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Immunization with L. sigmodontis microfilariae reduces peripheral microfilaraemia after challenge infection by inhibition of filarial embryogenesis.

Ziewer S, Hübner MP, Dubben B, Hoffmann WH, Bain O, Martin C, Hoerauf A, Specht S - PLoS Negl Trop Dis (2012)

Bottom Line: Protection was associated with the impairment of intrauterine filarial embryogenesis and with local and systemic microfilarial-specific host IgG, as well as IFN-γ secretion by host cells from the site of infection.Furthermore immunization significantly reduced adult worm burden.Our results present a tool to understand the immunological basis of vaccine induced protection in order to develop a microfilariae-based vaccine that reduces adult worm burden and prevents microfilaraemia, a powerful weapon to stop transmission of filariasis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.

ABSTRACT

Background: Lymphatic filariasis and onchocerciasis are two chronic diseases mediated by parasitic filarial worms causing long term disability and massive socioeconomic problems. Filariae are transmitted by blood-feeding mosquitoes that take up the first stage larvae from an infected host and deliver it after maturation into infective stage to a new host. After closure of vector control programs, disease control relies mainly on mass drug administration with drugs that are primarily effective against first stage larvae and require many years of annual/biannual administration. Therefore, there is an urgent need for alternative treatment ways, i.e. other effective drugs or vaccines.

Methodology/principal findings: Using the Litomosoides sigmodontis murine model of filariasis we demonstrate that immunization with microfilariae together with the adjuvant alum prevents mice from developing high microfilaraemia after challenge infection. Immunization achieved 70% to 100% protection in the peripheral blood and in the pleural space and furthermore strongly reduced the microfilarial load in mice that remained microfilaraemic. Protection was associated with the impairment of intrauterine filarial embryogenesis and with local and systemic microfilarial-specific host IgG, as well as IFN-γ secretion by host cells from the site of infection. Furthermore immunization significantly reduced adult worm burden.

Conclusions/significance: Our results present a tool to understand the immunological basis of vaccine induced protection in order to develop a microfilariae-based vaccine that reduces adult worm burden and prevents microfilaraemia, a powerful weapon to stop transmission of filariasis.

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Related in: MedlinePlus

Immunization induces Mf-specific IgG1 and IgG2.Mice were immunized three times s.c. with 100,000 Mf in alum (Al-Mf/naïve, Al-Mf/Inf). Control mice received alum alone (Al/naïve, Al/Inf). L. sigmodontis challenge infection was performed one week after the last immunization (Al/Inf, Al-Mf/Inf) or left uninfected (Al/naïve, Al-Mf/naïve). Plasma levels of Mf-specific IgG1 (A) and IgG2a/b (B) were measured. Two-way ANOVA was used for statistical analysis, day 0 indicates day of challenge infection. Asterisks indicate significant differences between the immunized and infected, and the corresponding control group (*** P<0.001) and pound signs between the immunized but uninfected, and the corresponding control group (#P<0.05, ##P<0.01, ###P<0.001). (C–F) Pleural space lavage was analyzed for specific IgG1 and IgG2a/b on days 22 (C, D) and 70 p.i. (E, F). Data analyzed with Welch-corrected t-test (mean, *** P<0.001). Graphs show representatives of three independent experiments with eight to ten mice each group (additional experiments see Figure S6A, B, E–J).
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pntd-0001558-g005: Immunization induces Mf-specific IgG1 and IgG2.Mice were immunized three times s.c. with 100,000 Mf in alum (Al-Mf/naïve, Al-Mf/Inf). Control mice received alum alone (Al/naïve, Al/Inf). L. sigmodontis challenge infection was performed one week after the last immunization (Al/Inf, Al-Mf/Inf) or left uninfected (Al/naïve, Al-Mf/naïve). Plasma levels of Mf-specific IgG1 (A) and IgG2a/b (B) were measured. Two-way ANOVA was used for statistical analysis, day 0 indicates day of challenge infection. Asterisks indicate significant differences between the immunized and infected, and the corresponding control group (*** P<0.001) and pound signs between the immunized but uninfected, and the corresponding control group (#P<0.05, ##P<0.01, ###P<0.001). (C–F) Pleural space lavage was analyzed for specific IgG1 and IgG2a/b on days 22 (C, D) and 70 p.i. (E, F). Data analyzed with Welch-corrected t-test (mean, *** P<0.001). Graphs show representatives of three independent experiments with eight to ten mice each group (additional experiments see Figure S6A, B, E–J).

Mentions: To investigate whether immunization-induced Mf-specific Ig responses were associated with protection, Mf-specific IgE, IgG1 and IgG2 levels were measured in the plasma and pleural space lavage at different time points throughout immunization and infection. As Figure 5A and B illustrate, the immunization induced an Mf-specific humoral response and both IgG1 and IgG2 antibodies were elevated in the blood. The most prominent increase was observed after the boost immunizations, as indicated by the levels seven days before the challenge infection. A comparison of both immunized groups (infected vs. uninfected) revealed that these humoral responses were not further enhanced by the infection itself. The same picture was found at the site of infection with Mf-specific IgG1 and IgG2 levels being significantly elevated in immunized mice compared to controls on day 22 (P<0.001, Figure 5C, D) as well as on day 70 p.i. (P<0.001, Figure 5E, F). Albeit the differences in IgG1 levels remained significantly higher in immunized mice at day 70 p.i., the IgG1 levels of infected but non-immunized mice increased on days 28 and 42 (Figure S6C, D) compared to day 22 p.i. (Figure S6A, B). This however indicates a Th2 shift induced by the parasite itself and is well-known for primary infected BALB/c mice [34], [35].


