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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 co-infection with the non-lethal P. yoelii XNL in C57BL/6 results in lethal malarial disease and suppressed Plasmodium specific IgG response.(A) Timeline of infection. 6–8 week old C57BL/6 mice were infected with 1000 PFU of MHV68 on day -7 followed by infection with 105pRBCs of non-lethal P. yoelii XNL or P. chabaudi AS. Infections consisted of 5 experimental groups: MHV68 + Plasmodium, Plasmodium, MHV68 or mock infected. Each experimental group consisted of n = 5 and was repeated twice. Animals were sacrificed at days 8, 12, 16 and 23 post P. yoelii XNL infection or day 7, 11, 15 and 23 post P. chabaudi AS infection for collection of spleen, lung and blood. (B) Survival analysis of animals co-infected with MHV68 and P. yoelii XNL or P. chabaudi AS. Total IgG and IgM levels in serum in (C) P. yoelii XNL (Day 23 IgG—P. yoelii vs co-infected: p<0.05 Mann Whitney U-test) or (D) P. chabaudi AS co-infection model (Day 11 IgG—P. chabaudi vs co-infected: p<0.05 Mann Whitney U-test). Parasite specific IgG levels in serum during (E) P. yoelii XNL (day 23 post infection, P. yoelii vs co-infected: p<0.05 Mann Whitney U-test) or (F) P. chabaudi AS (day 11 post infection, P. chabaudi vs co-infected: p<0.05 Mann Whitney U-test) co-infection.
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ppat.1004858.g001: MHV68 co-infection with the non-lethal P. yoelii XNL in C57BL/6 results in lethal malarial disease and suppressed Plasmodium specific IgG response.(A) Timeline of infection. 6–8 week old C57BL/6 mice were infected with 1000 PFU of MHV68 on day -7 followed by infection with 105pRBCs of non-lethal P. yoelii XNL or P. chabaudi AS. Infections consisted of 5 experimental groups: MHV68 + Plasmodium, Plasmodium, MHV68 or mock infected. Each experimental group consisted of n = 5 and was repeated twice. Animals were sacrificed at days 8, 12, 16 and 23 post P. yoelii XNL infection or day 7, 11, 15 and 23 post P. chabaudi AS infection for collection of spleen, lung and blood. (B) Survival analysis of animals co-infected with MHV68 and P. yoelii XNL or P. chabaudi AS. Total IgG and IgM levels in serum in (C) P. yoelii XNL (Day 23 IgG—P. yoelii vs co-infected: p<0.05 Mann Whitney U-test) or (D) P. chabaudi AS co-infection model (Day 11 IgG—P. chabaudi vs co-infected: p<0.05 Mann Whitney U-test). Parasite specific IgG levels in serum during (E) P. yoelii XNL (day 23 post infection, P. yoelii vs co-infected: p<0.05 Mann Whitney U-test) or (F) P. chabaudi AS (day 11 post infection, P. chabaudi vs co-infected: p<0.05 Mann Whitney U-test) co-infection.

Mentions: The humoral response is generally considered to be a critical effector mechanism for controlling peripheral parasitemia in both human and mouse malaria infection [23]. To understand the impact of acute MHV68 infection on the humoral response to a Plasmodium infection, we infected C57BL/6 mice with 1000 PFU of MHV68 intra-nasally (IN) on day -7 and 105 parasitized red blood cells (pRBCs) of P. yoelii XNL or P. chabaudi AS intra-peritoneally (IP) on day 0 (Fig 1A). Single infection with either of the Plasmodium species was non-lethal but, in the context of an MHV68 infected mouse, P. yoelii XNL, but not P. chabaudi AS, caused 100% lethality (Fig 1B). This corroborates a previous observation by Haque et al. who also observed lethality during MHV68 and P. yoelii XNL co-infection [24]. Knowing the importance of a robust humoral response in protection during Plasmodium infection [12,13], we hypothesized that MHV68 may impair the generation of an effective antibody response to control P. yoelii XNL parasitemia. Total IgM levels were reduced in co-infected animals relative to singly infected animals in P. yoelii XNL co-infection at day 23 post malaria infection (Mann Whitney-U test p<0.05) and at days 11 and 15 post malaria infection in P. chabaudi AS co-infection (both Mann Whitney-U test p<0.05) (Fig 1B and 1C). Total IgG levels were similarly affected and reduced at day 23 post malaria infection in P. yoelii XNL co-infected animals and at day 11 post malaria infection in P. chabaudi AS co-infected animals (both Mann Whitney U-test p<0.05; Fig 1B and 1D). This reduction in total IgG was mirrored in parasite-reactive IgG in both co-infection models compared with the relevant singly-infected animals (both Mann Whitney U-test p<0.05; Fig 1E and 1F). This observation shows that MHV68 acute infection can suppress the humoral response to malaria infection in mice. In one of the mouse malaria models tested (P. yoelii XNL), this suppression is correlated with the transformation of a non-lethal malaria infection into a lethal one (Fig 1B). This observation prompted us to evaluate how suppression of the anti-malaria humoral response impacts the control of peripheral parasitemia and to investigate why the acute phase of MHV68 co-infection impacted the virulence of P. yoelii XNL, but not P. chabaudi AS infection.


