scholarly journals PI3-kinase activation is critical for host barrier permissiveness to Listeria monocytogenes

2015 ◽  
Vol 212 (2) ◽  
pp. 165-183 ◽  
Author(s):  
Grégoire Gessain ◽  
Yu-Huan Tsai ◽  
Laetitia Travier ◽  
Matteo Bonazzi ◽  
Solène Grayo ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Critical Role ◽  
Intestinal Barrier ◽  
Surface Proteins ◽  
Target Cells ◽  
Placental Barrier ◽  
Bacterial Surface ◽  
Phosphoinositide 3 Kinase ◽  
K Activity ◽  
E Cadherin

Invasion of nonphagocytic cells, a critical property of Listeria monocytogenes (Lm) that enables it to cross host barriers, is mediated by the interaction of two bacterial surface proteins, InlA and InlB, with their respective receptors E-cadherin and c-Met. Although InlA–E-cadherin interaction is necessary and sufficient for Lm crossing of the intestinal barrier, both InlA and InlB are required for Lm crossing of the placental barrier. The mechanisms underlying these differences are unknown. Phosphoinositide 3-kinase (PI3-K) is involved in both InlA- and InlB-dependent pathways. Indeed, InlA-dependent entry requires PI3-K activity but does not activate it, whereas InlB–c-Met interaction activates PI3-K. We show that Lm intestinal target cells exhibit a constitutive PI3-K activity, rendering InlB dispensable for InlA-dependent Lm intestinal barrier crossing. In contrast, the placental barrier does not exhibit constitutive PI3-K activity, making InlB necessary for InlA-dependent Lm placental invasion. Here, we provide the molecular explanation for the respective contributions of InlA and InlB to Lm host barrier invasion, and reveal the critical role of InlB in rendering cells permissive to InlA-mediated invasion. This study shows that PI3-K activity is critical to host barrier permissiveness to microbes, and that pathogens exploit both similarities and differences of host barriers to disseminate.

scholarly journals Vertical Transmission of Listeria monocytogenes: Probing the Balance between Protection from Pathogens and Fetal Tolerance

Pathogens ◽  
2018 ◽  
Vol 7 (2) ◽  
pp. 52 ◽  
Author(s):  
Nicole Lamond ◽  
Nancy Freitag
Keyword(s):  
Cell Culture ◽  
Listeria Monocytogenes ◽  
Animal Models ◽  
Vertical Transmission ◽  
Surface Proteins ◽  
Placental Barrier ◽  
Bacterial Surface ◽  
Organ Models ◽  
The Many

Protection of the developing fetus from pathogens is one of the many critical roles of the placenta. Listeria monocytogenes is one of a select number of pathogens that can cross the placental barrier and cause significant harm to the fetus, leading to spontaneous abortion, stillbirth, preterm labor, and disseminated neonate infection despite antibiotic treatment. Such severe outcomes serve to highlight the importance of understanding how L. monocytogenes mediates infiltration of the placental barrier. Here, we review what is currently known regarding vertical transmission of L. monocytogenes as a result of cell culture and animal models of infection. In vitro cell culture and organ models have been useful for the identification of L. monocytogenes virulence factors that contribute to placental invasion. Examples include members of the Internalin family of bacterial surface proteins such as Interalin (Inl)A, InlB, and InlP that promote invasion of cells at the maternal-fetal interface. A number of animal models have been used to interrogate L. monocytogenes vertical transmission, including mice, guinea pigs, gerbils, and non-human primates; each of these models has advantages while still not providing a comprehensive understanding of L. monocytogenes invasion of the human placenta and/or fetus. These models do, however, allow for the molecular investigation of the balance between fetal tolerance and immune protection from L. monocytogenes during pregnancy.

scholarly journals Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin

2011 ◽  
Vol 208 (11) ◽  
pp. 2263-2277 ◽  
Author(s):  
Georgios Nikitas ◽  
Chantal Deschamps ◽  
Olivier Disson ◽  
Théodora Niault ◽  
Pascale Cossart ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Intestinal Epithelium ◽  
Foodborne Pathogen ◽  
Intestinal Barrier ◽  
Systemic Infection ◽  
Surface Protein ◽  
Intestinal Lumen ◽  
Specific Host ◽  
Species Specific ◽  
E Cadherin

Listeria monocytogenes (Lm) is a foodborne pathogen that crosses the intestinal barrier upon interaction between its surface protein InlA and its species-specific host receptor E-cadherin (Ecad). Ecad, the key constituent of adherens junctions, is typically situated below tight junctions and therefore considered inaccessible from the intestinal lumen. In this study, we investigated how Lm specifically targets its receptor on intestinal villi and crosses the intestinal epithelium to disseminate systemically. We demonstrate that Ecad is luminally accessible around mucus-expelling goblet cells (GCs), around extruding enterocytes at the tip and lateral sides of villi, and in villus epithelial folds. We show that upon preferential adherence to accessible Ecad on GCs, Lm is internalized, rapidly transcytosed across the intestinal epithelium, and released in the lamina propria by exocytosis from where it disseminates systemically. Together, these results show that Lm exploits intrinsic tissue heterogeneity to access its receptor and reveal transcytosis as a novel and unanticipated pathway that is hijacked by Lm to breach the intestinal epithelium and cause systemic infection.

