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Conserved protective mechanisms in radiation and genetically attenuated uis3(-) and uis4(-) Plasmodium sporozoites.

Kumar KA, Baxter P, Tarun AS, Kappe SH, Nussenzweig V - PLoS ONE (2009)

Bottom Line: Immunization with radiation attenuated Plasmodium sporozoites (RAS) elicits sterile protective immunity against sporozoite challenge in murine models and in humans.There were no differences in the immune responses to the circumsporozoite protein (CSP) generated by RAS and GAPs.We conclude that CSP is a powerful protective antigen in both RAS and GAPs viz., uis3(-) and uis4(-) and that the protective mechanisms are similar independently of the method of sporozoite attenuation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Micheal Hidelberg Division of Immunology, New York University School of Medicine, New York, New York, United States of America. kaksl@uohyd.ernet.in

ABSTRACT
Immunization with radiation attenuated Plasmodium sporozoites (RAS) elicits sterile protective immunity against sporozoite challenge in murine models and in humans. Similarly to RAS, the genetically attenuated sporozoites (GAPs) named uis3(-), uis4(-) and P36p(-) have arrested growth during the liver stage development, and generate a powerful protective immune response in mice. We compared the protective mechanisms in P. yoelii RAS, uis3(-) and uis4(-) in BALB/c mice. In RAS and GAPs, sterile immunity is only achieved after one or more booster injections. There were no differences in the immune responses to the circumsporozoite protein (CSP) generated by RAS and GAPs. To evaluate the role of non-CSP T-cell antigens we immunized antibody deficient, CSP-transgenic BALB/c mice, that are T cell tolerant to CSP, with P. yoelii RAS or with uis3(-) or uis4(-) GAPs, and challenged them with wild type sporozoites. In every instance the parasite liver stage burden was approximately 3 logs higher in antibody deficient CSP transgenic mice as compared to antibody deficient mice alone. We conclude that CSP is a powerful protective antigen in both RAS and GAPs viz., uis3(-) and uis4(-) and that the protective mechanisms are similar independently of the method of sporozoite attenuation.

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CS is a powerful protective T cell antigen in both P. yoelli RAS and uis3(-), uis4(-) GAPs.BALB/c CS-Tg JhT (−/−) mice were primed and boosted with 1×105 P. yoelli RAS or with uis3(-) or with uis4(-) GAPs. All immunized mice were challenged with 1×104 wild type infectious sporozoites and infected livers were isolated 42 hours post infection (A) Liver stage burden in indicated groups of immunized mice were assessed by measuring the parasite specific 18S rRNA copy numbers by q-RT PCR. The results are expressed as mean±s.d of 18S rRNA copy numbers from 5 mice per group. (B) IFN-gamma ELISPOT assay to quantify CS specific T cells from indicated groups of JhT (−/−) immunized mice. Results are expressed as mean±s.d of CS-specific CD8+ T cells obtained from 5 immunized mice per group.
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pone-0004480-g002: CS is a powerful protective T cell antigen in both P. yoelli RAS and uis3(-), uis4(-) GAPs.BALB/c CS-Tg JhT (−/−) mice were primed and boosted with 1×105 P. yoelli RAS or with uis3(-) or with uis4(-) GAPs. All immunized mice were challenged with 1×104 wild type infectious sporozoites and infected livers were isolated 42 hours post infection (A) Liver stage burden in indicated groups of immunized mice were assessed by measuring the parasite specific 18S rRNA copy numbers by q-RT PCR. The results are expressed as mean±s.d of 18S rRNA copy numbers from 5 mice per group. (B) IFN-gamma ELISPOT assay to quantify CS specific T cells from indicated groups of JhT (−/−) immunized mice. Results are expressed as mean±s.d of CS-specific CD8+ T cells obtained from 5 immunized mice per group.

Mentions: Next we compared the relative importance of CSP in the protective T cell responses to RAS and GAPs. For this purpose we used BALB/c mice that are both T-cell tolerant to CSP and cannot make antibodies [(CSP-transgenic, JhT (−/−)]. The mice were primed and boosted with RAS, or with uis3(-) or uis4(-) GAPs and challenged as above. We found that immunization with RAS or GAPs led to a reversal of protection by approximately 3 logs in CSP-transgenic, JhT (−/−) mice (Fig 2A), as compared to liver stage burden of an identically immunized JhT (−/−) mice. Further, RAS or GAP immunization in Jht (−/−) mice induced very similar numbers of interferon-γ producing T cells against the CD8+ T cell epitope of CSP (Fig 2B).


