scholarly journals The Effector TepP Mediates Recruitment and Activation of Phosphoinositide 3-Kinase on Early Chlamydia trachomatis Vacuoles

mSphere ◽  
2017 ◽  
Vol 2 (4) ◽  
Author(s):  
Victoria Carpenter ◽  
Yi-Shan Chen ◽  
Lee Dolat ◽  
Raphael H. Valdivia
Keyword(s):  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Immune Responses ◽  
Cell Survival ◽  
Host Cell ◽  
Adaptor Protein ◽  
Membrane Dynamics ◽  
Scaffolding Protein ◽  
Type I ◽  
Internal Membrane

ABSTRACT This article shows that chlamydia recruit PI3K, an enzyme important for host cell survival and internal membrane functions, to the pathogens inside cells by secreting a scaffolding protein called TepP. TepP enhances Chlamydia replication and dampens the activation of immune responses. Chlamydia trachomatis delivers multiple type 3 secreted effector proteins to host epithelial cells to manipulate cytoskeletal functions, membrane dynamics, and signaling pathways. TepP is the most abundant effector protein secreted early in infection, but its molecular function is poorly understood. In this report, we provide evidence that TepP is important for bacterial replication in cervical epithelial cells, activation of type I IFN genes, and recruitment of class I phosphoinositide 3-kinases (PI3K) and signaling adaptor protein CrkL to nascent pathogen-containing vacuoles (inclusions). We also show that TepP is a target of tyrosine phosphorylation by Src kinases but that these modifications do not appear to influence the recruitment of PI3K or CrkL. The translocation of TepP correlated with an increase in the intracellular pools of phosphoinositide-(3,4,5)-triphosphate but not the activation of the prosurvival kinase Akt, suggesting that TepP-mediated activation of PI3K is spatially restricted to early inclusions. Furthermore, we linked PI3K activity to the dampening of transcription of type I interferon (IFN)-induced genes early in infection. Overall, these findings indicate that TepP can modulate cell signaling and, potentially, membrane trafficking events by spatially restricted activation of PI3K. IMPORTANCE This article shows that Chlamydia recruits PI3K, an enzyme important for host cell survival and internal membrane functions, to the pathogens inside cells by secreting a scaffolding protein called TepP. TepP enhances Chlamydia replication and dampens the activation of immune responses.

scholarly journals The effector TepP mediates the recruitment and activation of Phosphoinositide 3 Kinase on early Chlamydia trachomatis vacuoles

2017 ◽  
Author(s):  
Victoria Carpenter ◽  
Yi-Shan Chen ◽  
Lee Dolat ◽  
Raphael H. Valdivia
Keyword(s):  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Membrane Trafficking ◽  
Adaptor Protein ◽  
Membrane Dynamics ◽  
Effector Proteins ◽  
Type I ◽  
Type I Ifn ◽  
Bacterial Replication ◽  
Phosphoinositide 3 Kinase

ABSTRACTChlamydia trachomatis delivers multiple Type 3 secreted effector proteins to host epithelial cells to manipulate cytoskeletal functions, membrane dynamics and signaling pathways. TepP is the most abundant effector protein secreted early in infection but its molecular function is poorly understood. In this report, we provide evidence that TepP is important for bacterial replication in cervical epithelial cells, the activation of Type I IFN genes, and the recruitment of Class I phosphoinositide 3 kinases (PI3K) and the signaling adaptor protein CrkL to nascent pathogen-containing vacuoles (inclusions). We also show that TepP is a target of tyrosine phosphorylation by Src kinases but these modifications do not appear to influence the recruitment of PI3K or CrkL. The translocation of TepP correlated with an increase in the intracellular pools of phosphoinositide 3,4,5 triphosphate but not the activation of the pro-survival kinase Akt, suggesting that TepP-mediated activation of PI3K is spatially restricted to early inclusions. Furthermore, we linked PI3K activity to the dampening of transcription of Type I IFN induced genes early in infection. Overall, these findings indicate that TepP can modulate cell signaling and potentially membrane trafficking events by spatially restricted activation of PI3K.

