scholarly journals Infection with Toxoplasma gondii Alters Lymphotoxin Expression Associated with Changes in Splenic Architecture

2012 ◽  
Vol 80 (10) ◽  
pp. 3602-3610 ◽  
Author(s):  
Arielle Glatman Zaretsky ◽  
Jonathan S. Silver ◽  
Marie Siwicki ◽  
Amy Durham ◽  
Carl F. Ware ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Specific Antibody ◽  
Germinal Center ◽  
Effector Proteins ◽  
Content Type ◽  
Partial Restoration ◽  
Follicular Helper ◽  
Β Receptor ◽  
Humoral Responses

ABSTRACTB cell responses are required for resistance toToxoplasma gondii; however, the events that lead to production of class-switched antibodies duringT. gondiiinfection have not been defined. Indeed, mice challenged with the parasite exhibited an expansion of T follicular helper cells and germinal center B cells in the spleen. Unexpectedly, this was not associated with germinal center formation and was instead accompanied by profound changes in splenic organization. This phenomenon was transient and was correlated with a decrease in expression of effector proteins that contribute to splenic organization, including lymphotoxins α and β. The importance of lymphotoxin was confirmed, as the use of a lymphotoxin β receptor agonist results in partial restoration of splenic structure. Splenectomized mice were used to test the splenic contribution to the antibody response duringT. gondiiinfection. Analysis of splenectomized mice revealed delayed kinetics in the production of parasite-specific antibody, but the mice did eventually develop normal levels of parasite-specific antibody. Together, these studies provide a better understanding of how infection withT. gondiiimpacts the customized structures required for the optimal humoral responses to the parasite and the role of lymphotoxin in these events.

scholarly journals The Role of CD4+ T Follicular Helper Cells in HIV Infection: From the Germinal Center to the Periphery

2017 ◽  
Vol 8 ◽  
Author(s):  
John Patrick Thornhill ◽  
Sarah Fidler ◽  
Paul Klenerman ◽  
John Frater ◽  
Chansavath Phetsouphanh
Keyword(s):  
Hiv Infection ◽  
Germinal Center ◽  
T Follicular Helper Cells ◽  
Helper Cells ◽  
Follicular Helper

scholarly journals Role of Memory B Cells in Hemagglutinin-Specific Antibody Production Following Human Influenza A Virus Infection

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 167 ◽  
Author(s):  
Mark Y. Sangster ◽  
Phuong Q. T. Nguyen ◽  
David J. Topham
Keyword(s):  
B Cells ◽  
Virus Infection ◽  
Antibody Response ◽  
Influenza A Virus ◽  
Antibody Production ◽  
Specific Antibody ◽  
Germinal Center ◽  
Influenza A ◽  
Influenza Virus Infection

When influenza A virus infects an immune individual, preexisting memory B cell (MBC) activation and rapid anamnestic antibody production plays a key role in viral clearance. The most effective neutralizing antibodies target the antigenically variable head of the viral hemagglutinin (HA); antibodies against the conserved HA stalk provide broader but less potent protection. In this review, we provide a comprehensive picture of an adult’s HA-specific antibody response to influenza virus infection. The process is followed from preexisting HA-specific MBC activation and rapid production of anti-HA antibodies, through to germinal center seeding and adaptation of the response to novel features of the HA. A major focus of the review is the role of competition between preexisting MBCs in determining the character of the HA-reactive antibody response. HA novelty modifies this competition and can shift the response from the immunodominant head to the stalk. We suggest that antibodies resulting from preexisting MBC activation are important regulators of anti-HA antibody production and play a role in positive selection of germinal center B cells reactive to novel HA epitopes. Our review also considers the role of MBCs in the effects of early-life imprinting on HA head- and stalk-specific antibody responses to influenza infection. An understanding of the processes described in this review will guide development of vaccination strategies that provide broadly effective protection.

scholarly journals Role of Toxoplasma gondii Chloroquine Resistance Transporter in Bradyzoite Viability and Digestive Vacuole Maintenance

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Geetha Kannan ◽  
Manlio Di Cristina ◽  
Aric J. Schultz ◽  
My-Hang Huynh ◽  
Fengrong Wang ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Chronic Infection ◽  
Chloroquine Resistance ◽  
Congenital Defects ◽  
Functional Link ◽  
Content Type ◽  
Chloroquine Resistance Transporter

