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Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function.

Millington OR, Di Lorenzo C, Phillips RS, Garside P, Brewer JM - J. Biol. (2006)

Bottom Line: This effect on T-cell activation can be transferred to uninfected recipients by DCs isolated from infected mice.Significantly, T cells activated by these DCs subsequently lack effector function, as demonstrated by a failure to migrate to lymphoid-organ follicles, resulting in an absence of B-cell responses to heterologous antigens.Fractionation studies show that hemozoin, rather than infected erythrocyte (red blood cell) membranes, reproduces the effect of intact infected red blood cells on DCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow G11 6NT, UK. owain.millington@strath.ac.uk

ABSTRACT

Background: Dendritic cells (DCs) are central to the initiation and regulation of the adaptive immune response during infection. Modulation of DC function may therefore allow evasion of the immune system by pathogens. Significant depression of the host's systemic immune response to both concurrent infections and heterologous vaccines has been observed during malaria infection, but the mechanisms underlying this immune hyporesponsiveness are controversial.

Results: Here, we demonstrate that the blood stages of malaria infection induce a failure of DC function in vitro and in vivo, causing suboptimal activation of T cells involved in heterologous immune responses. This effect on T-cell activation can be transferred to uninfected recipients by DCs isolated from infected mice. Significantly, T cells activated by these DCs subsequently lack effector function, as demonstrated by a failure to migrate to lymphoid-organ follicles, resulting in an absence of B-cell responses to heterologous antigens. Fractionation studies show that hemozoin, rather than infected erythrocyte (red blood cell) membranes, reproduces the effect of intact infected red blood cells on DCs. Furthermore, hemozoin-containing DCs could be identified in T-cell areas of the spleen in vivo.

Conclusion: Plasmodium infection inhibits the induction of adaptive immunity to heterologous antigens by modulating DC function, providing a potential explanation for epidemiological studies linking endemic malaria with secondary infections and reduced vaccine efficacy.

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Related in: MedlinePlus

Suppression of immunity by P. chabaudi infection. (a) BALB/c mice were infected with 106 P. chabaudi (AS strain) parasites by intra-peritoneal injection and the proportion of peripheral blood cells parasitized (parasitemia) was monitored by Giemsa's stain of peripheral blood smears. (b) Uninfected (squares) or P. chabaudi-infected (circles) BALB/c mice were immunized with OVA/LPS at the indicated times after infection. Three weeks after immunization, sera were analyzed for OVA-specific IgG. Data represent the mean of three mice per group ±1 standard deviation (s.d.) and are representative of two similar experiments (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected). (c) Spleen cells from uninfected (open bars) or P. chabaudi-infected (filled bars) BALB/c mice immunized with OVA/LPS 10 days post-infection were restimulated in vitro as indicated and supernatants assayed for levels of IFN-γ (left) and IL-5 (right) after 48 h. Uninfected, immunized animals generated OVA-specific IgG responses, but OVA and LPS administered 6 hours and 12 days after infection with P. chabaudi produced significantly reduced levels of IgG (Figure 1b). Interestingly, suppression was lower in mice immunized during increasing levels of parasite infection (parasitemia; Figure 1b, 4 days). By 21 days post-infection, infected animals had regained immune responsiveness and mounted antibody responses of a similar magnitude to those seen in uninfected controls (Figure 1b, 21 and 28 days). Production of OVA-stimulated and concanavalin A (ConA) mitogen-stimulated T-cell cytokines was reduced in cultures of splenocytes taken from mice infected with P. chabaudi 10 days before immunization (Figure 1c). Thus, as described for P. falciparum in humans, P. chabaudi infection in mice induces suppression of immune responses, although these studies reveal that, in the animal model at least, this is a highly dynamic phenomenon
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Figure 1: Suppression of immunity by P. chabaudi infection. (a) BALB/c mice were infected with 106 P. chabaudi (AS strain) parasites by intra-peritoneal injection and the proportion of peripheral blood cells parasitized (parasitemia) was monitored by Giemsa's stain of peripheral blood smears. (b) Uninfected (squares) or P. chabaudi-infected (circles) BALB/c mice were immunized with OVA/LPS at the indicated times after infection. Three weeks after immunization, sera were analyzed for OVA-specific IgG. Data represent the mean of three mice per group ±1 standard deviation (s.d.) and are representative of two similar experiments (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected). (c) Spleen cells from uninfected (open bars) or P. chabaudi-infected (filled bars) BALB/c mice immunized with OVA/LPS 10 days post-infection were restimulated in vitro as indicated and supernatants assayed for levels of IFN-γ (left) and IL-5 (right) after 48 h. Uninfected, immunized animals generated OVA-specific IgG responses, but OVA and LPS administered 6 hours and 12 days after infection with P. chabaudi produced significantly reduced levels of IgG (Figure 1b). Interestingly, suppression was lower in mice immunized during increasing levels of parasite infection (parasitemia; Figure 1b, 4 days). By 21 days post-infection, infected animals had regained immune responsiveness and mounted antibody responses of a similar magnitude to those seen in uninfected controls (Figure 1b, 21 and 28 days). Production of OVA-stimulated and concanavalin A (ConA) mitogen-stimulated T-cell cytokines was reduced in cultures of splenocytes taken from mice infected with P. chabaudi 10 days before immunization (Figure 1c). Thus, as described for P. falciparum in humans, P. chabaudi infection in mice induces suppression of immune responses, although these studies reveal that, in the animal model at least, this is a highly dynamic phenomenon

