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Immunity to distinct sand fly salivary proteins primes the anti-Leishmania immune response towards protection or exacerbation of disease.

Oliveira F, Lawyer PG, Kamhawi S, Valenzuela JG - PLoS Negl Trop Dis (2008)

Bottom Line: Two weeks post-infection, 31.5% of CD4(+) T cells produced IFN-gamma in PpSP15-mice compared to 7.1% in PpSP44-mice.This immune response is inducible by sand fly bites where PpSP15-mice showed a 3-fold higher IFN-gamma and a 5-fold lower IL-4 expression compared with PpSP44-mice.The demonstration for the first time that immunity to a defined salivary protein (PpSP44) results in disease enhancement stresses the importance of the proper selection of vector-based vaccine candidates.

View Article: PubMed Central - PubMed

Affiliation: Vector Molecular Biology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.

ABSTRACT

Background: Leishmania parasites are transmitted in the presence of sand fly saliva. Together with the parasite, the sand fly injects biologically active salivary components that favorably change the environment at the feeding site. Exposure to bites or to salivary proteins results in immunity specific to these components. Mice immunized with Phlebotomus papatasi salivary gland homogenate (SGH) or pre-exposed to uninfected bites were protected against Leishmania major infection delivered by needle inoculation with SGH or by infected sand fly bites. Immunization with individual salivary proteins of two sand fly species protected mice from L. major infection. Here, we analyze the immune response to distinct salivary proteins from P. papatasi that produced contrasting outcomes of L. major infection.

Methodology/principal findings: DNA immunization with distinct DTH-inducing salivary proteins from P. papatasi modulates L. major infection. PpSP15-immunized mice (PpSP15-mice) show lasting protection while PpSP44-immunized mice (PpSP44-mice) aggravate the infection, suggesting that immunization with these distinct molecules alters the course of anti-Leishmania immunity. Two weeks post-infection, 31.5% of CD4(+) T cells produced IFN-gamma in PpSP15-mice compared to 7.1% in PpSP44-mice. Moreover, IL-4-producing cells were 3-fold higher in PpSP44-mice. At an earlier time point of two hours after challenge with SGH and L. major, the expression profile of PpSP15-mice showed over 3-fold higher IFN-gamma and IL-12-Rbeta2 and 20-fold lower IL-4 expression relative to PpSP44-mice, suggesting that salivary proteins differentially prime anti-Leishmania immunity. This immune response is inducible by sand fly bites where PpSP15-mice showed a 3-fold higher IFN-gamma and a 5-fold lower IL-4 expression compared with PpSP44-mice.

Conclusions/significance: Immunization with two salivary proteins from P. papatasi, PpSP15 and PpSP44, produced distinct immune profiles that correlated with resistance or susceptibility to Leishmania infection. The demonstration for the first time that immunity to a defined salivary protein (PpSP44) results in disease enhancement stresses the importance of the proper selection of vector-based vaccine candidates.

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Early expression of cytokines after challenge with SGH-LM in CTL DNA, PpSP15- or PpSP44-immunized mice.Two hours after challenge with 500 L. major metacyclics and 0.5 pairs of SGH, expression of IFN-γ and IL-12Rβ2 was induced in mice immunized with PpSP15. In contrast, mice immunized with PpSP44 induced the expression of IL-4. Relative mRNA expression was determined by real time PCR and normalized to the18S housekeeping gene. Values represent the fold increase over naïve mice after challenge with SGH-LM. Bars represent the mean ± the SEM for 24 mice per group. Asterisks indicate statistical significance (p<0.05) between the PpSP15 and the PpSP44 experimental groups. Data represent the combined outcome of three independent experiments.
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pntd-0000226-g005: Early expression of cytokines after challenge with SGH-LM in CTL DNA, PpSP15- or PpSP44-immunized mice.Two hours after challenge with 500 L. major metacyclics and 0.5 pairs of SGH, expression of IFN-γ and IL-12Rβ2 was induced in mice immunized with PpSP15. In contrast, mice immunized with PpSP44 induced the expression of IL-4. Relative mRNA expression was determined by real time PCR and normalized to the18S housekeeping gene. Values represent the fold increase over naïve mice after challenge with SGH-LM. Bars represent the mean ± the SEM for 24 mice per group. Asterisks indicate statistical significance (p<0.05) between the PpSP15 and the PpSP44 experimental groups. Data represent the combined outcome of three independent experiments.

Mentions: To understand the basis of the different outcomes of L. major infection in mice immunized with PpSP15 and PpSP44 we compared the early mRNA expression profiles of the inflammatory cytokines in the ears of these mice two hours following challenge with SGH-LM. Using the “Inflammatory Cytokines and Receptors” macroarray, transcripts showing a four-fold or higher change in signal intensity of gene expression compared to naïve controls were further analyzed and are presented in Table 1. PpSp15-immunized mice consistently produced high levels of IFN-γ and IL-12-Rβ2 and low levels of IL-4 and IL-5 (Table 1). In contrast, PpSP44-immunized mice produced high levels of IL-4 and IL-5 and baseline levels of IFN-γ transcripts. TNF-α transcripts were present at relatively high levels in mice immunized with PpSP15 and PpSP44 (Table 1). Real-time PCR was used to validate the results of the macroarray and showed that PpSP15-immunized animals induced a three-fold increase in IFN-γ and IL-12-Rβ2 messages compared to mice immunized with PpSP44 (p<0.05) (Fig. 5). Conversely, mice immunized with PpSP44 showed a 20-fold increase in the expression of IL-4 (p<0.005) and no significant expression of IFN-γ and IL-12-Rβ2 (Fig. 5). No significant difference was observed in the expression of IL-5 or TNF-α.


