Enhancing immune responses by a novel multi-epitope ROP8 DNA vaccine plus interleukin-12 plasmid as a genetic adjuvant against acute Toxoplasma gondii infection in BALB/c mice

Toxoplasma gondii is a threat for immunocompromized individuals, and no treatment is available for enhancing immunity against infection. Molecular adjuvants may improve the efficacy of DNA vaccine-induced T cell immunity. Here, we report that cocktailed DNA immunization with ROP5 and ROP18 boosted immune responses induced by a single DNA immunization with ROP5 or ROP18, but also that co-administration of molecular adjuvant IL-33 enhanced immune efficacy induced by this cocktailed DNA vaccination. These improved immune responses were characterized by higher Toxoplasma-specific IgG2a titers, Th1 responses associated with the production of IFN-γ, IL-2, IL-12, as well as cell-mediated activity with higher frequencies of CD8+ and CD4+ T cells. More importantly, this enhanced immunity has the ability to confer remarkable protection against a high dose lethal challenge of the T. gondii RH strain and thus against chronic infection with the T. gondii PRU strain. These data show that IL-33 is a promising immunoadjuvant to facilitate humoral as well as cellular immunity in a vaccine setting against T. gondii, and suggest that it should be evaluated in strategies against other apicomplexan parasites.

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Immune Responses Induced by HSP60 DNA Vaccine against Toxoplasma gondii Infection in Kunming Mice

The Korean Journal of Parasitology ◽

10.3347/kjp.2018.56.3.237 ◽

2018 ◽

Vol 56 (3) ◽

pp. 237-245

Author(s):

Zhong-Yuan Li ◽

Jing Lu ◽

Nian-Zhang Zhang ◽

Jia Chen ◽

Xing-Quan Zhu

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Dna Vaccine ◽

Toxoplasma Gondii Infection

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Immune Responses Induced by pVAX/TgERK7 against Toxoplasma gondii Infection in BALB/c Mice

Iranian Journal of Parasitology ◽

10.18502/ijpa.v14i4.2097 ◽

2019 ◽

Author(s):

Hai-Ting GUO ◽

Zhong-Yuan LI ◽

Jin-Lei WANG ◽

Zhao-Yu GENG ◽

Xing-Quan ZHU

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Dna Vaccine ◽

Survival Times ◽

Vaccine Strategy ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Extracellular Signal ◽

Significant Difference ◽

Toxoplasma Gondii Infection

Background: Toxoplasma gondii can infect all the warm-blooded vertebrates and cause serious toxoplasmosis. Extracellular signal-regulated kinase 7 in T. gondii (TgERK7) mediated the proliferation of this parasite may be a potential vaccine candidate. Thus, immune responses induced by TgERK7 were investigated in this study using a DNA vaccine strategy. Methods: pVAX/TgERK7 plasmid was constructed and used to immunize BALB/c mice for three times with two-week intervals. The challenge and the investigation of humoral and cellular immune responses were performed at two weeks post the last immunization, and the survival times of the infected mice were daily recorded until all of them were dead. Results: The innate immune response with higher concentrations of IFN-γ, TNF-α, IL2 and IL12p70 in sera (P < 0.05), and the adaptive immune responses were evoked by the DNA immunizations, including specific antibody, lymphocyte proliferation, and the CD3e+CD4+ and CD3e+CD8a+ T cell-mediated response effects. Interestingly, no significant difference was detected in their survival times among all the experimental groups of mice that were challenged with GT1 tachyzoites or PRU cysts (P>0.05). Conclusion: The successive immunizations with pVAX/TgERK7 can provoke the innate and adaptive immune responses of BALB/c mice, whereas the DNA vaccine-induced immunological efficacy is not sufficient for complete protection the host against T. gondii infection.

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Induction of Protective Immune Responses by a Multiantigenic DNA Vaccine Encoding GRA7 and ROP1 of Toxoplasma gondii

Clinical and Vaccine Immunology ◽

10.1128/cvi.05385-11 ◽

2012 ◽

Vol 19 (5) ◽

pp. 666-674 ◽

Cited By ~ 31

Author(s):