scholarly journals Distinct roles of cadherin-6 and E-cadherin in tubulogenesis and lumen formation

2011 ◽  
Vol 22 (12) ◽  
pp. 2031-2041 ◽  
Author(s):  
Liwei Jia ◽  
Fengming Liu ◽  
Steen H. Hansen ◽  
Martin B.A. ter Beest ◽  
Mirjam M.P. Zegers
Keyword(s):  
Epithelial Cells ◽  
Mdck Cells ◽  
Critical Role ◽  
Madin Darby Canine Kidney ◽  
Lumen Formation ◽  
Epithelial Development ◽  
Phosphoinositide 3 Kinase ◽  
Darby Canine Kidney ◽  
E Cadherin

Classic cadherins are important regulators of tissue morphogenesis. The predominant cadherin in epithelial cells, E-cadherin, has been extensively studied because of its critical role in normal epithelial development and carcinogenesis. Epithelial cells may also coexpress other cadherins, but their roles are less clear. The Madin Darby canine kidney (MDCK) cell line has been a popular mammalian model to investigate the role of E-cadherin in epithelial polarization and tubulogenesis. However, MDCK cells also express relatively high levels of cadherin-6, and it is unclear whether the functions of this cadherin are redundant to those of E-cadherin. We investigate the specific roles of both cadherins using a knockdown approach. Although we find that both cadherins are able to form adherens junctions at the basolateral surface, we show that they have specific and mutually exclusive roles in epithelial morphogenesis. Specifically, we find that cadherin-6 functions as an inhibitor of tubulogenesis, whereas E-cadherin is required for lumen formation. Ablation of cadherin-6 leads to the spontaneous formation of tubules, which depends on increased phosphoinositide 3-kinase (PI3K) activity. In contrast, loss of E-cadherin inhibits lumen formation by a mechanism independent of PI3K.

scholarly journals Two Monoclonal Antibodies with Defined Epitopes of P44 Major Surface Proteins Neutralize Anaplasma phagocytophilum by Distinct Mechanisms

2006 ◽  
Vol 74 (3) ◽  
pp. 1873-1882 ◽  
Author(s):  
Xueqi Wang ◽  
Takane Kikuchi ◽  
Yasuko Rikihisa
Keyword(s):  
Monoclonal Antibodies ◽  
Anaplasma Phagocytophilum ◽  
Outer Membrane Proteins ◽  
Critical Role ◽  
Hypervariable Region ◽  
Passive Immunization ◽  
Amino Acid Sequences ◽  
Surface Proteins ◽  
Host Cells ◽  
Bacterial Surface

ABSTRACT Anaplasma phagocytophilum is an obligatory intracellular bacterium that causes human granulocytic anaplasmosis. The polymorphic 44-kDa major outer membrane proteins of A. phagocytophilum are dominant antigens recognized by patients and infected animals. However, the ability of anti-P44 antibody to neutralize the infection has been unclear due to a mixture of P44 proteins with diverse hypervariable region amino acid sequences expressed by a given bacterial population and lack of epitope-defined antibodies. Monoclonal antibodies (MAbs) 5C11 and 3E65 are directed to different domains of P44 proteins, the N-terminal conserved region and P44-18 central hypervariable region, respectively. Passive immunization with either MAb 5C11 or 3E65 partially protects mice from infection with A. phagocytophilum. In the present study, we demonstrated that the two monoclonal antibodies recognize bacterial surface-exposed epitopes of naturally folded P44 proteins and mapped these epitopes to specific peptide sequences. The two MAbs almost completely blocked the infection of the A. phagocytophilum population that predominantly expressed P44-18 in HL-60 cells by distinct mechanisms: MAb 5C11 blocked the binding, but MAb 3E65 did not block binding or internalization. Instead, MAb 3E65 inhibited internalized A. phagocytophilum to develop into microcolonies called morulae. Some plasma from experimentally infected horses and mice reacted with these two epitopes. Taken together, these data indicate the presence of at least two distinct bacterial surface-exposed neutralization epitopes in P44 proteins. The results indicate that antibodies directed to certain epitopes of P44 proteins have a critical role in inhibiting A. phagocytophilum infection of host cells.

scholarly journals Identification of Components of the Host Type IA Phosphoinositide 3-Kinase Pathway That Promote Internalization of Listeria monocytogenes