Conserved protective mechanisms in radiation and genetically attenuated uis3(-) and uis4(-) Plasmodium sporozoites.

Kumar KA, Baxter P, Tarun AS, Kappe SH, Nussenzweig V - PLoS ONE (2009)

CS is a powerful protective T cell antigen in both P. yoelli RAS and uis3(-), uis4(-) GAPs.BALB/c CS-Tg JhT (−/−) mice were primed and boosted with 1×105 P. yoelli RAS or with uis3(-) or with uis4(-) GAPs. All immunized mice were challenged with 1×104 wild type infectious sporozoites and infected livers were isolated 42 hours post infection (A) Liver stage burden in indicated groups of immunized mice were assessed by measuring the parasite specific 18S rRNA copy numbers by q-RT PCR. The results are expressed as mean±s.d of 18S rRNA copy numbers from 5 mice per group. (B) IFN-gamma ELISPOT assay to quantify CS specific T cells from indicated groups of JhT (−/−) immunized mice. Results are expressed as mean±s.d of CS-specific CD8+ T cells obtained from 5 immunized mice per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2637429&req=5

pone-0004480-g002: CS is a powerful protective T cell antigen in both P. yoelli RAS and uis3(-), uis4(-) GAPs.BALB/c CS-Tg JhT (−/−) mice were primed and boosted with 1×105 P. yoelli RAS or with uis3(-) or with uis4(-) GAPs. All immunized mice were challenged with 1×104 wild type infectious sporozoites and infected livers were isolated 42 hours post infection (A) Liver stage burden in indicated groups of immunized mice were assessed by measuring the parasite specific 18S rRNA copy numbers by q-RT PCR. The results are expressed as mean±s.d of 18S rRNA copy numbers from 5 mice per group. (B) IFN-gamma ELISPOT assay to quantify CS specific T cells from indicated groups of JhT (−/−) immunized mice. Results are expressed as mean±s.d of CS-specific CD8+ T cells obtained from 5 immunized mice per group.
Mentions: Next we compared the relative importance of CSP in the protective T cell responses to RAS and GAPs. For this purpose we used BALB/c mice that are both T-cell tolerant to CSP and cannot make antibodies [(CSP-transgenic, JhT (−/−)]. The mice were primed and boosted with RAS, or with uis3(-) or uis4(-) GAPs and challenged as above. We found that immunization with RAS or GAPs led to a reversal of protection by approximately 3 logs in CSP-transgenic, JhT (−/−) mice (Fig 2A), as compared to liver stage burden of an identically immunized JhT (−/−) mice. Further, RAS or GAP immunization in Jht (−/−) mice induced very similar numbers of interferon-γ producing T cells against the CD8+ T cell epitope of CSP (Fig 2B).

Bottom Line: Immunization with radiation attenuated Plasmodium sporozoites (RAS) elicits sterile protective immunity against sporozoite challenge in murine models and in humans.There were no differences in the immune responses to the circumsporozoite protein (CSP) generated by RAS and GAPs.We conclude that CSP is a powerful protective antigen in both RAS and GAPs viz., uis3(-) and uis4(-) and that the protective mechanisms are similar independently of the method of sporozoite attenuation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Micheal Hidelberg Division of Immunology, New York University School of Medicine, New York, New York, United States of America. kaksl@uohyd.ernet.in

ABSTRACT
Immunization with radiation attenuated Plasmodium sporozoites (RAS) elicits sterile protective immunity against sporozoite challenge in murine models and in humans. Similarly to RAS, the genetically attenuated sporozoites (GAPs) named uis3(-), uis4(-) and P36p(-) have arrested growth during the liver stage development, and generate a powerful protective immune response in mice. We compared the protective mechanisms in P. yoelii RAS, uis3(-) and uis4(-) in BALB/c mice. In RAS and GAPs, sterile immunity is only achieved after one or more booster injections. There were no differences in the immune responses to the circumsporozoite protein (CSP) generated by RAS and GAPs. To evaluate the role of non-CSP T-cell antigens we immunized antibody deficient, CSP-transgenic BALB/c mice, that are T cell tolerant to CSP, with P. yoelii RAS or with uis3(-) or uis4(-) GAPs, and challenged them with wild type sporozoites. In every instance the parasite liver stage burden was approximately 3 logs higher in antibody deficient CSP transgenic mice as compared to antibody deficient mice alone. We conclude that CSP is a powerful protective antigen in both RAS and GAPs viz., uis3(-) and uis4(-) and that the protective mechanisms are similar independently of the method of sporozoite attenuation.

Show MeSH
Related in: MedlinePlus