Immunization with L. sigmodontis microfilariae reduces peripheral microfilaraemia after challenge infection by inhibition of filarial embryogenesis.

Ziewer S, Hübner MP, Dubben B, Hoffmann WH, Bain O, Martin C, Hoerauf A, Specht S - PLoS Negl Trop Dis (2012)

Immunization induces Mf-specific IgG1 and IgG2.Mice were immunized three times s.c. with 100,000 Mf in alum (Al-Mf/naïve, Al-Mf/Inf). Control mice received alum alone (Al/naïve, Al/Inf). L. sigmodontis challenge infection was performed one week after the last immunization (Al/Inf, Al-Mf/Inf) or left uninfected (Al/naïve, Al-Mf/naïve). Plasma levels of Mf-specific IgG1 (A) and IgG2a/b (B) were measured. Two-way ANOVA was used for statistical analysis, day 0 indicates day of challenge infection. Asterisks indicate significant differences between the immunized and infected, and the corresponding control group (*** P<0.001) and pound signs between the immunized but uninfected, and the corresponding control group (#P<0.05, ##P<0.01, ###P<0.001). (C–F) Pleural space lavage was analyzed for specific IgG1 and IgG2a/b on days 22 (C, D) and 70 p.i. (E, F). Data analyzed with Welch-corrected t-test (mean, *** P<0.001). Graphs show representatives of three independent experiments with eight to ten mice each group (additional experiments see Figure S6A, B, E–J).
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Related In: Results  -  Collection

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pntd-0001558-g005: Immunization induces Mf-specific IgG1 and IgG2.Mice were immunized three times s.c. with 100,000 Mf in alum (Al-Mf/naïve, Al-Mf/Inf). Control mice received alum alone (Al/naïve, Al/Inf). L. sigmodontis challenge infection was performed one week after the last immunization (Al/Inf, Al-Mf/Inf) or left uninfected (Al/naïve, Al-Mf/naïve). Plasma levels of Mf-specific IgG1 (A) and IgG2a/b (B) were measured. Two-way ANOVA was used for statistical analysis, day 0 indicates day of challenge infection. Asterisks indicate significant differences between the immunized and infected, and the corresponding control group (*** P<0.001) and pound signs between the immunized but uninfected, and the corresponding control group (#P<0.05, ##P<0.01, ###P<0.001). (C–F) Pleural space lavage was analyzed for specific IgG1 and IgG2a/b on days 22 (C, D) and 70 p.i. (E, F). Data analyzed with Welch-corrected t-test (mean, *** P<0.001). Graphs show representatives of three independent experiments with eight to ten mice each group (additional experiments see Figure S6A, B, E–J).
Mentions: To investigate whether immunization-induced Mf-specific Ig responses were associated with protection, Mf-specific IgE, IgG1 and IgG2 levels were measured in the plasma and pleural space lavage at different time points throughout immunization and infection. As Figure 5A and B illustrate, the immunization induced an Mf-specific humoral response and both IgG1 and IgG2 antibodies were elevated in the blood. The most prominent increase was observed after the boost immunizations, as indicated by the levels seven days before the challenge infection. A comparison of both immunized groups (infected vs. uninfected) revealed that these humoral responses were not further enhanced by the infection itself. The same picture was found at the site of infection with Mf-specific IgG1 and IgG2 levels being significantly elevated in immunized mice compared to controls on day 22 (P<0.001, Figure 5C, D) as well as on day 70 p.i. (P<0.001, Figure 5E, F). Albeit the differences in IgG1 levels remained significantly higher in immunized mice at day 70 p.i., the IgG1 levels of infected but non-immunized mice increased on days 28 and 42 (Figure S6C, D) compared to day 22 p.i. (Figure S6A, B). This however indicates a Th2 shift induced by the parasite itself and is well-known for primary infected BALB/c mice [34], [35].

Bottom Line: Protection was associated with the impairment of intrauterine filarial embryogenesis and with local and systemic microfilarial-specific host IgG, as well as IFN-γ secretion by host cells from the site of infection.Furthermore immunization significantly reduced adult worm burden.Our results present a tool to understand the immunological basis of vaccine induced protection in order to develop a microfilariae-based vaccine that reduces adult worm burden and prevents microfilaraemia, a powerful weapon to stop transmission of filariasis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.

ABSTRACT

Background: Lymphatic filariasis and onchocerciasis are two chronic diseases mediated by parasitic filarial worms causing long term disability and massive socioeconomic problems. Filariae are transmitted by blood-feeding mosquitoes that take up the first stage larvae from an infected host and deliver it after maturation into infective stage to a new host. After closure of vector control programs, disease control relies mainly on mass drug administration with drugs that are primarily effective against first stage larvae and require many years of annual/biannual administration. Therefore, there is an urgent need for alternative treatment ways, i.e. other effective drugs or vaccines.

Methodology/principal findings: Using the Litomosoides sigmodontis murine model of filariasis we demonstrate that immunization with microfilariae together with the adjuvant alum prevents mice from developing high microfilaraemia after challenge infection. Immunization achieved 70% to 100% protection in the peripheral blood and in the pleural space and furthermore strongly reduced the microfilarial load in mice that remained microfilaraemic. Protection was associated with the impairment of intrauterine filarial embryogenesis and with local and systemic microfilarial-specific host IgG, as well as IFN-γ secretion by host cells from the site of infection. Furthermore immunization significantly reduced adult worm burden.

Conclusions/significance: Our results present a tool to understand the immunological basis of vaccine induced protection in order to develop a microfilariae-based vaccine that reduces adult worm burden and prevents microfilaraemia, a powerful weapon to stop transmission of filariasis.

Show MeSH
Related in: MedlinePlus