Juan-Hua Quan ◽

Jia-Qi Chu ◽

Hassan Ahmed Hassan Ahmed Ismail ◽

Wei Zhou ◽

Eun-Kyeong Jo ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Dna Vaccine ◽

Protective Efficacy ◽

Single Gene ◽

Reduction Rate ◽

Interleukin 12 ◽

Content Type ◽

Tnf Α ◽

Ifn Γ

ABSTRACTToxoplasma gondiiis distributed worldwide and infects most species of warm-blooded animals, including humans. The heavy incidence and severe or lethal damage caused byT. gondiiinfection clearly indicates the need for the development of a vaccine. To evaluate the protective efficacy of a multiantigenic DNA vaccine expressing GRA7 and ROP1 ofT. gondiiwith or without a plasmid encoding murine interleukin-12 (pIL12), we constructed DNA vaccines using the eukaryotic plasmids pGRA7, pROP1, and pGRA7-ROP1. Mice immunized with pGRA7, pROP1, or pGRA7-ROP1 showed significantly increased serum IgG2a titers; production of gamma interferon (IFN-γ), IL-10, and tumor necrosis factor alpha (TNF-α);in vitroT cell proliferation; and survival, as well as decreased cyst burdens in the brain, compared to mice immunized with either the empty plasmid, pIL12, or vector with pIL12 (vector+pIL12). Moreover, mice immunized with the multiantigenic DNA vaccine pGRA7-ROP1 had higher IgG2a titers, production of IFN-γ and TNF-α, survival time, and cyst reduction rate compared to those of mice vaccinated with either pGRA7 or pROP1 alone. Furthermore, mice immunized with either a pGRA7-ROP1+pIL12 or a single-gene vaccine combined with pIL12 showed greater Th1 immune response and protective efficacy than the single-gene-vaccinated groups. Our data suggest that the multiantigenic DNA antigen pGRA7-ROP1 was more effective in stimulating host protective immune responses than separately injected single antigens, and that IL-12 serves as a good DNA adjuvant.

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Immediate Interferon Gamma Induction Determines Murine Host Compatibility Differences between Toxoplasma gondii and Neospora caninum

Infection and Immunity ◽

10.1128/iai.00027-20 ◽

2020 ◽

Vol 88 (4) ◽

Cited By ~ 1

Author(s):

Rachel S. Coombs ◽

Matthew L. Blank ◽

Elizabeth D. English ◽

Yaw Adomako-Ankomah ◽

Ifeanyi-Chukwu Samuel Urama ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Interferon Gamma ◽

Neospora Caninum ◽

Ectopic Expression ◽

Parasite Burden ◽

Interleukin 12 ◽

Content Type ◽

Ifn Γ ◽

And Control

ABSTRACT Rodents are critical for the transmission of Toxoplasma gondii to the definitive feline host via predation, and this relationship has been extensively studied as a model for immune responses to parasites. Neospora caninum is a closely related coccidian parasite of ruminants and canines but is not naturally transmitted by rodents. We compared mouse innate immune responses to N. caninum and T. gondii and found marked differences in cytokine levels and parasite growth kinetics during the first 24 h postinfection (hpi). N. caninum-infected mice produced significantly higher levels of interleukin-12 (IL-12) and interferon gamma (IFN-γ) by as early as 4 hpi, but the level of IFN-γ was significantly lower or undetectable in T. gondii-infected mice during the first 24 hpi. “Immediate” IFN-γ and IL-12p40 production was not detected in MyD88−/− mice. However, unlike IL-12p40−/− and IFN-γ−/− mice, MyD88−/− mice survived N. caninum infections at the dose used in this study. Serial measures of parasite burden showed that MyD88−/− mice were more susceptible to N. caninum infections than wild-type (WT) mice, and control of parasite burdens correlated with a pulse of serum IFN-γ at 3 to 4 days postinfection in the absence of detectable IL-12. Immediate IFN-γ was partially dependent on the T. gondii mouse profilin receptor Toll-like receptor 11 (TLR11), but the ectopic expression of N. caninum profilin in T. gondii had no impact on early IFN-γ production or parasite proliferation. Our data indicate that T. gondii is capable of evading host detection during the first hours after infection, while N. caninum is not, and this is likely due to the early MyD88-dependent recognition of ligands other than profilin.

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Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0353-9 ◽

2019 ◽

Vol 51 (12) ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Miwa Sasai ◽

Masahiro Yamamoto

Keyword(s):

Immune Response ◽

Toxoplasma Gondii ◽

Immune Responses ◽

Parasitophorous Vacuole ◽

Interferon Γ ◽

Protective Role ◽

Ifn Γ ◽

Acquired Immune Responses ◽

Toxoplasma Gondii Infection ◽

Antimicrobial Immunity

AbstractHosts have been fighting pathogens throughout the evolution of all infectious diseases. Toxoplasma gondii is one of the most common infectious agents in humans but causes only opportunistic infection in healthy individuals. Similar to antimicrobial immunity against other organisms, the immune response against T. gondii activates innate immunity and in turn induces acquired immune responses. After activation of acquired immunity, host immune cells robustly produce the proinflammatory cytokine interferon-γ (IFN-γ), which activates a set of IFN-γ-inducible proteins, including GTPases. IFN-inducible GTPases are essential for cell-autonomous immunity and are specialized for effective clearance and growth inhibition of T. gondii by accumulating in parasitophorous vacuole membranes. Recent studies suggest that the cell-autonomous immune response plays a protective role in host defense against not only T. gondii but also various intracellular bacteria. Moreover, the negative regulatory mechanisms of such strong immune responses are also important for host survival after infection. In this review, we will discuss in detail recent advances in the understanding of host defenses against T. gondii and the roles played by cell-autonomous immune responses.