ABSTRACT Toxoplasma gondii is a ubiquitous pathogen that can cause encephalitis, congenital defects, and ocular disease. T. gondii has also been implicated as a risk factor for mental illness in humans. The parasite persists in the brain as slow-growing bradyzoites contained within intracellular cysts. No treatments exist to eliminate this form of parasite. Although proteolytic degradation within the parasite lysosome-like vacuolar compartment (VAC) is critical for bradyzoite viability, whether other aspects of the VAC are important for parasite persistence remains unknown. An ortholog of Plasmodium falciparum chloroquine resistance transporter (CRT), TgCRT, has previously been identified in T. gondii. To interrogate the function of TgCRT in chronic-stage bradyzoites and its role in persistence, we knocked out TgCRT in a cystogenic strain and assessed VAC size, VAC digestion of host-derived proteins and parasite autophagosomes, and the viability of in vitro and in vivo bradyzoites. We found that whereas parasites deficient in TgCRT exhibit normal digestion within the VAC, they display a markedly distended VAC and their viability is compromised both in vitro and in vivo. Interestingly, impairing VAC proteolysis in TgCRT-deficient bradyzoites restored VAC size, consistent with a role for TgCRT as a transporter of products of digestion from the VAC. In conjunction with earlier studies, our current findings suggest a functional link between TgCRT and VAC proteolysis. This study provides further evidence of a crucial role for the VAC in bradyzoite persistence and a new potential VAC target to abate chronic Toxoplasma infection. IMPORTANCE Individuals chronically infected with the intracellular parasite Toxoplasma gondii are at risk of experiencing reactivated disease that can result in progressive loss of vision. No effective treatments exist for chronic toxoplasmosis due in part to a poor understanding of the biology underlying chronic infection and a lack of well-validated potential targets. We show here that a T. gondii transporter is functionally linked to protein digestion within the parasite lysosome-like organelle and that this transporter is necessary to sustain chronic infection in culture and in experimentally infected mice. Ablating the transporter results in severe bloating of the lysosome-like organelle. Together with earlier work, this study suggests the parasite’s lysosome-like organelle is vital for parasite survival, thus rendering it a potential target for diminishing infection and reducing the risk of reactivated disease.

scholarly journals Coimmunoprecipitation with MYR1 Identifies Three Additional Proteins within the Toxoplasma gondii Parasitophorous Vacuole Required for Translocation of Dense Granule Effectors into Host Cells

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Alicja M. Cygan ◽  
Terence C. Theisen ◽  
Alma G. Mendoza ◽  
Nicole D. Marino ◽  
Michael W. Panas ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Protein Translocation ◽  
Affinity Purification ◽  
Parasitophorous Vacuole ◽  
Dense Granule ◽  
Effector Proteins ◽  
Host Cells ◽  
Content Type ◽  
Cyclin E1 ◽  
Infected Cells

ABSTRACT Toxoplasma gondii is a ubiquitous, intracellular protozoan that extensively modifies infected host cells through secreted effector proteins. Many such effectors must be translocated across the parasitophorous vacuole (PV), in which the parasites replicate, ultimately ending up in the host cytosol or nucleus. This translocation has previously been shown to be dependent on five parasite proteins: MYR1, MYR2, MYR3, ROP17, and ASP5. We report here the identification of several MYR1-interacting and novel PV-localized proteins via affinity purification of MYR1, including TGGT1_211460 (dubbed MYR4), TGGT1_204340 (dubbed GRA54), and TGGT1_270320 (PPM3C). Further, we show that three of the MYR1-interacting proteins, GRA44, GRA45, and MYR4, are essential for the translocation of the Toxoplasma effector protein GRA16 and for the upregulation of human c-Myc and cyclin E1 in infected cells. GRA44 and GRA45 contain ASP5 processing motifs, but like MYR1, processing at these sites appears to be nonessential for their role in protein translocation. These results expand our understanding of the mechanism of effector translocation in Toxoplasma and indicate that the process is highly complex and dependent on at least eight discrete proteins. IMPORTANCE Toxoplasma is an extremely successful intracellular parasite and important human pathogen. Upon infection of a new cell, Toxoplasma establishes a replicative vacuole and translocates parasite effectors across this vacuole to function from the host cytosol and nucleus. These effectors play a key role in parasite virulence. The work reported here newly identifies three parasite proteins that are necessary for protein translocation into the host cell. These results significantly increase our knowledge of the molecular players involved in protein translocation in Toxoplasma-infected cells and provide additional potential drug targets.

scholarly journals The role of follicular helper T cells and the germinal center in HIV-1 gp120 DNA prime and gp120 protein boost vaccination

