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Cell Host & Microbe, designed to capture the reemerging interest in microbial pathogenesis.

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Elsevier

Publications in this journal

• Shigella navigates tight corners.

  Authors: Manuel Amieva

  Cell host & microbe. 11(4):319-20.

  In this issue, Fukumatsu and colleagues (2012) find that Shigella preferentially spread from cell-to-cell at unique intercellular junctions. Shigella protrusions invade adjacent cells at junctionsIn this issue, Fukumatsu and colleagues (2012) find that Shigella preferentially spread from cell-to-cell at unique intercellular junctions. Shigella protrusions invade adjacent cells at junctions where three cells meet, the tricellular junction. The tight junction protein tricellulin marks these sites and is important for Shigella spread.

• Be a Good Neighbor: Organ-to-Organ Communication during the Innate Immune Response.

  Authors: Alla Amcheslavsky, Y Tony Ip

  Cell host & microbe. 11(4):323-4.

  Local infection in the Drosophila larval intestine elicits a systemic immune reaction in fat bodies. In this issue, Wu and colleagues (2012) show that this is a reactive oxygen species-dependentLocal infection in the Drosophila larval intestine elicits a systemic immune reaction in fat bodies. In this issue, Wu and colleagues (2012) show that this is a reactive oxygen species-dependent communication.

• Yersinia pseudotuberculosis Effector YopJ Subverts the Nod2/RICK/TAK1 Pathway and Activates Caspase-1 to Induce Intestinal Barrier Dysfunction.

  Authors: Ulrich Meinzer, Frederick Barreau, Sophie Esmiol-Welterlin, Camille Jung, Claude Villard, Thibaut Léger, Sanah Ben-Mkaddem, Dominique Berrebi, Monique Dussaillant, Ziad Alnabhani, Maryline Roy, Stéphane Bonacorsi, Hans Wolf-Watz, Julie Perroy, Vincent Ollendorff, Jean-Pierre Hugot

  Cell host & microbe. 11(4):337-51.

  Yersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that theYersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that the Y. pseudotuberculosis effector YopJ induces intestinal barrier dysfunction by subverting signaling of the innate immune receptor Nod2, a phenotype that can be reversed by pretreating with the Nod2 ligand muramyl-dipeptide. YopJ, but not the catalytically inactive mutant YopJ(C172A), acetylates critical sites in the activation loops of the RICK and TAK1 kinases, which are central mediators of Nod2 signaling, and decreases the affinity of Nod2 for RICK. Concomitantly, Nod2 interacts with and activates caspase-1, resulting in increased levels of IL-1β. Finally, IL-1β within PP plays an essential role in inducing intestinal barrier dysfunction. Thus, YopJ alters intestinal permeability and promotes the dissemination of Yersinia as well as commensal bacteria by exploiting the mucosal inflammatory response.

• Host Translational Inhibition by Pseudomonas aeruginosa Exotoxin A Triggers an Immune Response in Caenorhabditis elegans.

  Authors: Deborah L McEwan, Natalia V Kirienko, Frederick M Ausubel

  Cell host & microbe. 11(4):364-74.

  Intestinal epithelial cells are exposed to both innocuous and pathogenic microbes, which need to be distinguished to mount an effective immune response. To understand the mechanisms underlyingIntestinal epithelial cells are exposed to both innocuous and pathogenic microbes, which need to be distinguished to mount an effective immune response. To understand the mechanisms underlying pathogen recognition, we investigated how Pseudomonas aeruginosa triggers intestinal innate immunity in Caenorhabditis elegans, a process independent of Toll-like pattern recognition receptors. We show that the P. aeruginosa translational inhibitor Exotoxin A (ToxA), which ribosylates elongation factor 2 (EF2), upregulates a significant subset of genes normally induced by P. aeruginosa. Moreover, immune pathways involving the ATF-7 and ZIP-2 transcription factors, which protect C. elegans from P. aeruginosa, are required for preventing ToxA-mediated lethality. ToxA-responsive genes are not induced by enzymatically inactive ToxA protein but can be upregulated independently of ToxA by disruption of host protein translation. Thus, C. elegans has a surveillance mechanism to recognize ToxA through its effect on protein translation rather than by direct recognition of either ToxA or ribosylated EF2.

• Lactocepin secreted by lactobacillus exerts anti-inflammatory effects by selectively degrading proinflammatory chemokines.

