Functional Inactivation of Immature Dendritic Cells by the Intracellular Parasite <i>Toxoplasma gondii</i>

McKee, Amy S.; Dzierszinski, Florence; Boes, Marianne; Roos, David S.; Pearce, Edward J.

doi:10.4049/jimmunol.173.4.2632

Cited by 92 publications

(96 citation statements)

References 69 publications

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“…Although it is tempting to suggest that the intracellular localization of TLR11 facilitates recognition of the invading parasite, our experiments revealed that infection of DCs by T. gondii was not required for TLR11 activation. In contrast, others and our group have observed that T. gondiiinfected DCs fail to up-regulate the necessary co-stimulatory molecules and produce significantly diminished amounts of proinflammatory cytokines compared with noninfected DCs (45)(46)(47). Consequently, the infected DCs demonstrate a decreased capacity to induce efficient parasite-specific T cell responses.…”

Section: Discussioncontrasting

confidence: 41%

UNC93B1 Is Essential for TLR11 Activation and IL-12-dependent Host Resistance to Toxoplasma gondii

Pifer

Benson

Sturge

et al. 2011

Journal of Biological Chemistry

106

104

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Toll-like receptor (TLR) activation relies on biochemical recognition of microbial molecules and localization of the TLR within specific cellular compartments. Cell surface TLRs largely recognize bacterial membrane components, and intracellular TLRs are exclusively involved in sensing nucleic acids. Here we show that TLR11, an innate sensor for the Toxoplasma protein profilin, is an intracellular receptor that resides in the endoplasmic reticulum. The 12 membrane-spanning endoplasmic reticulum-resident protein UNC93B1 interacts directly with TLR11 and regulates the activation of dendritic cells in response to Toxoplasma gondii profilin and parasitic infection in vivo. A deficiency in functional UNC93B1 protein abolished TLR11-dependent IL-12 secretion by dendritic cells, attenuated Th1 responses against T. gondii, and dramatically enhanced susceptibility to the parasite. Our results reveal that the association with UNC93B1 and the intracellular localization of TLRs are not unique features of nucleic acid-sensing TLRs but is also essential for TLR11-dependent recognition of T. gondii profilin and for host protection against this parasite. Toll-like receptors (TLRs)2 are a family of type I transmembrane proteins with ectodomains containing leucine-rich repeats that are involved in sensing varied microbial products, including lipids, peptidoglycans, proteins, and nucleic acids (1). TLR activation relies on the ability to sense molecules that are unique to microorganisms (2-4). TLRs involved in sensing bacterial membrane components such as LPS and lipoproteins are expressed and function on the cell surface (5, 6). Host and viral nucleic acids share an additional mechanism for self/nonself discrimination that relies on the localization of nucleic acid-recognizing TLR3, TLR7, and TLR9 within endosomal compartments (7-9). The intracellular localization of these TLRs is important not only for the recognition of viral DNA and RNA but also for the prevention of activation by host-derived nucleic acids (10 -13). Importantly, although the intracellular localization of TLRs can be achieved by distinct targeting sequences, all nucleic acid-recognizing receptors access their ligands in the same intracellular location (14 -16). It has been demonstrated that nucleotide-recognizing TLRs reside in the ER prior to stimulation, and a recently identified protein, UNC93B1, plays a major role in regulating the activation of these TLRs (17, 18). The missense mutation H412R in the UNC93B1 protein completely abolishes the signaling initiated by TLR3, TLR7, and TLR9 (17). Concomitantly, the functions of TLR2, TLR4, and TLR5, which are involved in sensing bacterial membrane and protein components, are not impaired in the absence of functional UNC93B1 protein (17). These data strongly support a surface localization of these "bacterial" innate immune receptors (7). Based on these observations, it has been postulated that nucleic acid-recognizing TLRs are uniquely positioned within intracellular compartments, whereas other TLRs involved in sen...

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Section: Discussioncontrasting

confidence: 41%

UNC93B1 Is Essential for TLR11 Activation and IL-12-dependent Host Resistance to Toxoplasma gondii

Pifer

Benson

Sturge

et al. 2011

Journal of Biological Chemistry

106

104

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“…Thus, it is unsurprising that many pathogens have developed mechanisms to modulate and disable DCs (1,6,33,40,(45)(46)(47)(48). One way in which pathogens interfere with host immune responses, including those mediated by DCs, is manipulation of normal host systems meant to limit hyperresponsiveness to microbial products, resulting in control of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