2014 ◽  
Vol 10 (7) ◽  
pp. 1985-1992 ◽  
Author(s):  
Kristin Hollister ◽  
Yuxin Chen ◽  
Shixia Wang ◽  
Hao Wu ◽  
Arpita Mondal ◽  
...  
Keyword(s):  
T Cells ◽  
Germinal Center ◽  
Helper T Cells ◽  
Follicular Helper T Cells ◽  
Boost Vaccination ◽  
Follicular Helper ◽  
Gp120 Protein ◽  
Protein Boost ◽  
Hiv 1

scholarly journals Migratory Activation of Primary Cortical Microglia upon Infection with Toxoplasma gondii

2011 ◽  
Vol 79 (8) ◽  
pp. 3046-3052 ◽  
Author(s):  
Isabel Dellacasa-Lindberg ◽  
Jonas M. Fuks ◽  
Romanico B. G. Arrighi ◽  
Henrik Lambert ◽  
Robert P. A. Wallin ◽  
...  
Keyword(s):  
T Cells ◽  
Toxoplasma Gondii ◽  
Mhc Class Ii ◽  
Glial Cells ◽  
Costimulatory Molecule ◽  
Toxoplasmic Encephalitis ◽  
Immune Functions ◽  
Content Type

ABSTRACTDisseminated toxoplasmosis in the central nervous system (CNS) is often accompanied by a lethal outcome. Studies with murine models of infection have focused on the role of systemic immunity in control of toxoplasmic encephalitis, while knowledge remains limited on the contributions of resident cells with immune functions in the CNS. In this study, the role of glial cells was addressed in the setting of recrudescentToxoplasmainfection in mice. Activated astrocytes and microglia were observed in the close vicinity of foci with replicating parasitesin situin the brain parenchyma.Toxoplasma gondiitachyzoites were allowed to infect primary microglia and astrocytesin vitro. Microglia were permissive to parasite replication, and infected microglia readily transmigrated across transwell membranes and cell monolayers. Thus, infected microglia, but not astrocytes, exhibited a hypermotility phenotype reminiscent of that recently described for infected dendritic cells. In contrast to gamma interferon-activated microglia,Toxoplasma-infected microglia did not upregulate major histocompatibility complex (MHC) class II molecules and the costimulatory molecule CD86. YetToxoplasma-infected microglia and astrocytes exhibited increased sensitivity to T cell-mediated killing, leading to rapid parasite transfer to effector T cellsin vitro. We hypothesize that glial cells and T cells, besides their role in triggering antiparasite immunity, may also act as “Trojan horses,” paradoxically facilitating dissemination ofToxoplasmawithin the CNS. To our knowledge, this constitutes the first report of migratory activation of a resident CNS cell by an intracellular parasite.

scholarly journals Rap1 Is Essential for B-Cell Locomotion, Germinal Center Formation and Normal B-1a Cell Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Sayaka Ishihara ◽  
Tsuyoshi Sato ◽  
Risa Sugioka ◽  
Ryota Miwa ◽  
Haruka Saito ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Specific Antibody ◽  
Stromal Cells ◽  
Germinal Center ◽  
Specific Antibody Production ◽  
Humoral Responses ◽  
Integrin Regulation ◽  
Germinal Center Formation

Integrin regulation by Rap1 is indispensable for lymphocyte recirculation. In mice having B-cell-specific Rap1a/b double knockouts (DKO), the number of B cells in lymph nodes decreased to approximately 4% of that of control mice, and B cells were present in the spleen and blood. Upon the immunization with NP-CGG, DKO mice demonstrated the defective GC formation in the spleen, and the reduced NP-specific antibody production. In vitro, Rap1 deficiency impaired the movement of activated B cells along the gradients of chemoattractants known to be critical for their localization in the follicles. Furthermore, B-1a cells were almost completely absent in the peritoneal cavity, spleen and blood of adult DKO mice, and the number of B-cell progenitor/precursor (B-p) were reduced in neonatal and fetal livers. However, DKO B-ps normally proliferated, and differentiated into IgM+ cells in the presence of IL-7. CXCL12-dependent migration of B-ps on the VCAM-1 was severely impaired by Rap1 deficiency. Immunostaining study of fetal livers revealed defects in the co-localization of DKO B-ps and IL-7-producing stromal cells. This study proposes that the profound effects of Rap1-deficiency on humoral responses and B-1a cell generation may be due to or in part caused by impairments of the chemoattractant-dependent positioning and the contact with stromal cells.

scholarly journals ROP16-Mediated Activation of STAT6 Suppresses Host Cell Reactive Oxygen Species Production, Facilitating Type III Toxoplasma gondii Growth and Survival

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Joshua A. Kochanowsky ◽  
Kaitlin K. Thomas ◽  
Anita A. Koshy
Keyword(s):  
Reactive Oxygen Species ◽  
Toxoplasma Gondii ◽  
Host Cell ◽  
Parasite Growth ◽  
Effector Proteins ◽  
Oxygen Species ◽  
Content Type ◽  
Growth And Survival ◽  
Type Iii ◽  
Ifn Γ

