) and IL-4, compared with control mice. The immunization resulted in a reduced bacterial load in respiratory tissues following lung infection with S. pneumoniae TIGR4 or D39 compared with control mice. With S. mitis TIGR4cps, protection upon challenge with S. pneumoniae TIGR4 was superior. Thus, these findings show the potential of S. mitis to elicit natural serotype-independent protection against two pneumococcal serotypes and to provide the benefits of the well-recognized protective effect of capsule-targeting vaccines.IMPORTANCEStreptococcus pneumoniae causes various diseases worldwide. Current pneumococcal vaccines protect against a limited number of more than 90 pneumococcal serotypes, accentuating the urgent need to develop novel prophylactic strategies. S. pneumoniae and the commensal Streptococcus mitis share immunogenic characteristics that make S. mitis an attractive vaccine candidate against S. pneumoniae In this study, we evaluated the potential of S. mitis and its mutant expressing pneumococcal capsule type 4 (S. mitis TIGR4cps) to induce protection against S. pneumoniae lung infection in mice. Our findings show that intranasal vaccination with S. mitis protects against S. pneumoniae strains D39 (serotype 2) and TIGR4 (serotype 4) in a serotype-independent fashion, which is associated with enhanced antibody and T cell responses. Furthermore, S. mitis TIGR4cps conferred additional protection against S. pneumoniae TIGR4, but not against D39. The findings highlight the potential of S. mitis to generate protection that combines both serotype-independent and serotype-specific responses.

Project description:BACKGROUND: Toxoplasma gondii can infect all warm-blooded animals including humans. Infection with T. gondii is probably the leading cause of posterior uveitis in humans and the most comment route of transmission is raw and undercooked meat from infected animals. T. gondii calcium-dependent protein kinase 1 (TgCDPK1) plays a critical role in direct parasite motility, host-cell invasion, and egress. METHODS: We constructed a DNA vaccine expressing TgCDPK1 inserted into eukaryotic expression vector pVAX I and evaluated the immune protection induced by pVAX-CDPK1 in Kunming mice. Mice immunized with pVAX-CDPK1 intramuscularly and/or with a plasmid encoding IL-15 and IL-21 (pVAX-IL-21-IL-15). The immune responses were analyzed including lymphoproliferative assay, cytokine, antibody measurements, lymphocyte surface markers by flow cytometry and protective efficacy were measured as survival and cysts numbers after challenge 1 to 2 months post vaccination. RESULTS: Immunization with pVAX-CDPK1 or pVAX-IL-21-IL-15 alone developed strong humoral responses and Th1 type cellular immune responses, and the significantly (P < 0.05) increase of both the percentages of CD4+ and CD8+ T cells compared with all the controls (blank control, PBS, and pVAX). Co-injection of pVAX-IL-21-IL-15 significantly increased humoral and cellular immune responses compared to the group of pVAX-CDPK1 or pVAX-IL-21-IL-15. Challenge experiments showed that co-administration of pVAX-IL-21-IL-15 and pVAX-CDPK1 significantly (P < 0.05) increased survival time (19.2 ± 5.1 days) compared with pVAX-CDPK1 (17.3 ± 4.3 days) or pVAX-IL-21-IL-15 (12.0 ± 2.0 days) alone, and pVAX-IL-21-IL-15 +?pVAX-CDPK1 significantly reduced the number of brain cysts (72.7%) in contrast to pVAX-ROP13 (45.7%) or pVAX-IL-21-IL-15 alone (43.6%). CONCLUSIONS: TgCDPK1 is identified to be a promising vaccine candidate for inducing a strong humoral and cellular response against T. gondii infection, and thus synergistic of mIL-21 and mIL-15 can induce non-specific immune responses, but also facilitate specific humoral as well as cellular immune responses elicited by DNA vaccine against acute and chronic T. gondii infection in mice.

Dataset Information

Intranasal immunization with recombinant Toxoplasma gondii actin depolymerizing factor confers protective efficacy against toxoplasmosis in mice.

Publications

Intranasal immunization with recombinant Toxoplasma gondii actin depolymerizing factor confers protective efficacy against toxoplasmosis in mice.

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