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Interferon-γ: The Jekyll and Hyde of Malaria.

King T, Lamb T - PLoS Pathog. (2015)

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America.

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IFN-γ secretion by both innate and adaptive immune cells is essential for control of intracellular pathogens and tumors, yet aberrant production of IFN-γ contributes to autoimmunity and inflammation in certain disease settings... IFN-γ is a central cytokine in controlling Plasmodium infection in both the liver and blood stages of the parasite life cycle, but it can also exacerbate the severity of malarial disease depending on the temporal and spatial production of IFN-γ... The protective capacity of IFN-γ in malaria appears to be, in part, related to the timing of IFN-γ production with the early appearance of IFN-γ after infection in humans correlated with protection against the development of clinical symptoms of malaria in some studies... However, study conclusions are often complicated by factors that include differing patterns of Plasmodium transmission between study sites or varying levels of pathogen coinfection giving rise to conflicting data... It should be noted that the latter two functions are not mutually exclusive... IFN-γ exerts its effects on immune cells that express the IFNGR1/2 cell surface receptor, and signaling through this receptor results in activation of transcription factors such as IRF1, STAT1, JAK2, IRF9, CIITA, and T-bet... This leads to expression of a number of proteins such as nitric oxide synthase and FcγRI (CD64, a high-affinity Fc receptor), as well as induction of B cell class-switching to the IgG2a antibody isotype... As a result, the aforementioned events can lead to enhanced phagocytosis and destruction of intracellular pathogens... The pathology associated with malaria is caused by the blood stages of Plasmodium infection and, in particular, immune responses targeting iRBCs sequestered in various organs... These pathogenic T cells induce cerebral pathology most likely through perforin- and granzyme-dependent disruption of the blood-brain barrier upon recognition of malaria-derived peptides presented in the context of MHC-I on brain endothelial cells... Thus, while IFN-γ is necessary for the recruitment of CD8 T cells to the brain during ECM, other effector molecules produced by activated CD8 T cells such as perforin and granzyme B are the critical mediators of pathology... For example, phase IIa clinical trials for the RTS,S pre-erythrocytic malaria vaccine candidate showed a correlation between prolonged CD4 and CD8 T cell IFN-γ responses against a malaria-specific protein and protection upon challenge infection in human volunteers... In mice, the loss of protective immunity against P. chabaudi is associated with a decrease in memory CD4 Th1 cells after parasite clearance along with a concomitant decrease in IFN-γ production from splenocytes... Splenic IFN-γ has been shown to be required for optimal priming of effector and effector memory T cells by splenic innate cells, demonstrating the importance of this cytokine in maintenance of optimal immunity... However, it is clear that the dynamic roles of IFN-γ during malaria are complex, and more work is needed to understand the delicate balance of IFN-γ necessary for achieving optimal protection while minimizing pathology.

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Related in: MedlinePlus

Effector mechanisms induced by IFN-γ during malaria.Various immune cell subsets produce IFN-γ in response to Plasmodium infection. NK, γδ, and NKT cells are largely responsible for early production of IFN-γ in response to liver and blood stages of the parasite and play a role in early control of parasite growth. IFN-γ-producing CD8+ T cells have also been shown to limit intrahepatic parasite growth through an IFN-γ-inducible, nitric oxide-dependent mechanism (1). Once an adaptive immune response is initiated, IFN-γ produced by CD4+ T cells optimally activates CD8+ T cells, B cells, and macrophages. IFN-γ influences isotype switching in B cells leading to production of cytophilic antibodies capable of binding free parasites and blocking red blood cell invasion (2), mediating parasite clearance through opsonization (3), and binding the surface of infected red blood cells promoting antibody-dependent phagocytosis (4). Production of IFN-γ from CD4+ T cells also optimally activates macrophages to phagocytose infected red blood cells and free parasites (5). All of these mechanisms are important for optimal control of parasite growth during Plasmodium infection.
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ppat.1005118.g001: Effector mechanisms induced by IFN-γ during malaria.Various immune cell subsets produce IFN-γ in response to Plasmodium infection. NK, γδ, and NKT cells are largely responsible for early production of IFN-γ in response to liver and blood stages of the parasite and play a role in early control of parasite growth. IFN-γ-producing CD8+ T cells have also been shown to limit intrahepatic parasite growth through an IFN-γ-inducible, nitric oxide-dependent mechanism (1). Once an adaptive immune response is initiated, IFN-γ produced by CD4+ T cells optimally activates CD8+ T cells, B cells, and macrophages. IFN-γ influences isotype switching in B cells leading to production of cytophilic antibodies capable of binding free parasites and blocking red blood cell invasion (2), mediating parasite clearance through opsonization (3), and binding the surface of infected red blood cells promoting antibody-dependent phagocytosis (4). Production of IFN-γ from CD4+ T cells also optimally activates macrophages to phagocytose infected red blood cells and free parasites (5). All of these mechanisms are important for optimal control of parasite growth during Plasmodium infection.

Mentions: IFN-γ secreted by CD4+ Th1 cells is critical for optimal activation of CD8+ T cells, B cells, and macrophages, all of which perform vital roles in the control of Plasmodium infection (Fig 1). The primary immune effector mechanisms by which IFN-γ can influence destruction of Plasmodium-infected cells include increasing the cytotoxic potential of CD8+ T cells, inducing production of cytophilic antibodies by B cells and enhancing phagocytic abilities of immune cells such as macrophages. It should be noted that the latter two functions are not mutually exclusive.