  Authors: Marie-Anne von Schillde, Gabriele Hörmannsperger, Monika Weiher, Carl-Alfred Alpert, Hannes Hahne, Christine Bäuerl, Karolien van Huynegem, Lothar Steidler, Tomas Hrncir, Gaspar Pérez-Martínez, Bernhard Kuster, Dirk Haller

  Cell host & microbe. 11(4):387-96.

  The intestinal microbiota has been linked to inflammatory bowel diseases (IBD), and oral treatment with specific bacteria can ameliorate IBD. One bacterial mixture, VSL#3, containing Lactobacillus,The intestinal microbiota has been linked to inflammatory bowel diseases (IBD), and oral treatment with specific bacteria can ameliorate IBD. One bacterial mixture, VSL#3, containing Lactobacillus, Bifidobacterium, and Streptococcus, was clinically shown to reduce inflammation in IBD patients and normalize intestinal levels of IP-10, a lymphocyte-recruiting chemokine, in a murine colitis model. We identified Lactobacillus paracasei prtP-encoded lactocepin as a protease that selectively degrades secreted, cell-associated, and tissue-distributed IP-10, resulting in significantly reduced lymphocyte recruitment after intraperitoneal injection in an ileitis model. A human Lactobacillus casei isolate was also found to encode lactocepin and degrade IP-10. L. casei feeding studies in a murine colitis model (T cell transferred Rag2(-/-) mice) revealed that a prtP-disruption mutant was significantly less potent in reducing IP-10 levels, T cell infiltration and inflammation in cecal tissue compared to the isogenic wild-type strain. Thus, lactocepin-based therapies may be effective treatments for chemokine-mediated diseases like IBD.

• Infection-Induced Intestinal Oxidative Stress Triggers Organ-to-Organ Immunological Communication in Drosophila.

  Authors: Shih-Cheng Wu, Chih-Wei Liao, Rong-Long Pan, Jyh-Lyh Juang

  Cell host & microbe. 11(4):410-7.

  Local infections can trigger immune responses in distant organs, and this interorgan immunological crosstalk helps maintain immune homeostasis. We find that enterobacterial infection or chemicallyLocal infections can trigger immune responses in distant organs, and this interorgan immunological crosstalk helps maintain immune homeostasis. We find that enterobacterial infection or chemically and genetically stimulating reactive oxygen species (ROS)-induced stress responses in the Drosophila gut triggers global antimicrobial peptide (AMP) responses in the fat body, a major immune organ in flies. ROS stress induces nitric oxide (NO) production in the gut, which triggers production of the AMP Diptericin, but not Drosomycin, in the fat body. Hemocytes serve as a signaling relay for communication between intestinal ROS/NO signaling and fat body AMP responses. The induction of AMP responses requires Rel/NF-κB activation within the fat body. Although Rel-mediated Drosomycin induction is repressed by the AP-1 transcription factor, this repressor activity is inhibited by intestinal ROS. Thus, intestinal ROS signaling plays an important role in initiating gut-to-fat body immunological communication in Drosophila.

• UnZIPping Mechanisms of Effector-Triggered Immunity in Animals.

  Authors: Anni Kleino, Neal Silverman

  Cell host & microbe. 11(4):320-2.

  The mechanisms by which epithelial cells distinguish pathogens from commensal microbes have long puzzled us. Now, McEwan et al. (2012) and Dunbar et al. (2012), in this issue of Cell Host & Microbe,The mechanisms by which epithelial cells distinguish pathogens from commensal microbes have long puzzled us. Now, McEwan et al. (2012) and Dunbar et al. (2012), in this issue of Cell Host & Microbe, demonstrate that in C. elegans, microbial toxin-induced inhibition of host cellular functions, especially blockade of protein translation, activates the effector-triggered immune response dependent on the transcription factor ZIP-2.

• Shigella targets epithelial tricellular junctions and uses a noncanonical clathrin-dependent endocytic pathway to spread between cells.

  Authors: Makoto Fukumatsu, Michinaga Ogawa, Satoko Arakawa, Masato Suzuki, Kazuhisa Nakayama, Shigeomi Shimizu, Minsoo Kim, Hitomi Mimuro, Chihiro Sasakawa

  Cell host & microbe. 11(4):325-36.

