Antigen-Responsive CD4<sup>+</sup>T Cells from C3H Mice Chronically Infected with<i>Leishmania amazonensis</i>Are Impaired in the Transition to an Effector Phenotype

Ramer, Amanda E.; Vanloubbeeck, Yannick; Jones, Douglas E.

doi:10.1128/iai.74.3.1547-1554.2006

Cited by 22 publications

(14 citation statements)

References 29 publications

(33 reference statements)

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“…15 Our laboratory has shown that CD4 ϩ T cells from mice chronically infected with L. amazonensis are impaired in their ability to transition into an effector phenotype. 6 We propose that these differences in BMDC phenotype previously observed to be elicited by L. amazonensis promastigotes and amastigotes in vitro, would be reflected during in vivo infection as the infection progresses from peracute (2 days postinfection [dpi]) to acute (7 dpi). Mice were infected subcutaneously in the left footpad with L. amazonensis or L. major promastigotes and sacrificed at 2 and 7 dpi.…”

Section: In the Draining Lymph Node Of L Amazonensis-infected Micmentioning

confidence: 85%

“…Alteration of surface marker expression, cytokine production, maturation, and function of DC following L. amazonensis infection has been previously characterized in vitro. 15,25 Defects in DC maturation may, in part, contribute to the unpolarized T cell phenotype observed during L. amazonensis infection, 6 and lead to a non-healing immune response. As early as 7 dpi CD11c ϩ DLN cells from L. amazonensis-infected C3HeB/FeJ mice have significantly reduced CD40 surface expression and a decreased number of IL-12p40-producing cells, as compared with L. major-infected mice.…”

Section: Discussionmentioning

confidence: 99%

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Altered Dendritic Cell Phenotype in Response to Leishmania amazonensis Amastigote Infection Is Mediated by MAP Kinase, ERK

Boggiatto

Jie

Ghosh

et al. 2009

The American Journal of Pathology

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Initiation of productive immune responses againstLeishmania depends on the successful transition of dendritic cells (DC) from an immature to a mature phenotype. This process is characterized by high CD40 surface expression as well as interleukin-12 production, which are frequently seen in response to L. major infection. In vivo footpad infection of C3HeB/FeJ mice for 7 days with L. amazonensis promoted an immature CD11c ؉ DC phenotype characterized by both significantly low CD40 surface expression and significantly decreased interleukin-12p40 production compared with L. major infection of these same mice. In vitro infection of bone marrow-derived dendritic cells with L. amazonensis amastigotes resulted in rapid and significant phosphorylation of the mitogen activated protein kinase, extracellular signal-regulated kinase 1/2, observed within minutes of exposure to the parasite. Infection with L. amazonensis promastigotes led to increased 1/2 phosphorylation after 4 hours of infection compared with L. major infection, which correlated with promastigote transformation into amastigotes. Treatment of bone marrow-derived dendritic cells with a mitogen activated protein kinase kinase-specific inhibitor, PD98059, led to regained surface CD40 expression and interleukin-12p40 production following L. amazonensis amastigote infection compared with non-treated, infected DC. Treatment of L. amazonensis-infected mice with the highly-specific mitogen activated protein kinase kinase inhibitor, CI-1040, enhanced surface CD40 expression on CD11c؉ DC obtained from the draining lymph node. L. amazonensis amastigotes, through activation of extracellular signal-regulated kinase 1/2, inhibit the ability of DC to undergo proper maturation both in vitro and in vivo.

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Section: In the Draining Lymph Node Of L Amazonensis-infected Micmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Altered Dendritic Cell Phenotype in Response to Leishmania amazonensis Amastigote Infection Is Mediated by MAP Kinase, ERK

Boggiatto

Jie

Ghosh

et al. 2009

The American Journal of Pathology

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“…L. amazonensis modulates DC maturation through activation of ERK1/2 [11], altering a critical step for promotion of a T helper 1 immune response and clearance of L. amazonensis infection [21–23]. It was previously unknown if L. amazonensis -mediated ERK1/2 phosphorylation was an active process by the parasite or produced by cell entry via phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

Targeted extracellular signal-regulated kinase activation mediated by Leishmania amazonensis requires MP1 scaffold

