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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

P. yoelii XNL requires Plasmodium specific IgG response to clear primary peak of parasitemia.(A) Percent parasitemia in the periphery during P. yoelii XNL (p<0.05; area under curve, Mann Whitney U-test) or P. chabaudi AS co-infection models (p>0.05; area under the curve, Mann Whitney U-test). (B) Anemia during P. yoelii XNL (p>0.05; area over curve, Mann Whitney U-test, P. yoelii vs. co-infected) or P. chabaudi AS co-infection (p>0.05; area over curve, Mann Whitney U-test, P. chabaudi vs. co-infected). (C) Percent parasitemia in periphery during infection of single P. yoelii XNL or P. chabaudi AS in C57BL/6 or μMT (B cell-deficient) mice. (D) Anemia during infection of single P. yoelii XNL or P. chabaudi AS in C57BL/6 or μMT mice.
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ppat.1004858.g002: P. yoelii XNL requires Plasmodium specific IgG response to clear primary peak of parasitemia.(A) Percent parasitemia in the periphery during P. yoelii XNL (p<0.05; area under curve, Mann Whitney U-test) or P. chabaudi AS co-infection models (p>0.05; area under the curve, Mann Whitney U-test). (B) Anemia during P. yoelii XNL (p>0.05; area over curve, Mann Whitney U-test, P. yoelii vs. co-infected) or P. chabaudi AS co-infection (p>0.05; area over curve, Mann Whitney U-test, P. chabaudi vs. co-infected). (C) Percent parasitemia in periphery during infection of single P. yoelii XNL or P. chabaudi AS in C57BL/6 or μMT (B cell-deficient) mice. (D) Anemia during infection of single P. yoelii XNL or P. chabaudi AS in C57BL/6 or μMT mice.

Mentions: To extend the above observations, we evaluated the impact of an acute MHV68 infection on clearance of the primary peak of parasitemia during secondary challenge with Plasmodium. During the initial stages of malaria infection, MHV68 and P. yoelii XNL co-infected animals had comparable peripheral parasitemia when compared with P. yoelii XNL singly infected animals (Fig 2A). However, by day 17 post-infection, singly infected animals began to control peripheral parasitemia while co-infected animals were unable to do so (Fig 2A; Mann Whitney-U test p<0.05). There was a trend for co-infected animals to have more severe malarial anemia during P. yoelii XNL and MHV68 co-infection compared to P. yoelii XNL singly infected animals, but this did not reach statistical significance (Fig 2B; Mann Whitney-U test on the area above the curve p = 0.056). There was no difference in P. chabaudi AS parasitemia or anemia in singly infected or MHV68 co-infected groups (Mann Whitney-U test on the area under or above the curve respectively p>0.05) (Fig 2A and 2B).


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)

P. yoelii XNL requires Plasmodium specific IgG response to clear primary peak of parasitemia.(A) Percent parasitemia in the periphery during P. yoelii XNL (p<0.05; area under curve, Mann Whitney U-test) or P. chabaudi AS co-infection models (p>0.05; area under the curve, Mann Whitney U-test). (B) Anemia during P. yoelii XNL (p>0.05; area over curve, Mann Whitney U-test, P. yoelii vs. co-infected) or P. chabaudi AS co-infection (p>0.05; area over curve, Mann Whitney U-test, P. chabaudi vs. co-infected). (C) Percent parasitemia in periphery during infection of single P. yoelii XNL or P. chabaudi AS in C57BL/6 or μMT (B cell-deficient) mice. (D) Anemia during infection of single P. yoelii XNL or P. chabaudi AS in C57BL/6 or μMT mice.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004858.g002: P. yoelii XNL requires Plasmodium specific IgG response to clear primary peak of parasitemia.(A) Percent parasitemia in the periphery during P. yoelii XNL (p<0.05; area under curve, Mann Whitney U-test) or P. chabaudi AS co-infection models (p>0.05; area under the curve, Mann Whitney U-test). (B) Anemia during P. yoelii XNL (p>0.05; area over curve, Mann Whitney U-test, P. yoelii vs. co-infected) or P. chabaudi AS co-infection (p>0.05; area over curve, Mann Whitney U-test, P. chabaudi vs. co-infected). (C) Percent parasitemia in periphery during infection of single P. yoelii XNL or P. chabaudi AS in C57BL/6 or μMT (B cell-deficient) mice. (D) Anemia during infection of single P. yoelii XNL or P. chabaudi AS in C57BL/6 or μMT mice.
Mentions: To extend the above observations, we evaluated the impact of an acute MHV68 infection on clearance of the primary peak of parasitemia during secondary challenge with Plasmodium. During the initial stages of malaria infection, MHV68 and P. yoelii XNL co-infected animals had comparable peripheral parasitemia when compared with P. yoelii XNL singly infected animals (Fig 2A). However, by day 17 post-infection, singly infected animals began to control peripheral parasitemia while co-infected animals were unable to do so (Fig 2A; Mann Whitney-U test p<0.05). There was a trend for co-infected animals to have more severe malarial anemia during P. yoelii XNL and MHV68 co-infection compared to P. yoelii XNL singly infected animals, but this did not reach statistical significance (Fig 2B; Mann Whitney-U test on the area above the curve p = 0.056). There was no difference in P. chabaudi AS parasitemia or anemia in singly infected or MHV68 co-infected groups (Mann Whitney-U test on the area under or above the curve respectively p>0.05) (Fig 2A and 2B).

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