  Bacteria move between cells in the epithelium using a sequential pseudopodium-mediated process but the underlying mechanisms remain unclear. We show that during cell-to-cell movement,Bacteria move between cells in the epithelium using a sequential pseudopodium-mediated process but the underlying mechanisms remain unclear. We show that during cell-to-cell movement, Shigella-containing pseudopodia target epithelial tricellular junctions, the contact point where three epithelial cells meet. The bacteria-containing pseudopodia were engulfed by neighboring cells only in the presence of tricellulin, a protein essential for tricellular junction integrity. Shigella cell-to-cell spread, but not pseudopodium protrusion, also depended on phosphoinositide 3-kinase, clathrin, Epsin-1, and Dynamin-2, which localized beneath the plasma membrane of the engulfing cell. Depleting tricellulin, Epsin-1, clathrin, or Dynamin-2 expression reduced Shigella cell-to-cell spread, whereas AP-2, Dab2, and Eps15 were not critical for this process. Our findings highlight a mechanism for Shigella dissemination into neighboring cells via targeting of tricellular junctions and a noncanonical clathrin-dependent endocytic pathway.

• Strong Immunogenicity and Cross-Reactivity of Mycobacterium tuberculosis ESX-5 Type VII Secretion -Encoded PE-PPE Proteins Predicts Vaccine Potential.

  Authors: Fadel Sayes, Lin Sun, Mariagrazia Di Luca, Roxane Simeone, Nathalie Degaiffier, Laurence Fiette, Semih Esin, Roland Brosch, Daria Bottai, Claude Leclerc, Laleh Majlessi

  Cell host & microbe. 11(4):352-63.

  The genome of Mycobacterium tuberculosis (Mtb) encodes five type VII secretion systems, ESX-1 to ESX-5, most of which are associated with genes encoding PE/PPE proteins, named after their N-terminalThe genome of Mycobacterium tuberculosis (Mtb) encodes five type VII secretion systems, ESX-1 to ESX-5, most of which are associated with genes encoding PE/PPE proteins, named after their N-terminal Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs. Here, we describe the strong T cell immunogenicity of the ESX-5-encoded PE/PPE proteins, which share a large panel of cross-reactive CD4(+) epitopes with substantial numbers of their ESX-5-nonassociated PE/PPE homologs. The immunogenicity of these numerous PE/PPE proteins is dependent on their export by a functional EccD(5), the predicted transmembrane channel of the ESX-5 secretion apparatus. The Mtb Δppe25-pe19 mutant deleted for all ESX-5-associated pe and ppe genes, although highly attenuated in immunocompetent mice, remains able to induce immunity against the ESX-5-associated PE/PPE virulence factors, via cross-reactivity with their numerous homologs, and against the ESX-1 virulence factors ESAT-6/CFP-10. The Δppe25-pe19 strain is strongly protective against Mtb infection in mice and represents a potential antituberculosis vaccine candidate.

• C. elegans Detects Pathogen-Induced Translational Inhibition to Activate Immune Signaling.

  Authors: Tiffany L Dunbar, Zhi Yan, Keir M Balla, Margery G Smelkinson, Emily R Troemel

  Cell host & microbe. 11(4):375-86.

  Pathogens commonly disrupt host cell processes or cause damage, but the surveillance mechanisms used by animals to monitor these attacks are poorly understood. Upon infection with pathogenicPathogens commonly disrupt host cell processes or cause damage, but the surveillance mechanisms used by animals to monitor these attacks are poorly understood. Upon infection with pathogenic Pseudomonas aeruginosa, the nematode C. elegans upregulates infection response gene irg-1 using the zip-2 bZIP transcription factor. Here we show that P. aeruginosa infection inhibits mRNA translation in the intestine via the endocytosed translation inhibitor Exotoxin A, which leads to an increase in ZIP-2 protein levels. In the absence of infection we find that the zip-2/irg-1 pathway is upregulated following disruption of several core host processes, including inhibition of mRNA translation. ZIP-2 induction is conferred by a conserved upstream open reading frame in zip-2 that could derepress ZIP-2 translation upon infection. Thus, translational inhibition, a common pathogenic strategy, can trigger activation of an immune surveillance pathway to provide host defense.

• Nondegradative Role of Atg5-Atg12/ Atg16L1 Autophagy Protein Complex in Antiviral Activity of Interferon Gamma.