Immunity to distinct sand fly salivary proteins primes the anti-Leishmania immune response towards protection or exacerbation of disease.

Oliveira F, Lawyer PG, Kamhawi S, Valenzuela JG - PLoS Negl Trop Dis (2008)

Early expression of cytokines after challenge with SGH-LM in CTL DNA, PpSP15- or PpSP44-immunized mice.Two hours after challenge with 500 L. major metacyclics and 0.5 pairs of SGH, expression of IFN-γ and IL-12Rβ2 was induced in mice immunized with PpSP15. In contrast, mice immunized with PpSP44 induced the expression of IL-4. Relative mRNA expression was determined by real time PCR and normalized to the18S housekeeping gene. Values represent the fold increase over naïve mice after challenge with SGH-LM. Bars represent the mean ± the SEM for 24 mice per group. Asterisks indicate statistical significance (p<0.05) between the PpSP15 and the PpSP44 experimental groups. Data represent the combined outcome of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2291569&req=5

pntd-0000226-g005: Early expression of cytokines after challenge with SGH-LM in CTL DNA, PpSP15- or PpSP44-immunized mice.Two hours after challenge with 500 L. major metacyclics and 0.5 pairs of SGH, expression of IFN-γ and IL-12Rβ2 was induced in mice immunized with PpSP15. In contrast, mice immunized with PpSP44 induced the expression of IL-4. Relative mRNA expression was determined by real time PCR and normalized to the18S housekeeping gene. Values represent the fold increase over naïve mice after challenge with SGH-LM. Bars represent the mean ± the SEM for 24 mice per group. Asterisks indicate statistical significance (p<0.05) between the PpSP15 and the PpSP44 experimental groups. Data represent the combined outcome of three independent experiments.
Mentions: To understand the basis of the different outcomes of L. major infection in mice immunized with PpSP15 and PpSP44 we compared the early mRNA expression profiles of the inflammatory cytokines in the ears of these mice two hours following challenge with SGH-LM. Using the “Inflammatory Cytokines and Receptors” macroarray, transcripts showing a four-fold or higher change in signal intensity of gene expression compared to naïve controls were further analyzed and are presented in Table 1. PpSp15-immunized mice consistently produced high levels of IFN-γ and IL-12-Rβ2 and low levels of IL-4 and IL-5 (Table 1). In contrast, PpSP44-immunized mice produced high levels of IL-4 and IL-5 and baseline levels of IFN-γ transcripts. TNF-α transcripts were present at relatively high levels in mice immunized with PpSP15 and PpSP44 (Table 1). Real-time PCR was used to validate the results of the macroarray and showed that PpSP15-immunized animals induced a three-fold increase in IFN-γ and IL-12-Rβ2 messages compared to mice immunized with PpSP44 (p<0.05) (Fig. 5). Conversely, mice immunized with PpSP44 showed a 20-fold increase in the expression of IL-4 (p<0.005) and no significant expression of IFN-γ and IL-12-Rβ2 (Fig. 5). No significant difference was observed in the expression of IL-5 or TNF-α.

Bottom Line: Two weeks post-infection, 31.5% of CD4(+) T cells produced IFN-gamma in PpSP15-mice compared to 7.1% in PpSP44-mice.This immune response is inducible by sand fly bites where PpSP15-mice showed a 3-fold higher IFN-gamma and a 5-fold lower IL-4 expression compared with PpSP44-mice.The demonstration for the first time that immunity to a defined salivary protein (PpSP44) results in disease enhancement stresses the importance of the proper selection of vector-based vaccine candidates.

View Article: PubMed Central - PubMed

Affiliation: Vector Molecular Biology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.

ABSTRACT

Background: Leishmania parasites are transmitted in the presence of sand fly saliva. Together with the parasite, the sand fly injects biologically active salivary components that favorably change the environment at the feeding site. Exposure to bites or to salivary proteins results in immunity specific to these components. Mice immunized with Phlebotomus papatasi salivary gland homogenate (SGH) or pre-exposed to uninfected bites were protected against Leishmania major infection delivered by needle inoculation with SGH or by infected sand fly bites. Immunization with individual salivary proteins of two sand fly species protected mice from L. major infection. Here, we analyze the immune response to distinct salivary proteins from P. papatasi that produced contrasting outcomes of L. major infection.

Methodology/principal findings: DNA immunization with distinct DTH-inducing salivary proteins from P. papatasi modulates L. major infection. PpSP15-immunized mice (PpSP15-mice) show lasting protection while PpSP44-immunized mice (PpSP44-mice) aggravate the infection, suggesting that immunization with these distinct molecules alters the course of anti-Leishmania immunity. Two weeks post-infection, 31.5% of CD4(+) T cells produced IFN-gamma in PpSP15-mice compared to 7.1% in PpSP44-mice. Moreover, IL-4-producing cells were 3-fold higher in PpSP44-mice. At an earlier time point of two hours after challenge with SGH and L. major, the expression profile of PpSP15-mice showed over 3-fold higher IFN-gamma and IL-12-Rbeta2 and 20-fold lower IL-4 expression relative to PpSP44-mice, suggesting that salivary proteins differentially prime anti-Leishmania immunity. This immune response is inducible by sand fly bites where PpSP15-mice showed a 3-fold higher IFN-gamma and a 5-fold lower IL-4 expression compared with PpSP44-mice.

Conclusions/significance: Immunization with two salivary proteins from P. papatasi, PpSP15 and PpSP44, produced distinct immune profiles that correlated with resistance or susceptibility to Leishmania infection. The demonstration for the first time that immunity to a defined salivary protein (PpSP44) results in disease enhancement stresses the importance of the proper selection of vector-based vaccine candidates.

Show MeSH
Related in: MedlinePlus