Mentions: We first examined the response to a heterologous antigen during Plasmodium chabaudi (AS strain) infection (Figure 1a) to determine whether this murine model reflected the clinical immunosuppression observed with P. falciparum infection [18-21]. Mice were immunized with the model antigen ovalbumin (OVA) and lipopolysaccharide (LPS) to act as adjuvant at various times after infection, and OVA-specific serum immunoglobulin G (IgG) was measured 21 days later.


Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function.

Millington OR, Di Lorenzo C, Phillips RS, Garside P, Brewer JM - J. Biol. (2006)

Suppression of immunity by P. chabaudi infection. (a) BALB/c mice were infected with 106 P. chabaudi (AS strain) parasites by intra-peritoneal injection and the proportion of peripheral blood cells parasitized (parasitemia) was monitored by Giemsa's stain of peripheral blood smears. (b) Uninfected (squares) or P. chabaudi-infected (circles) BALB/c mice were immunized with OVA/LPS at the indicated times after infection. Three weeks after immunization, sera were analyzed for OVA-specific IgG. Data represent the mean of three mice per group ±1 standard deviation (s.d.) and are representative of two similar experiments (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected). (c) Spleen cells from uninfected (open bars) or P. chabaudi-infected (filled bars) BALB/c mice immunized with OVA/LPS 10 days post-infection were restimulated in vitro as indicated and supernatants assayed for levels of IFN-γ (left) and IL-5 (right) after 48 h. Uninfected, immunized animals generated OVA-specific IgG responses, but OVA and LPS administered 6 hours and 12 days after infection with P. chabaudi produced significantly reduced levels of IgG (Figure 1b). Interestingly, suppression was lower in mice immunized during increasing levels of parasite infection (parasitemia; Figure 1b, 4 days). By 21 days post-infection, infected animals had regained immune responsiveness and mounted antibody responses of a similar magnitude to those seen in uninfected controls (Figure 1b, 21 and 28 days). Production of OVA-stimulated and concanavalin A (ConA) mitogen-stimulated T-cell cytokines was reduced in cultures of splenocytes taken from mice infected with P. chabaudi 10 days before immunization (Figure 1c). Thus, as described for P. falciparum in humans, P. chabaudi infection in mice induces suppression of immune responses, although these studies reveal that, in the animal model at least, this is a highly dynamic phenomenon
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1561486&req=5