scholarly journals Recruitment of BAD by the Chlamydia trachomatis Vacuole Correlates with Host-Cell Survival

2006 ◽  
Vol 2 (5) ◽  
pp. e45 ◽  
Author(s):  
Philippe Verbeke ◽  
Lynn Welter-Stahl ◽  
Songmin Ying ◽  
Jon Hansen ◽  
Georg Häcker ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Cell Survival ◽  
Host Cell

scholarly journals TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

2014 ◽  
Vol 82 (5) ◽  
pp. 2068-2078 ◽  
Author(s):  
Christopher R. Doyle ◽  
Ji-An Pan ◽  
Patricio Mena ◽  
Wei-Xing Zong ◽  
David G. Thanassi
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Host Cell ◽  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Live Vaccine ◽  
Live Vaccine Strain ◽  
Type I ◽  
Content Type ◽  
Host Cell Death

ABSTRACTFrancisella tularensisis a facultative intracellular, Gram-negative pathogen and the causative agent of tularemia. We previously identified TolC as a virulence factor of theF. tularensislive vaccine strain (LVS) and demonstrated that a ΔtolCmutant exhibits increased cytotoxicity toward host cells and elicits increased proinflammatory responses compared to those of the wild-type (WT) strain. TolC is the outer membrane channel component used by the type I secretion pathway to export toxins and other bacterial virulence factors. Here, we show that the LVS delays activation of the intrinsic apoptotic pathway in a TolC-dependent manner, both during infection of primary macrophages and during organ colonization in mice. The TolC-dependent delay in host cell death is required forF. tularensisto preserve its intracellular replicative niche. We demonstrate that TolC-mediated inhibition of apoptosis is an active process and not due to defects in the structural integrity of the ΔtolCmutant. These findings support a model wherein the immunomodulatory capacity ofF. tularensisrelies, at least in part, on TolC-secreted effectors. Finally, mice vaccinated with the ΔtolCLVS are protected from lethal challenge and clear challenge doses faster than WT-vaccinated mice, demonstrating that the altered host responses to primary infection with the ΔtolCmutant led to altered adaptive immune responses. Taken together, our data demonstrate that TolC is required for temporal modulation of host cell death during infection byF. tularensisand highlight how shifts in the magnitude and timing of host innate immune responses may lead to dramatic changes in the outcome of infection.

scholarly journals Herpes Simplex Virus 1 Infection of Neuronal and Non-Neuronal Cells Elicits Specific Innate Immune Responses and Immune Evasion Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Amanda L. Verzosa ◽  
Lea A. McGeever ◽  
Shun-Je Bhark ◽  
Tracie Delgado ◽  
Nicole Salazar ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Epithelial Cells ◽  
Immune Responses ◽  
Host Cell ◽  
Signaling Pathways ◽  
Sensory Neurons ◽  
Immune Evasion ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Hsv 1

Alphaherpesviruses (α-HV) are a large family of double-stranded DNA viruses which cause many human and animal diseases. There are three human α-HVs: Herpes Simplex Viruses (HSV-1 and HSV-2) and Varicella Zoster Virus (VZV). All α-HV have evolved multiple strategies to suppress or exploit host cell innate immune signaling pathways to aid in their infections. All α-HVs initially infect epithelial cells (primary site of infection), and later spread to infect innervating sensory neurons. As with all herpesviruses, α-HVs have both a lytic (productive) and latent (dormant) stage of infection. During the lytic stage, the virus rapidly replicates in epithelial cells before it is cleared by the immune system. In contrast, latent infection in host neurons is a life-long infection. Upon infection of mucosal epithelial cells, herpesviruses immediately employ a variety of cellular mechanisms to evade host detection during active replication. Next, infectious viral progeny bud from infected cells and fuse to neuronal axonal terminals. Here, the nucleocapsid is transported via sensory neuron axons to the ganglion cell body, where latency is established until viral reactivation. This review will primarily focus on how HSV-1 induces various innate immune responses, including host cell recognition of viral constituents by pattern-recognition receptors (PRRs), induction of IFN-mediated immune responses involving toll-like receptor (TLR) signaling pathways, and cyclic GMP‐AMP synthase stimulator of interferon genes (cGAS-STING). This review focuses on these pathways along with other mechanisms including autophagy and the complement system. We will summarize and discuss recent evidence which has revealed how HSV-1 is able to manipulate and evade host antiviral innate immune responses both in neuronal (sensory neurons of the trigeminal ganglia) and non-neuronal (epithelial) cells. Understanding the innate immune response mechanisms triggered by HSV-1 infection, and the mechanisms of innate immune evasion, will impact the development of future therapeutic treatments.