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 co-infection with the non-lethal P. yoelii XNL in C57BL/6 results in lethal malarial disease and suppressed Plasmodium specific IgG response.(A) Timeline of infection. 6–8 week old C57BL/6 mice were infected with 1000 PFU of MHV68 on day -7 followed by infection with 105pRBCs of non-lethal P. yoelii XNL or P. chabaudi AS. Infections consisted of 5 experimental groups: MHV68 + Plasmodium, Plasmodium, MHV68 or mock infected. Each experimental group consisted of n = 5 and was repeated twice. Animals were sacrificed at days 8, 12, 16 and 23 post P. yoelii XNL infection or day 7, 11, 15 and 23 post P. chabaudi AS infection for collection of spleen, lung and blood. (B) Survival analysis of animals co-infected with MHV68 and P. yoelii XNL or P. chabaudi AS. Total IgG and IgM levels in serum in (C) P. yoelii XNL (Day 23 IgG—P. yoelii vs co-infected: p<0.05 Mann Whitney U-test) or (D) P. chabaudi AS co-infection model (Day 11 IgG—P. chabaudi vs co-infected: p<0.05 Mann Whitney U-test). Parasite specific IgG levels in serum during (E) P. yoelii XNL (day 23 post infection, P. yoelii vs co-infected: p<0.05 Mann Whitney U-test) or (F) P. chabaudi AS (day 11 post infection, P. chabaudi vs co-infected: p<0.05 Mann Whitney U-test) co-infection.
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ppat.1004858.g001: MHV68 co-infection with the non-lethal P. yoelii XNL in C57BL/6 results in lethal malarial disease and suppressed Plasmodium specific IgG response.(A) Timeline of infection. 6–8 week old C57BL/6 mice were infected with 1000 PFU of MHV68 on day -7 followed by infection with 105pRBCs of non-lethal P. yoelii XNL or P. chabaudi AS. Infections consisted of 5 experimental groups: MHV68 + Plasmodium, Plasmodium, MHV68 or mock infected. Each experimental group consisted of n = 5 and was repeated twice. Animals were sacrificed at days 8, 12, 16 and 23 post P. yoelii XNL infection or day 7, 11, 15 and 23 post P. chabaudi AS infection for collection of spleen, lung and blood. (B) Survival analysis of animals co-infected with MHV68 and P. yoelii XNL or P. chabaudi AS. Total IgG and IgM levels in serum in (C) P. yoelii XNL (Day 23 IgG—P. yoelii vs co-infected: p<0.05 Mann Whitney U-test) or (D) P. chabaudi AS co-infection model (Day 11 IgG—P. chabaudi vs co-infected: p<0.05 Mann Whitney U-test). Parasite specific IgG levels in serum during (E) P. yoelii XNL (day 23 post infection, P. yoelii vs co-infected: p<0.05 Mann Whitney U-test) or (F) P. chabaudi AS (day 11 post infection, P. chabaudi vs co-infected: p<0.05 Mann Whitney U-test) co-infection.
Mentions: The humoral response is generally considered to be a critical effector mechanism for controlling peripheral parasitemia in both human and mouse malaria infection [23]. To understand the impact of acute MHV68 infection on the humoral response to a Plasmodium infection, we infected C57BL/6 mice with 1000 PFU of MHV68 intra-nasally (IN) on day -7 and 105 parasitized red blood cells (pRBCs) of P. yoelii XNL or P. chabaudi AS intra-peritoneally (IP) on day 0 (Fig 1A). Single infection with either of the Plasmodium species was non-lethal but, in the context of an MHV68 infected mouse, P. yoelii XNL, but not P. chabaudi AS, caused 100% lethality (Fig 1B). This corroborates a previous observation by Haque et al. who also observed lethality during MHV68 and P. yoelii XNL co-infection [24]. Knowing the importance of a robust humoral response in protection during Plasmodium infection [12,13], we hypothesized that MHV68 may impair the generation of an effective antibody response to control P. yoelii XNL parasitemia. Total IgM levels were reduced in co-infected animals relative to singly infected animals in P. yoelii XNL co-infection at day 23 post malaria infection (Mann Whitney-U test p<0.05) and at days 11 and 15 post malaria infection in P. chabaudi AS co-infection (both Mann Whitney-U test p<0.05) (Fig 1B and 1C). Total IgG levels were similarly affected and reduced at day 23 post malaria infection in P. yoelii XNL co-infected animals and at day 11 post malaria infection in P. chabaudi AS co-infected animals (both Mann Whitney U-test p<0.05; Fig 1B and 1D). This reduction in total IgG was mirrored in parasite-reactive IgG in both co-infection models compared with the relevant singly-infected animals (both Mann Whitney U-test p<0.05; Fig 1E and 1F). This observation shows that MHV68 acute infection can suppress the humoral response to malaria infection in mice. In one of the mouse malaria models tested (P. yoelii XNL), this suppression is correlated with the transformation of a non-lethal malaria infection into a lethal one (Fig 1B). This observation prompted us to evaluate how suppression of the anti-malaria humoral response impacts the control of peripheral parasitemia and to investigate why the acute phase of MHV68 co-infection impacted the virulence of P. yoelii XNL, but not P. chabaudi AS infection.

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