Interferon-γ: The Jekyll and Hyde of Malaria.

King T, Lamb T - PLoS Pathog. (2015)

Effector mechanisms induced by IFN-γ during malaria.Various immune cell subsets produce IFN-γ in response to Plasmodium infection. NK, γδ, and NKT cells are largely responsible for early production of IFN-γ in response to liver and blood stages of the parasite and play a role in early control of parasite growth. IFN-γ-producing CD8+ T cells have also been shown to limit intrahepatic parasite growth through an IFN-γ-inducible, nitric oxide-dependent mechanism (1). Once an adaptive immune response is initiated, IFN-γ produced by CD4+ T cells optimally activates CD8+ T cells, B cells, and macrophages. IFN-γ influences isotype switching in B cells leading to production of cytophilic antibodies capable of binding free parasites and blocking red blood cell invasion (2), mediating parasite clearance through opsonization (3), and binding the surface of infected red blood cells promoting antibody-dependent phagocytosis (4). Production of IFN-γ from CD4+ T cells also optimally activates macrophages to phagocytose infected red blood cells and free parasites (5). All of these mechanisms are important for optimal control of parasite growth during Plasmodium infection.
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getmorefigures.php?uid=PMC4591348&req=5

ppat.1005118.g001: Effector mechanisms induced by IFN-γ during malaria.Various immune cell subsets produce IFN-γ in response to Plasmodium infection. NK, γδ, and NKT cells are largely responsible for early production of IFN-γ in response to liver and blood stages of the parasite and play a role in early control of parasite growth. IFN-γ-producing CD8+ T cells have also been shown to limit intrahepatic parasite growth through an IFN-γ-inducible, nitric oxide-dependent mechanism (1). Once an adaptive immune response is initiated, IFN-γ produced by CD4+ T cells optimally activates CD8+ T cells, B cells, and macrophages. IFN-γ influences isotype switching in B cells leading to production of cytophilic antibodies capable of binding free parasites and blocking red blood cell invasion (2), mediating parasite clearance through opsonization (3), and binding the surface of infected red blood cells promoting antibody-dependent phagocytosis (4). Production of IFN-γ from CD4+ T cells also optimally activates macrophages to phagocytose infected red blood cells and free parasites (5). All of these mechanisms are important for optimal control of parasite growth during Plasmodium infection.
Mentions: IFN-γ secreted by CD4+ Th1 cells is critical for optimal activation of CD8+ T cells, B cells, and macrophages, all of which perform vital roles in the control of Plasmodium infection (Fig 1). The primary immune effector mechanisms by which IFN-γ can influence destruction of Plasmodium-infected cells include increasing the cytotoxic potential of CD8+ T cells, inducing production of cytophilic antibodies by B cells and enhancing phagocytic abilities of immune cells such as macrophages. It should be noted that the latter two functions are not mutually exclusive.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

IFN-γ secretion by both innate and adaptive immune cells is essential for control of intracellular pathogens and tumors, yet aberrant production of IFN-γ contributes to autoimmunity and inflammation in certain disease settings... IFN-γ is a central cytokine in controlling Plasmodium infection in both the liver and blood stages of the parasite life cycle, but it can also exacerbate the severity of malarial disease depending on the temporal and spatial production of IFN-γ... The protective capacity of IFN-γ in malaria appears to be, in part, related to the timing of IFN-γ production with the early appearance of IFN-γ after infection in humans correlated with protection against the development of clinical symptoms of malaria in some studies... However, study conclusions are often complicated by factors that include differing patterns of Plasmodium transmission between study sites or varying levels of pathogen coinfection giving rise to conflicting data... It should be noted that the latter two functions are not mutually exclusive... IFN-γ exerts its effects on immune cells that express the IFNGR1/2 cell surface receptor, and signaling through this receptor results in activation of transcription factors such as IRF1, STAT1, JAK2, IRF9, CIITA, and T-bet... This leads to expression of a number of proteins such as nitric oxide synthase and FcγRI (CD64, a high-affinity Fc receptor), as well as induction of B cell class-switching to the IgG2a antibody isotype... As a result, the aforementioned events can lead to enhanced phagocytosis and destruction of intracellular pathogens... The pathology associated with malaria is caused by the blood stages of Plasmodium infection and, in particular, immune responses targeting iRBCs sequestered in various organs... These pathogenic T cells induce cerebral pathology most likely through perforin- and granzyme-dependent disruption of the blood-brain barrier upon recognition of malaria-derived peptides presented in the context of MHC-I on brain endothelial cells... Thus, while IFN-γ is necessary for the recruitment of CD8 T cells to the brain during ECM, other effector molecules produced by activated CD8 T cells such as perforin and granzyme B are the critical mediators of pathology... For example, phase IIa clinical trials for the RTS,S pre-erythrocytic malaria vaccine candidate showed a correlation between prolonged CD4 and CD8 T cell IFN-γ responses against a malaria-specific protein and protection upon challenge infection in human volunteers... In mice, the loss of protective immunity against P. chabaudi is associated with a decrease in memory CD4 Th1 cells after parasite clearance along with a concomitant decrease in IFN-γ production from splenocytes... Splenic IFN-γ has been shown to be required for optimal priming of effector and effector memory T cells by splenic innate cells, demonstrating the importance of this cytokine in maintenance of optimal immunity... However, it is clear that the dynamic roles of IFN-γ during malaria are complex, and more work is needed to understand the delicate balance of IFN-γ necessary for achieving optimal protection while minimizing pathology.

No MeSH data available.


Related in: MedlinePlus