scholarly journals Tarp regulates early Chlamydia-induced host cell survival through interactions with the human adaptor protein SHC1

2010 ◽  
Vol 190 (1) ◽  
pp. 143-157 ◽  
Author(s):  
Adrian Mehlitz ◽  
Sebastian Banhart ◽  
André P. Mäurer ◽  
Alexis Kaushansky ◽  
Andrew G. Gordus ◽  
...  
Keyword(s):  
Cell Survival ◽  
Host Cell ◽  
Early Phase ◽  
Protein Microarray ◽  
Critical Role ◽  
Adaptor Protein ◽  
Effector Proteins ◽  
Host Cells ◽  
Cell Functions ◽  
Induced Apoptosis

Many bacterial pathogens translocate effector proteins into host cells to manipulate host cell functions. Here, we used a protein microarray comprising virtually all human SRC homology 2 (SH2) and phosphotyrosine binding domains to comprehensively and quantitatively assess interactions between host cell proteins and the early phase Chlamydia trachomatis effector protein translocated actin-recruiting phosphoprotein (Tarp), which is rapidly tyrosine phosphorylated upon host cell entry. We discovered numerous novel interactions between human SH2 domains and phosphopeptides derived from Tarp. The adaptor protein SHC1 was among Tarp’s strongest interaction partners. Transcriptome analysis of SHC1-dependent gene regulation during infection indicated that SHC1 regulates apoptosis- and growth-related genes. SHC1 knockdown sensitized infected host cells to tumor necrosis factor–induced apoptosis. Collectively, our findings reveal a critical role for SHC1 in early C. trachomatis–induced cell survival and suggest that Tarp functions as a multivalent phosphorylation-dependent signaling hub that is important during the early phase of chlamydial infection.

scholarly journals A host cell long noncoding RNA NR_033736 regulates type I interferon-mediated gene transcription and modulates intestinal epithelial anti-Cryptosporidium defense

2021 ◽  
Vol 17 (1) ◽  
pp. e1009241
Author(s):  
Juan Li ◽  
Kehua Jin ◽  
Min Li ◽  
Nicholas W. Mathy ◽  
Ai-Yu Gong ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Host Cell ◽  
Gene Transcription ◽  
Intestinal Epithelial Cells ◽  
Immune Defense ◽  
Fine Tuning ◽  
Type I ◽  
Intestinal Epithelial ◽  
Type I Ifn ◽  
Innate Defense

