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Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity.

Matar CG, Anthony NR, O'Flaherty BM, Jacobs NT, Priyamvada L, Engwerda CR, Speck SH, Lamb TJ - PLoS Pathog. (2015)

Bottom Line: Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh) cells in the spleen.Notably, co-infection with an M2- mutant MHV68 eliminates lethality of P. yoelii XNL.Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America; Microbiology and Molecular Genetics Graduate Program, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America.

ABSTRACT
Immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for Plasmodium falciparum. Yet, nearly 20% of infected children die annually as a result of severe malaria. Multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV) by the age of 6 months. This timing overlaps with the waning of protective maternal antibodies and susceptibility to primary Plasmodium infection. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Using well established mouse models of infection, we show here that acute, but not latent murine gammaherpesvirus 68 (MHV68) infection suppresses the anti-malarial humoral response to a secondary malaria infection. Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh) cells in the spleen. Furthermore, we have identified the MHV68 M2 protein as an important virus encoded protein that can: (i) suppress anti-MHV68 humoral responses during acute MHV68 infection; and (ii) plays a critical role in the observed suppression of anti-malarial humoral responses in the setting of co-infection. Notably, co-infection with an M2- mutant MHV68 eliminates lethality of P. yoelii XNL. Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response. This suggests that acute infection with EBV should be investigated as a risk factor for non-cerebral severe malaria in young children living in areas endemic for Plasmodium transmission.

No MeSH data available.


Related in: MedlinePlus

MHV68 suppresses splenic B cell responses during co-infection with Plasmodium.The timeline and experimental set up was identical to that shown in Fig 1A. (A) Absolute numbers of splenic GC B cell populations (B220+ GL7+ CD95+) during P. yoelii XNL and P. chabaudi AS co-infection models with representative gating strategy (Day 12 post P. yoelii or Day 15 post P. chabaudi; Plasmodium vs. co-infected, p<0.05, Mann Whitney U-test). (B) Absolute numbers of splenic plasma cell populations (CD3- B220int CD138+) during P. yoelii XNL AND P. chabaudi AS co-infection models with representative gating strategy (Day 12 post P. yoelii or Day 11 post P. chabaudi; Plasmodium vs. co-infected, p<0.05, Mann Whitney U-test). (C) Spleen section for mock infected, MHV68 infected, P. yoelii XNL infected and MHV68 and P. yoelii XNL co-infected animals at day 8 post infection with P. yoelii XNL (or day 15 post-infection with MHV68). Green: B220-FITC (B cells), Blue: GL7-AF660 (Germinal center B cells) and Red: CD3-AF568 (T cells).
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ppat.1004858.g003: MHV68 suppresses splenic B cell responses during co-infection with Plasmodium.The timeline and experimental set up was identical to that shown in Fig 1A. (A) Absolute numbers of splenic GC B cell populations (B220+ GL7+ CD95+) during P. yoelii XNL and P. chabaudi AS co-infection models with representative gating strategy (Day 12 post P. yoelii or Day 15 post P. chabaudi; Plasmodium vs. co-infected, p<0.05, Mann Whitney U-test). (B) Absolute numbers of splenic plasma cell populations (CD3- B220int CD138+) during P. yoelii XNL AND P. chabaudi AS co-infection models with representative gating strategy (Day 12 post P. yoelii or Day 11 post P. chabaudi; Plasmodium vs. co-infected, p<0.05, Mann Whitney U-test). (C) Spleen section for mock infected, MHV68 infected, P. yoelii XNL infected and MHV68 and P. yoelii XNL co-infected animals at day 8 post infection with P. yoelii XNL (or day 15 post-infection with MHV68). Green: B220-FITC (B cells), Blue: GL7-AF660 (Germinal center B cells) and Red: CD3-AF568 (T cells).

Mentions: We hypothesized that the impairment of the anti-malarial humoral response in MHV68 infected animals was due to a defect in the generation or function of plasma cells upon infection with malaria. We assessed the populations of plasma cells and germinal center (GC) B cells (a precursor of memory and plasma cells) in the spleen at different times post-infection with malaria. Mice that were co-infected with MHV68 and malaria had a comparable number of GC B cells compared to singly infected animals at day 7–8 post infection with malaria (S2 and S3 Figs; co-infected compared with singly infected animals Mann Whitney-U test p>0.05 in both models). However, by day 12 post-infection with P. yoelii XNL or day 15 post-infection with P. chabaudi AS, GC B cell numbers were significantly reduced as compared to a single Plasmodium infection (both Mann Whitney-U test p<0.05). At day 8 post co-infection, the GC B cells present were located in T cell-containing germinal centers in representative P. yoelii XNL singly infected and MHV68 co-infected animals (Fig 3C), suggesting that the defect was in the maintenance of the germinal center rather than a follicular structural defect. The impaired GC response correlated with greatly reduced numbers of plasma cells by day 11/12 post-infection with malaria in MHV68 co-infected animals compared with malaria singly infected animals (Mann Whitney-U test p<0.05 in both cases). This observation suggests that the defect in anti-malarial antibody responses to the Plasmodium infection in MHV68 co-infected animals is likely due to a defect in the generation and/or maintenance of GC B cells.


Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity.

Matar CG, Anthony NR, O'Flaherty BM, Jacobs NT, Priyamvada L, Engwerda CR, Speck SH, Lamb TJ - PLoS Pathog. (2015)

MHV68 suppresses splenic B cell responses during co-infection with Plasmodium.The timeline and experimental set up was identical to that shown in Fig 1A. (A) Absolute numbers of splenic GC B cell populations (B220+ GL7+ CD95+) during P. yoelii XNL and P. chabaudi AS co-infection models with representative gating strategy (Day 12 post P. yoelii or Day 15 post P. chabaudi; Plasmodium vs. co-infected, p<0.05, Mann Whitney U-test). (B) Absolute numbers of splenic plasma cell populations (CD3- B220int CD138+) during P. yoelii XNL AND P. chabaudi AS co-infection models with representative gating strategy (Day 12 post P. yoelii or Day 11 post P. chabaudi; Plasmodium vs. co-infected, p<0.05, Mann Whitney U-test). (C) Spleen section for mock infected, MHV68 infected, P. yoelii XNL infected and MHV68 and P. yoelii XNL co-infected animals at day 8 post infection with P. yoelii XNL (or day 15 post-infection with MHV68). Green: B220-FITC (B cells), Blue: GL7-AF660 (Germinal center B cells) and Red: CD3-AF568 (T cells).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440701&req=5

ppat.1004858.g003: MHV68 suppresses splenic B cell responses during co-infection with Plasmodium.The timeline and experimental set up was identical to that shown in Fig 1A. (A) Absolute numbers of splenic GC B cell populations (B220+ GL7+ CD95+) during P. yoelii XNL and P. chabaudi AS co-infection models with representative gating strategy (Day 12 post P. yoelii or Day 15 post P. chabaudi; Plasmodium vs. co-infected, p<0.05, Mann Whitney U-test). (B) Absolute numbers of splenic plasma cell populations (CD3- B220int CD138+) during P. yoelii XNL AND P. chabaudi AS co-infection models with representative gating strategy (Day 12 post P. yoelii or Day 11 post P. chabaudi; Plasmodium vs. co-infected, p<0.05, Mann Whitney U-test). (C) Spleen section for mock infected, MHV68 infected, P. yoelii XNL infected and MHV68 and P. yoelii XNL co-infected animals at day 8 post infection with P. yoelii XNL (or day 15 post-infection with MHV68). Green: B220-FITC (B cells), Blue: GL7-AF660 (Germinal center B cells) and Red: CD3-AF568 (T cells).
Mentions: We hypothesized that the impairment of the anti-malarial humoral response in MHV68 infected animals was due to a defect in the generation or function of plasma cells upon infection with malaria. We assessed the populations of plasma cells and germinal center (GC) B cells (a precursor of memory and plasma cells) in the spleen at different times post-infection with malaria. Mice that were co-infected with MHV68 and malaria had a comparable number of GC B cells compared to singly infected animals at day 7–8 post infection with malaria (S2 and S3 Figs; co-infected compared with singly infected animals Mann Whitney-U test p>0.05 in both models). However, by day 12 post-infection with P. yoelii XNL or day 15 post-infection with P. chabaudi AS, GC B cell numbers were significantly reduced as compared to a single Plasmodium infection (both Mann Whitney-U test p<0.05). At day 8 post co-infection, the GC B cells present were located in T cell-containing germinal centers in representative P. yoelii XNL singly infected and MHV68 co-infected animals (Fig 3C), suggesting that the defect was in the maintenance of the germinal center rather than a follicular structural defect. The impaired GC response correlated with greatly reduced numbers of plasma cells by day 11/12 post-infection with malaria in MHV68 co-infected animals compared with malaria singly infected animals (Mann Whitney-U test p<0.05 in both cases). This observation suggests that the defect in anti-malarial antibody responses to the Plasmodium infection in MHV68 co-infected animals is likely due to a defect in the generation and/or maintenance of GC B cells.

Bottom Line: Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh) cells in the spleen.Notably, co-infection with an M2- mutant MHV68 eliminates lethality of P. yoelii XNL.Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America; Microbiology and Molecular Genetics Graduate Program, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America.

ABSTRACT
Immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for Plasmodium falciparum. Yet, nearly 20% of infected children die annually as a result of severe malaria. Multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV) by the age of 6 months. This timing overlaps with the waning of protective maternal antibodies and susceptibility to primary Plasmodium infection. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Using well established mouse models of infection, we show here that acute, but not latent murine gammaherpesvirus 68 (MHV68) infection suppresses the anti-malarial humoral response to a secondary malaria infection. Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh) cells in the spleen. Furthermore, we have identified the MHV68 M2 protein as an important virus encoded protein that can: (i) suppress anti-MHV68 humoral responses during acute MHV68 infection; and (ii) plays a critical role in the observed suppression of anti-malarial humoral responses in the setting of co-infection. Notably, co-infection with an M2- mutant MHV68 eliminates lethality of P. yoelii XNL. Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response. This suggests that acute infection with EBV should be investigated as a risk factor for non-cerebral severe malaria in young children living in areas endemic for Plasmodium transmission.

No MeSH data available.


Related in: MedlinePlus