  Authors: Seungmin Hwang, Nicole S Maloney, Monique W Bruinsma, Gautam Goel, Erning Duan, Lei Zhang, Bimmi Shrestha, Michael S Diamond, Adish Dani, Stanislav V Sosnovtsev, Kim Y Green, Carlos Lopez-Otin, Ramnik J Xavier, Larissa B Thackray, Herbert W Virgin

  Cell host & microbe. 11(4):397-409.

  Host resistance to viral infection requires type I (α/β) and II (γ) interferon (IFN) production. Another important defense mechanism is the degradative activity of macroautophagy (herein autophagy),Host resistance to viral infection requires type I (α/β) and II (γ) interferon (IFN) production. Another important defense mechanism is the degradative activity of macroautophagy (herein autophagy), mediated by the coordinated action of evolutionarily conserved autophagy proteins (Atg). We show that the Atg5-Atg12/Atg16L1 protein complex, whose prior known function is in autophagosome formation, is required for IFNγ-mediated host defense against murine norovirus (MNV) infection. Importantly, the direct antiviral activity of IFNγ against MNV in macrophages required Atg5-Atg12, Atg7, and Atg16L1, but not induction of autophagy, the degradative activity of lysosomal proteases, fusion of autophagosomes and lysosomes, or the Atg8-processing protein Atg4B. IFNγ, via Atg5-Atg12/Atg16L1, inhibited formation of the membranous cytoplasmic MNV replication complex, where Atg16L1 localized. Thus, the Atg5-Atg12/Atg16L1 complex performs a pivotal, nondegradative role in IFNγ-mediated antiviral defense, establishing that multicellular organisms have evolved to use portions of the autophagy pathway machinery in a cassette-like fashion for host defense.

• To die or not to die-Shigella has an answer.

  Authors: Thomas Rudel

  Cell host & microbe. 11(3):219-21.

  Invasion of epithelial cells by Shigella is a critical step in the pathogenesis of bacillary dysentery. In this issue of Cell Host & Microbe, Bergounioux et al. (2012) uncover a complex interplay ofInvasion of epithelial cells by Shigella is a critical step in the pathogenesis of bacillary dysentery. In this issue of Cell Host & Microbe, Bergounioux et al. (2012) uncover a complex interplay of proinvasion, prosurvival, and prodeath signals centered on the activation of calpain protease by the Shigella VirA protein.

• A Way to DAI.

  Authors: Patrick-Simon Welz, Manolis Pasparakis

  Cell host & microbe. 11(3):223-5.

  RIP3-regulated necrosis has recently emerged as an important antiviral host defense mechanism. A new study by Upton et al. (2012) identifies DAI, a cytoplasmic DNA sensor, as a partner of RIP3 thatRIP3-regulated necrosis has recently emerged as an important antiviral host defense mechanism. A new study by Upton et al. (2012) identifies DAI, a cytoplasmic DNA sensor, as a partner of RIP3 that is essential for the induction of regulated necrosis in cytomegalovirus-infected cells.

• Calpain Activation by the Shigella flexneri Effector VirA Regulates Key Steps in the Formation and Life of the Bacterium's Epithelial Niche.

  Authors: Jean Bergounioux, Ruben Elisee, Anne-Laure Prunier, Françoise Donnadieu, Brice Sperandio, Philippe Sansonetti, Laurence Arbibe

  Cell host & microbe. 11(3):240-52.

  The enteropathogen Shigella flexneri invades epithelial cells, leading to inflammation and tissue destruction. We report that Shigella infection of epithelial cells induces an early genotoxic stress,The enteropathogen Shigella flexneri invades epithelial cells, leading to inflammation and tissue destruction. We report that Shigella infection of epithelial cells induces an early genotoxic stress, but the resulting p53 response and cell death are impaired due to the bacterium's ability to promote p53 degradation, mainly through calpain protease activation. Calpain activation is promoted by the Shigella virulence effector VirA and dependent on calcium flux and the depletion of the endogenous calpain inhibitor calpastatin. Further, although VirA-induced calpain activity is critical for regulating cytoskeletal events driving bacterial uptake, calpain activation ultimately leads to necrotic cell death, thereby restricting Shigella intracellular growth. Therefore, calpains work at multiple steps in regulating Shigella pathogenesis by disrupting the p53-dependent DNA repair response early during infection and regulating both formation and ultimate death of the Shigella epithelial replicative niche.

• Autophagy Protein Rubicon Mediates Phagocytic NADPH Oxidase Activation in Response to Microbial Infection or TLR Stimulation.