The gastrointestinal epithelium guides the immune system to differentiate between commensal and pathogenic microbiota, which relies on intimate links with the type I IFN signal pathway. Epithelial cells along the epithelium provide the front line of host defense against pathogen infection in the gastrointestinal tract. Increasing evidence supports the regulatory potential of long noncoding RNAs (lncRNAs) in immune defense but their role in regulating intestinal epithelial antimicrobial responses is still unclear. Cryptosporidium, a protozoan parasite that infects intestinal epithelial cells, is an important opportunistic pathogen in AIDS patients and a common cause of diarrhea in young children in developing countries. Recent advances in Cryptosporidium research have revealed a strong type I IFN response in infected intestinal epithelial cells. We previously identified a panel of host cell lncRNAs that are upregulated in murine intestinal epithelial cells following microbial challenge. One of these lncRNAs, NR_033736, is upregulated in intestinal epithelial cells following Cryptosporidium infection and displays a significant suppressive effect on type I IFN-controlled gene transcription in infected host cells. NR_033736 can be assembled into the ISGF3 complex and suppresses type I IFN-mediated gene transcription. Interestingly, upregulation of NR_033736 itself is triggered by the type I IFN signaling. Moreover, NR_033736 modulates epithelial anti-Cryptosporidium defense. Our data suggest that upregulation of NR_033736 provides negative feedback regulation of type I IFN signaling through suppression of type I IFN-controlled gene transcription, and consequently, contributing to fine-tuning of epithelial innate defense against microbial infection.

scholarly journals Plasmacytoid DCs mediate control of Ross River virus infection via a type I IFN-dependent, MAVS-independent mechanism

2020 ◽  
Author(s):  
Kelsey C. Haist ◽  
Kathryn S. Carpentier ◽  
Bennett J. Davenport ◽  
Thomas E. Morrison
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Adaptor Protein ◽  
Musculoskeletal Disease ◽  
Innate Immune ◽  
Interferon Response ◽  
Ross River Virus ◽  
Type I ◽  
Type I Ifn ◽  
Public Health Burden

Ross River virus (RRV) is a mosquito-borne alphavirus that causes epidemics of debilitating musculoskeletal disease. To define the innate immune mechanisms that mediate control of RRV infection, we studied a RRV strain encoding 6 nonsynonymous mutations in nsP1 (RRV-T48-nsP16M) that is attenuated in WT mice and Rag1-/- mice, which are unable to mount adaptive immune responses, but not in mice that lack the capacity to respond to type I IFN (Ifnar1-/-). Utilizing this attenuated strain, our prior studies revealed that MAVS-dependent production of type I IFN by Ly6Chi monocytes is critical for control of acute RRV infection. Here, we infected Mavs-/- mice with either WT RRV or RRV-T48-nsP16M to elucidate MAVS-independent protective mechanisms. Mavs-/- mice infected with WT RRV developed severe disease and succumbed to infection, whereas those infected with RRV-T48-nsP16M exhibited minimal disease signs. Mavs-/- mice infected with RRV-T48-nsP16M had higher levels of systemic type I IFN compared with Mavs-/- mice infected with WT virus, and treatment of Mavs-/- mice infected with the attenuated nsP1 mutant virus with an IFNAR1 blocking antibody resulted in a lethal infection. In vitro, type I IFN expression was induced in plasmacytoid dendritic cells (pDCs) co-cultured with RRV-infected cells in a MAVS-independent manner, and depletion of pDCs in Mavs-/- mice resulted in increased viral burdens in joint and muscle tissues, suggesting that pDCs are a source of the protective IFN in Mavs-/- mice. These data suggest that pDC production of type I IFN through a MAVS-independent pathway contributes to control of RRV infection. IMPORTANCE Arthritogenic alphaviruses, including Ross River virus (RRV), are human pathogens that cause debilitating acute and chronic musculoskeletal disease and are a significant public health burden. Using an attenuated RRV with enhanced susceptibility to host innate immune responses has revealed key cellular and molecular mechanisms that can mediate control of attenuated RRV infection and that are evaded by more virulent RRV. In this study, we found that pDCs contribute to the protective type I interferon response during RRV infection through a mechanism that is independent of the mitochondrial antiviral signaling (MAVS) adaptor protein. These findings highlight a key innate immune mechanism that contributes to control of alphavirus infections.

scholarly journals Chlamydia trachomatis Plasmid Protein pORF5 Up-Regulates ZFAS1 to Promote Host Cell Survival via MAPK/p38 Pathway