ABSTRACT Polymorphic effector proteins determine the susceptibility of Toxoplasma gondii strains to IFN-γ-mediated clearance mechanisms deployed by murine host cells. However, less is known about the influence of these polymorphic effector proteins on IFN-γ-independent clearance mechanisms. Here, we show that deletion of one such polymorphic effector protein, ROP16, from a type III background leads to a defect in parasite growth and survival in unstimulated human fibroblasts and murine macrophages. Rescue of these defects requires a ROP16 with a functional kinase domain and the ability to activate a specific family of host cell transcription factors (STAT3, 5a, and 6). The growth and survival defects correlate with an accumulation of host cell reactive oxygen species (ROS) and are prevented by treatment with an ROS inhibitor. Exogenous activation of STAT3 and 6 suppresses host cell ROS production during infection with ROP16-deficient parasites and depletion of STAT6, but not STAT3 or 5a, causes an accumulation of ROS in cells infected with wild-type parasites. Pharmacological inhibition of NOX2 and mitochondrially derived ROS also rescues growth and survival of ROP16-deficient parasites. Collectively, these findings reveal an IFN-γ-independent mechanism of parasite restriction in human cells that is subverted by injection of ROP16 by type III parasites. IMPORTANCE Toxoplasma gondii is an obligate intracellular parasite that infects up to one-third of the world’s population. Control of the parasite is largely accomplished by IFN-γ-dependent mechanisms that stimulate innate and adaptive immune responses. Parasite suppression of IFN-γ-stimulated responses has been linked to proteins that the parasite secretes into its host cell. These secreted proteins vary by T. gondii strain and determine strain-specific lethality in mice. How these strain-specific polymorphic effector proteins affect IFN-γ-independent parasite control mechanisms in human and murine cells is not well known. This study shows that one such secreted protein, ROP16, enables efficient parasite growth and survival by suppressing IFN-γ-independent production of ROS by human and mouse cells.

scholarly journals Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis

2020 ◽  
Author(s):  
Alex Rosenberg ◽  
L. David Sibley
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Host Cell ◽  
Kinase Domain ◽  
Effector Proteins ◽  
Type I ◽  
Immune Functions ◽  
Protein Kinase R ◽  
Repressor Complex

SummaryDuring infection, Toxoplasma gondii translocates effector proteins directly into its host cell to subvert various signaling pathways. Here we characterize a novel secreted effector that localizes to the host cell nucleus where it modulates NCoR/SMRT repressor complex levels to repress interferon regulated genes involved in cell death. Type I and type II interferons upregulate many genes including protein kinase R (PKR), inducing formation of the necrosome complex that activates Mixed Lineage Kinase Domain Like Pseudokinase (MLKL) to execute necrotic cell death. Toxoplasma NCoR/SMRT modulator (TgNSM) acts together with another secreted effector TgIST, previously shown to down-modulate IFN-γ signaling to block immune functions. Together TgNSM and TgIST block IFN driven expression of PKR and MLKL, thus preventing host cell necroptotic death. The mechanism of action of TgNSM highlights a previously unappreciated role of NCoR/SMRT in regulation of necroptosis, assuring survival of intracellular cysts, and maintenance of chronic infection.

scholarly journals An Inside Job: Hacking into Janus Kinase/Signal Transducer and Activator of Transcription Signaling Cascades by the Intracellular Protozoan Toxoplasma gondii

2011 ◽  
Vol 80 (2) ◽  
pp. 476-482 ◽  
Author(s):  
Eric Y. Denkers ◽  
David J. Bzik ◽  
Barbara A. Fox ◽  
Barbara A. Butcher
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cell ◽  
Secretory Protein ◽  
Effector Proteins ◽  
Janus Kinase ◽  
Host Cells ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Content Type ◽  
Transcription 3

ABSTRACTThe intracellular protozoanToxoplasma gondiiis well known for its skill at invading and living within host cells. New discoveries are now also revealing the astounding ability of the parasite to inject effector proteins into the cytoplasm to seize control of the host cell. This review summarizes recent advances in our understanding of one such secretory protein called ROP16. This molecule is released from rhoptries into the host cell during invasion. The ROP16 molecule acts as a kinase, directly activating both signal transducer and activator of transcription 3 (STAT3) and STAT6 signaling pathways. In macrophages, an important and preferential target cell of parasite infection, the injection of ROP16 has multiple consequences, including downregulation of proinflammatory cytokine signaling and macrophage deviation to an alternatively activated phenotype.

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