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Mechanisms of innate resistance to Toxoplasma gondii infection

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1997.0120 ◽

1997 ◽

Vol 352 (1359) ◽

pp. 1355-1359 ◽

Cited By ~ 50

Author(s):

J. Alexander ◽

T. M. Scharton-Kersten ◽

G. Yap ◽

C. W. Roberts ◽

F. Y. Liew ◽

...

Keyword(s):

Nitric Oxide ◽

Toxoplasma Gondii ◽

Chronic Infection ◽

Preliminary Evidence ◽

Metabolic Inhibitors ◽

Interleukin 12 ◽

Tumour Necrosis Factor Receptor ◽

Apparent Paradox ◽

Ifn Gamma ◽

Toxoplasma Gondii Infection

The interaction of protozoan parasites with innate host defences is critical in determining the character of the subsequent infection. The initial steps in the encounter of Toxoplasma gondii with the vertebrate immune system provide a striking example of this important aspect of the host–parasite relationship. In immunocompetent individuals this intracellular protozoan produces an asymptomatic chronic infection as part of its strategy for transmission. Nevertheless, T. gondii is inherently a highly virulent pathogen. The rapid induction by the parasite of a potent cell–mediated immune response that both limits its growth and drives conversion to a dormant cyst stage explains this apparent paradox. Studies with gene–deficient mice have demonstrated the interleukin–12 (IL–12)–dependent production of interferon gamma (IFN–gamma) to be of paramount importance in controlling early parasite growth. However, this seems to be independent of nitric oxide production as mice deficient in inducible nitric oxide synthase (iNOS) and tumour necrosis factor receptor were able to control early growth of T. gondii , although they later succumbed to infection. Nitric oxide does, however, seem to be important in controlling persistent infection; treating chronic infection with iNOS metabolic inhibitors results in disease reactivation. Preliminary evidence implicates neutrophils in effector pathways against this parasite distinct from that described for macrophages. Once initiated, IL–12–dependent IFN–gamma production in synergy with other proinflammatory cytokines can positively feed back on itself to induce ‘cytokine shock’. Regulatory cytokines, particularly IL–10, are essential to down–regulate inflammation and limit host pathology.

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Antitumor Effect of a DNA Vaccine Harboring Prostate Cancer-Specific Antigen with IL-12 as an Intramolecular Adjuvant

Journal of Molecular Microbiology and Biotechnology ◽

10.1159/000477245 ◽

2017 ◽

Vol 27 (3) ◽

pp. 168-174 ◽

Cited By ~ 1

Author(s):

Yu Yang ◽

Zhiqiang Shao ◽

Jiangping Gao

Keyword(s):

Prostate Cancer ◽

Immune Responses ◽

Dna Vaccine ◽

Dna Vaccines ◽

Electric Pulse ◽

Specific Antigen ◽

Interleukin 12 ◽

Cellular Immune Responses ◽

Prostate Cancer Therapy ◽

Cellular Immune

To improve the lower immune intensity of DNA vaccines, we developed a DNA vaccine based on prostate cancer-specific antigen (PSA), which has been suggested as a potential target for prostate cancer therapy, and enhanced the DNA vaccine potency using interleukin-12 (IL-12) as an intramolecular adjuvant. A series of DNA plasmids encoding human PSA, IL-12, and their conjugates was constructed and injected into female mice intramuscularly, followed by an electric pulse. The humoral and cellular immune responses after immunization were detected by ELISA and ELISPOT, respectively. To evaluate the therapeutic efficacy of these plasmids, a mouse model with a PSA-expressing tumor was constructed. Mice vaccinated with PSA-IL-12 plasmids elicited the strongest PSA-specific humoral and cellular immune responses. Furthermore, these vaccinations inhibited the growth of PSA-expressing tumors and prolonged mouse survival. These observations emphasize the potential of the IL-12 gene as an intramolecular adjuvant for DNA vaccines. Moreover, the vaccine based on PSA and IL-12 may be a promising treatment for prostate cancer.

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