2020 ◽  
Vol 11 ◽  
Author(s):  
Yating Wen ◽  
Hongliang Chen ◽  
Fangzhen Luo ◽  
Lanhua Zhao ◽  
Mingyi Shu ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Cell Survival ◽  
Host Cell ◽  
Bioinformatics Analysis ◽  
Expression Profiles ◽  
Quantitative Real Time Pcr ◽  
Apoptotic Effect ◽  
Important Virulence Factor ◽  
Non Coding Rnas ◽  
P38 Pathway

Long non-coding RNAs (lncRNAs) have been demonstrated to play essential roles in many diseases. However, few studies have shown that lncRNAs take part in the pathogenesis of Chlamydia trachomatis (C. trachomatis). Here, we used a lncRNA microarray to detect the global lncRNA expression profiles in HeLa cells transfected with pORF5 plasmid protein, an important virulence factor for C. trachomatis. The differentially expressed lncRNAs and mRNAs screened by microarray were selected for validation by quantitative real-time PCR. The up-regulated lncRNA zinc finger antisense 1 (ZFAS1) was presumed to involved in MAPK pathways by bioinformatics analysis. Inhibition of ZFAS1 decreased the apoptotic rate of pORF5 and reduced the infectivity of C. trachomatis, and MAPK/p38 pathway was involved in anti-apoptotic effect induced by ZFAS1. Therefore, the present study confirmed that pORF5 up-regulates ZFAS1 to promote host cell survival via MAPK/p38 pathway and influences the infectivity of C. trachomatis.

scholarly journals Molecular and Structural Basis of DNA Sensors in Antiviral Innate Immunity

2020 ◽  
Vol 11 ◽  
Author(s):  
Ayesha Zahid ◽  
Hazrat Ismail ◽  
Bofeng Li ◽  
Tengchuan Jin
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Rna Polymerase Iii ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Structural Basis ◽  
Type I ◽  
Dna Sensors ◽  
Dna Sensing

DNA viruses are a source of great morbidity and mortality throughout the world by causing many diseases; thus, we need substantial knowledge regarding viral pathogenesis and the host’s antiviral immune responses to devise better preventive and therapeutic strategies. The innate immune system utilizes numerous germ-line encoded receptors called pattern-recognition receptors (PRRs) to detect various pathogen-associated molecular patterns (PAMPs) such as viral nucleic acids, ultimately resulting in antiviral immune responses in the form of proinflammatory cytokines and type I interferons. The immune-stimulatory role of DNA is known for a long time; however, DNA sensing ability of the innate immune system was unraveled only recently. At present, multiple DNA sensors have been proposed, and most of them use STING as a key adaptor protein to exert antiviral immune responses. In this review, we aim to provide molecular and structural underpinnings on endosomal DNA sensor Toll-like receptor 9 (TLR9) and multiple cytosolic DNA sensors including cyclic GMP-AMP synthase (cGAS), interferon-gamma inducible 16 (IFI16), absent in melanoma 2 (AIM2), and DNA-dependent activator of IRFs (DAI) to provide new insights on their signaling mechanisms and physiological relevance. We have also addressed less well-understood DNA sensors such as DEAD-box helicase DDX41, RNA polymerase III (RNA pol III), DNA-dependent protein kinase (DNA-PK), and meiotic recombination 11 homolog A (MRE11). By comprehensive understanding of molecular and structural aspects of DNA-sensing antiviral innate immune signaling pathways, potential new targets for viral and autoimmune diseases can be identified.

scholarly journals Type I Alveolar Epithelial Cells Mount Innate Immune Responses during Pneumococcal Pneumonia

2012 ◽  
Vol 189 (5) ◽  
pp. 2450-2459 ◽  
Author(s):  
Kazuko Yamamoto ◽  
Joseph D. Ferrari ◽  
Yuxia Cao ◽  
Maria I. Ramirez ◽  
Matthew R. Jones ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Immune Responses ◽  
Pneumococcal Pneumonia ◽  
Innate Immune ◽  
Alveolar Epithelial Cells ◽  
Type I ◽  
Innate Immune Responses ◽  
Alveolar Epithelial
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