Figure 1: Suppression of immunity by P. chabaudi infection. (a) BALB/c mice were infected with 106 P. chabaudi (AS strain) parasites by intra-peritoneal injection and the proportion of peripheral blood cells parasitized (parasitemia) was monitored by Giemsa's stain of peripheral blood smears. (b) Uninfected (squares) or P. chabaudi-infected (circles) BALB/c mice were immunized with OVA/LPS at the indicated times after infection. Three weeks after immunization, sera were analyzed for OVA-specific IgG. Data represent the mean of three mice per group ±1 standard deviation (s.d.) and are representative of two similar experiments (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected). (c) Spleen cells from uninfected (open bars) or P. chabaudi-infected (filled bars) BALB/c mice immunized with OVA/LPS 10 days post-infection were restimulated in vitro as indicated and supernatants assayed for levels of IFN-γ (left) and IL-5 (right) after 48 h. Uninfected, immunized animals generated OVA-specific IgG responses, but OVA and LPS administered 6 hours and 12 days after infection with P. chabaudi produced significantly reduced levels of IgG (Figure 1b). Interestingly, suppression was lower in mice immunized during increasing levels of parasite infection (parasitemia; Figure 1b, 4 days). By 21 days post-infection, infected animals had regained immune responsiveness and mounted antibody responses of a similar magnitude to those seen in uninfected controls (Figure 1b, 21 and 28 days). Production of OVA-stimulated and concanavalin A (ConA) mitogen-stimulated T-cell cytokines was reduced in cultures of splenocytes taken from mice infected with P. chabaudi 10 days before immunization (Figure 1c). Thus, as described for P. falciparum in humans, P. chabaudi infection in mice induces suppression of immune responses, although these studies reveal that, in the animal model at least, this is a highly dynamic phenomenon
Mentions: We first examined the response to a heterologous antigen during Plasmodium chabaudi (AS strain) infection (Figure 1a) to determine whether this murine model reflected the clinical immunosuppression observed with P. falciparum infection [18-21]. Mice were immunized with the model antigen ovalbumin (OVA) and lipopolysaccharide (LPS) to act as adjuvant at various times after infection, and OVA-specific serum immunoglobulin G (IgG) was measured 21 days later.

Bottom Line: This effect on T-cell activation can be transferred to uninfected recipients by DCs isolated from infected mice.Significantly, T cells activated by these DCs subsequently lack effector function, as demonstrated by a failure to migrate to lymphoid-organ follicles, resulting in an absence of B-cell responses to heterologous antigens.Fractionation studies show that hemozoin, rather than infected erythrocyte (red blood cell) membranes, reproduces the effect of intact infected red blood cells on DCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow G11 6NT, UK. owain.millington@strath.ac.uk

ABSTRACT

Background: Dendritic cells (DCs) are central to the initiation and regulation of the adaptive immune response during infection. Modulation of DC function may therefore allow evasion of the immune system by pathogens. Significant depression of the host's systemic immune response to both concurrent infections and heterologous vaccines has been observed during malaria infection, but the mechanisms underlying this immune hyporesponsiveness are controversial.

Results: Here, we demonstrate that the blood stages of malaria infection induce a failure of DC function in vitro and in vivo, causing suboptimal activation of T cells involved in heterologous immune responses. This effect on T-cell activation can be transferred to uninfected recipients by DCs isolated from infected mice. Significantly, T cells activated by these DCs subsequently lack effector function, as demonstrated by a failure to migrate to lymphoid-organ follicles, resulting in an absence of B-cell responses to heterologous antigens. Fractionation studies show that hemozoin, rather than infected erythrocyte (red blood cell) membranes, reproduces the effect of intact infected red blood cells on DCs. Furthermore, hemozoin-containing DCs could be identified in T-cell areas of the spleen in vivo.

Conclusion: Plasmodium infection inhibits the induction of adaptive immunity to heterologous antigens by modulating DC function, providing a potential explanation for epidemiological studies linking endemic malaria with secondary infections and reduced vaccine efficacy.

Show MeSH
Related in: MedlinePlus