2009

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The gram-negative, facultative intracellular bacterium Francisella tularensis causes acute, lethal pneumonic disease following infection with only 10 CFU. The mechanisms used by the bacterium to accomplish this in humans are unknown. Here, we demonstrate that virulent, type A F. tularensis strain Schu S4 efficiently infects and replicates in human myeloid dendritic cells (DCs). Despite exponential replication over time, Schu S4 failed to stimulate transforming growth factor ␤, interleukin-10 (IL-10), IL-6, IL-1␤, IL-12, tumor necrosis factor alpha, alpha interferon (IFN-␣), and IFN-␤ throughout the course of infection. Schu S4 also suppressed the ability of directly infected DCs to respond to different Toll-like receptor agonists. Furthermore, we also observed functional inhibition of uninfected bystander cells. This inhibition was mediated, in part, by a heat-stable bacterial component. Lipopolysaccharide (LPS) from Schu S4 was present in Schu S4-conditioned medium. However, Schu S4 LPS was weakly inflammatory and failed to induce suppression of DCs at concentrations below 10 g/ml, and depletion of Schu S4 LPS did not significantly alleviate the inhibitory effect of Schu S4-conditioned medium in uninfected human DCs. Together, these data show that type A F. tularensis interferes with the ability of a central cell type of the immune system, DCs, to alert the host of infection both intra-and extracellularly. This suggests that immune dysregulation by F. tularensis operates on a broader and more comprehensive scale than previously appreciated.Francisella tularensis is a gram-negative, facultative intracellular bacterium and the causative agent of tularemia. Although the bacteria was identified nearly 100 years ago, the nature of its interaction with host cells and tissues has remained largely undefined until recent times. The unfortunate realization of the potential of F. tularensis as a biological weapon has resulted in a resurgence of research on tularemia. Much of our recent understanding of tularemia pathogenesis has come from manipulation of the mouse model of Francisella infections. While these murine studies have yielded many important advances in our understanding of tularemia pathogenesis, very little is understood about how Francisella, especially the most virulent type A strains such as Schu S4, interacts with human cells.Dendritic cells (DCs) serve as a central cell type in the immune system, bridging the innate and adaptive immune response to effectively eradicate invading pathogens.

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“…Toxoplasma has been observed to subvert host response by dysregulation of apoptosis (48) and IFN-␥-induced STAT1 activation (49) as well as inhibition of dendritic cell maturation (50). All of these host responses have been shown to be influenced by STAT6 activation (17,24,51).…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

Ong

Reese

Boothroyd

2010

Journal of Biological Chemistry

203

179

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The obligate intracellular parasite, Toxoplasma gondii, modulates host immunity in a variety of highly specific ways. Previous work revealed a polymorphic, injected parasite factor, ROP16, to be a key virulence determinant and regulator of host cell transcription. These properties were shown to be partially mediated by dysregulation of the host transcription factors STAT3 and STAT6, but the molecular mechanisms underlying this phenotype were unclear. Here, we use a Type I Toxoplasma strain deficient in ROP16 to show that ROP16 induces not only sustained activation but also an extremely rapid (within 1 min) initial activation of STAT6. Using recombinant wild-type and kinase-deficient ROP16, we demonstrate in vitro that ROP16 has intrinsic tyrosine kinase activity and is capable of directly phosphorylating the key tyrosine residue for STAT6 activation, Tyr 641 . Furthermore, ROP16 co-immunoprecipitates with STAT6 from infected cells. Taken together, these data strongly suggest that STAT6 is a direct substrate for ROP16 in vivo.Toxoplasma gondii, a ubiquitous, intracellular parasite of the phylum Apicomplexa, infects an estimated one-third of the human population as well as a broad range of warm-blooded animals. Infection is typically asymptomatic and chronic; however, severe and even fatal disease can result from acute infections of congenitally infected or immunocompromised hosts. Strikingly, Toxoplasma-induced inflammatory pathology in adult immunocompetent patients has also been reported (1, 2).Understanding the host/parasite interactions that underpin these various disease manifestations has become an area of active investigation, and recent work has implicated as key players a set of polymorphic proteins that are secreted from the apical organelles known as rhoptries (3). One of these, a putative serine-threonine kinase known as ROP16, was revealed as a parasite factor responsible for many changes in host gene expression (4). Much of the effect of ROP16 on transcription was found to depend on sustained activation of STAT3 and STAT6, two host transcription factors that can negatively regulate Th1 inflammatory responses. ROP16 is thus poised to mediate the inflammatory status of the host, an intriguing role for a parasite effector because Th1-driven immunopathology, not just uncontrolled parasite growth and dissemination, has been proposed to be a significant contributor to the disease outcome (5).Although the potential significance of the ROP16 effect on STATs is clear, the molecular mechanism by which it accomplishes this sustained activation was not apparent from the initial studies. STAT activation requires phosphorylation at specific, conserved tyrosine residues; this phosphorylation, which induces dimerization and nuclear translocation of the STATs, is canonically initiated and maintained in the cytosol by either receptorassociated tyrosine kinases (such as the JAKs) or non-receptor tyrosine kinases (e.g. Src family kinases) (6). The duration of STAT activation is usually limited by negative feedback beca...

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Functional Inactivation of Immature Dendritic Cells by the Intracellular Parasite Toxoplasma gondii

Cited by 92 publications

References 69 publications

UNC93B1 Is Essential for TLR11 Activation and IL-12-dependent Host Resistance to Toxoplasma gondii

UNC93B1 Is Essential for TLR11 Activation and IL-12-dependent Host Resistance to Toxoplasma gondii

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

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