Boggiatto¹,

Martínez²,

Pullikuth³

et al. 2014

Microbes and Infection

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Leishmania amazonensis infection promotes alteration of host cellular signaling and intracellular parasite survival, but specific mechanisms are poorly understood. We previously demonstrated that L. amazonensis infection of dendritic cells (DC) activated extracellular signal-regulated kinase (ERK), a MAP-kinase kinase kinase, leading to altered DC maturation and non-healing cutaneous leishmaniasis. Studies using growth factors and cell lines have shown that targeted, robust, intracellular phosphorylation of ERK1/2 from phagolysosomes required recruitment and association with scaffolding proteins, including p14/MP1 and MORG1, on the surface of late endosomes. Based on the intracellular localization of L. amazonensis within a parasitophorous vacuole with late endosome characteristics, we speculated that scaffolding proteins would be important for intracellular parasite-mediated ERK signaling. Our findings demonstrate that MP1, MORG1, and ERK all co-localized on the surface of parasite-containing LAMP2-positive phagolysosomes. Infection of MEK1 mutant fibroblasts unable to bind MP1 demonstrated dramatically reduced ERK1/2 phosphorylation following L. amazonensis infection but not following positive control EGF treatment. This novel mechanism for localization of intracellular L. amazonensis-mediated ERK1/2 phosphorylation required the endosomal scaffold protein MP1 and localized to L. amazonensis parasitophorous vacuoles. Understanding how L. amazonensis parasites hijack host cell scaffold proteins to modulate signaling cascades provides targets for antiprotozoal drug development.

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“…L. amazonensis utilizes the hosts scaffolding complex and because use of this complex provides spatial specificity, L. amazonensis brings ERK1/2 next to the vacuole it inhabits (Figure 6B). Use of a PV/endosomal-specific p14/MP1 scaffold complex promotes sustained ERK1/2 phosphorylation [53], alteration of the phagocyte oxidative burst [56] and leads to chronic infection [54, 53, 76, 77]. L. amazonensis has been shown to inhabit the perinuclear region within its PV [78-80].…”

Section: Introductionmentioning

confidence: 99%

Chronic infection by Leishmania amazonensis mediated through MAPK ERK mechanisms

Martínez

Petersen

2014

Immunol Res

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Leishmania amazonensis is an intracellular protozoan parasite responsible for chronic cutaneous leishmaniasis (CL). CL is a neglected tropical disease responsible for infecting millions of people worldwide. L. amazonensis promotes alteration of various signaling pathways that are essential for host cell survival. Specifically, through parasite-mediated phosphorylation of extracellular signal regulated kinase (ERK), L. amazonensis inhibits cell-mediated parasite killing and promotes its own survival by co-opting multiple host cell functions. In this review we highlight Leishmania-host cell signaling alterations focusing on those specific to 1) motor proteins, 2) prevention of NADPH subunit phosphorylation impairing reactive oxygen species production (ROS), and 3) localized endosomal signaling to up-regulate ERK phosphorylation. This review will focus upon mechanisms and possible explanations as to how Leishmania spp. evades the various layers of defense employed by the host immune response.

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Antigen-Responsive CD4⁺T Cells from C3H Mice Chronically Infected withLeishmania amazonensisAre Impaired in the Transition to an Effector Phenotype

Cited by 22 publications

References 29 publications

Altered Dendritic Cell Phenotype in Response to Leishmania amazonensis Amastigote Infection Is Mediated by MAP Kinase, ERK

Altered Dendritic Cell Phenotype in Response to Leishmania amazonensis Amastigote Infection Is Mediated by MAP Kinase, ERK

Targeted extracellular signal-regulated kinase activation mediated by Leishmania amazonensis requires MP1 scaffold

Chronic infection by Leishmania amazonensis mediated through MAPK ERK mechanisms

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Antigen-Responsive CD4+T Cells from C3H Mice Chronically Infected withLeishmania amazonensisAre Impaired in the Transition to an Effector Phenotype

Cited by 22 publications

References 29 publications

Altered Dendritic Cell Phenotype in Response to Leishmania amazonensis Amastigote Infection Is Mediated by MAP Kinase, ERK

Altered Dendritic Cell Phenotype in Response to Leishmania amazonensis Amastigote Infection Is Mediated by MAP Kinase, ERK

Targeted extracellular signal-regulated kinase activation mediated by Leishmania amazonensis requires MP1 scaffold

Chronic infection by Leishmania amazonensis mediated through MAPK ERK mechanisms

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Antigen-Responsive CD4⁺T Cells from C3H Mice Chronically Infected withLeishmania amazonensisAre Impaired in the Transition to an Effector Phenotype