2011 ◽  
Vol 80 (3) ◽  
pp. 1252-1266 ◽  
Author(s):  
Shahanawaz Jiwani ◽  
Yi Wang ◽  
Georgina C. Dowd ◽  
Antonella Gianfelice ◽  
Phannipha Pichestapong ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Bacterial Pathogen ◽  
Human Cell Line ◽  
Content Type ◽  
Cell Line Hela ◽  
Type Ia ◽  
Phosphoinositide 3 Kinase ◽  
Kinase Pathway

The bacterial pathogenListeria monocytogenescauses food-borne illnesses resulting in gastroenteritis, meningitis, or abortion.Listeriapromotes its internalization into some human cells through binding of the bacterial surface protein InlB to the host receptor tyrosine kinase Met. The interaction of InlB with the Met receptor stimulates host signaling pathways that promote cell surface changes driving bacterial uptake. One human signaling protein that plays a critical role inListeriaentry is type IA phosphoinositide 3-kinase (PI 3-kinase). The molecular mechanism by which PI 3-kinase promotes bacterial internalization is not understood. Here we perform an RNA interference (RNAi)-based screen to identify components of the type IA PI 3-kinase pathway that control the entry ofListeriainto the human cell line HeLa. The 64 genes targeted encode known upstream regulators or downstream effectors of type IA PI 3-kinase. The results of this screen indicate that at least 9 members of the PI 3-kinase pathway play important roles inListeriauptake. These 9 human proteins include a Rab5 GTPase, several regulators of Arf or Rac1 GTPases, and the serine/threonine kinases phosphoinositide-dependent kinase 1 (PDK1), mammalian target of rapamycin (mTor), and protein kinase C-ζ. These findings represent a key first step toward understanding the mechanism by which type IA PI 3-kinase controls bacterial internalization.

scholarly journals Listeria monocytogenes Surface Proteins: from Genome Predictions to Function

2007 ◽  
Vol 71 (2) ◽  
pp. 377-397 ◽  
Author(s):  
Hélène Bierne ◽  
Pascale Cossart
Keyword(s):  
Listeria Monocytogenes ◽  
Structural Features ◽  
Protein Processing ◽  
Surface Proteins ◽  
Host Cells ◽  
Bacterial Surface ◽  
Food Borne ◽  
Surface Proteome ◽  
Molecular Bases ◽  
Host Tissues

SUMMARY The genome of the human food-borne pathogen Listeria monocytogenes is predicted to encode a high number of surface proteins. This abundance likely reflects the ability of this bacterium to survive in diverse environments, including soil, food, and the human host. This review focuses on the various mechanisms by which listerial proteins are attached at the bacterial surface and their many functions, including peptidoglycan metabolism, protein processing, adhesion to host cells, and invasion of host tissues. Extensive in silico analysis of the domains or motifs present in these mosaic proteins reveals that diverse structural features allow the surface proteome to interact with diverse bacterial or host components. This diversity offers new clues about the molecular bases of Listeria pathogenesis.

scholarly journals Critical Role for the Host GTPase-Activating Protein ARAP2 in InlB-Mediated Entry of Listeria monocytogenes

2010 ◽  
Vol 78 (11) ◽  
pp. 4532-4541 ◽  
Author(s):  
Balramakrishna Gavicherla ◽  
Lisa Ritchey ◽  
Antonella Gianfelice ◽  
Andrey A. Kolokoltsov ◽  
Robert A. Davey ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Mammalian Cells ◽  
Critical Role ◽  
Bacterial Pathogen ◽  
Surface Protein ◽  
Rho Proteins ◽  
Gtpase Activating Protein ◽  
Bacterial Surface ◽  
Downstream Signaling ◽  
Binding Domains

ABSTRACT The bacterial pathogen Listeria monocytogenes causes food-borne illnesses culminating in gastroenteritis, meningitis, or abortion. Listeria induces its internalization into some mammalian cells through binding of the bacterial surface protein InlB to the host receptor tyrosine kinase Met. Interaction of InlB with the Met receptor elicits host downstream signaling pathways that promote F-actin cytoskeletal changes responsible for pathogen engulfment. Here we show that the mammalian signaling protein ARAP2 plays a critical role in cytoskeletal remodeling and internalization of Listeria. Depletion of ARAP2 through RNA interference (RNAi) caused a marked inhibition of InlB-mediated F-actin rearrangements and bacterial entry. ARAP2 contains multiple functional domains, including a GTPase-activating protein (GAP) domain that antagonizes the GTPase Arf6 and a domain capable of binding the GTPase RhoA. Genetic data indicated roles for both the Arf GAP and RhoA binding domains in Listeria entry. Experiments involving Arf6 RNAi or a constitutively activated allele of Arf6 demonstrated that one of the ways in which ARAP2 promotes bacterial uptake is by restraining the activity of Arf6. Conversely, Rho activity was dispensable for Listeria internalization, suggesting that the RhoA binding domain in ARAP2 acts by engaging a host ligand other than Rho proteins. Collectively, our findings indicate that ARAP2 promotes InlB-mediated entry of Listeria, in part, by antagonizing the host GTPase Arf6.

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