  Authors: Chul-Su Yang, Jong-Soo Lee, Mary Rodgers, Chan-Ki Min, June-Yong Lee, Hee Jin Kim, Kwang-Hoon Lee, Chul-Joong Kim, Byungha Oh, Ebrahim Zandi, Zhenyu Yue, Igor Kramnik, Chengyu Liang, Jae U Jung

  Cell host & microbe. 11(3):264-76.

  Phagocytosis and autophagy are two important and related arms of the host's first-line defense against microbial invasion. Rubicon is a RUN domain containing cysteine-rich protein that functions asPhagocytosis and autophagy are two important and related arms of the host's first-line defense against microbial invasion. Rubicon is a RUN domain containing cysteine-rich protein that functions as part of a Beclin-1-Vps34-containing autophagy complex. We report that Rubicon is also an essential, positive regulator of the NADPH oxidase complex. Upon microbial infection or Toll-like-receptor 2 (TLR2) activation, Rubicon interacts with the p22phox subunit of the NADPH oxidase complex, facilitating its phagosomal trafficking to induce a burst of reactive oxygen species (ROS) and inflammatory cytokines. Consequently, ectopic expression or depletion of Rubicon profoundly affected ROS, inflammatory cytokine production, and subsequent antimicrobial activity. Rubicon's actions in autophagy and in the NADPH oxidase complex are functionally and genetically separable, indicating that Rubicon functions in two ancient innate immune machineries, autophagy and phagocytosis, depending on the environmental stimulus. Rubicon may thus be pivotal to generating an optimal intracellular immune response against microbial infection.

• DAI/ZBP1/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRA.

  Authors: Jason W Upton, William J Kaiser, Edward S Mocarski

  Cell host & microbe. 11(3):290-7.

  Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypicProgrammed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by murine cytomegalovirus (MCMV) infection or death receptor activation and suppressed by the MCMV-encoded viral inhibitor of RIP activation (vIRA). We find that interferon-independent expression of DNA-dependent activator of interferon regulatory factors (DAI, also known as ZBP1 or DLM-1) sensitizes cells to virus-induced necrosis and that DAI knockdown or knockout cells are resistant to this death pathway. Importantly, as with RIP3(-/-) mice, vIRA mutant MCMV pathogenesis is restored in DAI(-/-) mice, consistent with a DAI-RIP3 complex being the natural target of vIRA. Thus, DAI interacts with RIP3 to mediate virus-induced necrosis analogous to the RIP1-RIP3 complex controlling death receptor-induced necroptosis. These studies unveil a role for DAI as the RIP3 partner mediating virus-induced necrosis.

• Cofactors Required for TLR7- and TLR9-Dependent Innate Immune Responses.

  Authors: Chih-Yuan Chiang, Alex Engel, Amanda M Opaluch, Irene Ramos, Ana M Maestre, Ismael Secundino, Paul D De Jesus, Quy T Nguyen, Genevieve Welch, Ghislain M C Bonamy, Loren J Miraglia, Anthony P Orth, Victor Nizet, Ana Fernandez-Sesma, Yingyao Zhou, Gregory M Barton, Sumit K Chanda

  Cell host & microbe. 11(3):306-18.

  Pathogens commonly utilize endocytic pathways to gain cellular access. The endosomal pattern recognition receptors TLR7 and TLR9 detect pathogen-encoded nucleic acids to initiate MyD88-dependentPathogens commonly utilize endocytic pathways to gain cellular access. The endosomal pattern recognition receptors TLR7 and TLR9 detect pathogen-encoded nucleic acids to initiate MyD88-dependent proinflammatory responses to microbial infection. Using genome-wide RNAi screening and integrative systems-based analysis, we identify 190 cofactors required for TLR7- and TLR9-directed signaling responses. A set of cofactors were crossprofiled for their activities downstream of several immunoreceptors and then functionally mapped based on the known architecture of NF-κB signaling pathways. Protein complexes and pathways involved in ubiquitin-protein ligase activities, sphingolipid metabolism, chromatin modifications, and ancient stress responses were found to modulate innate recognition of endosomal nucleic acids. Additionally, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) was characterized as necessary for ubiquitin-dependent TLR9 targeting to the endolysosome. Proteins and pathways identified here should prove useful in delineating strategies to manipulate innate responses for treatment of autoimmune disorders and microbial infection.

• Crossing the rubicon: new roads lead to host defense.

  Authors: Clinton J Bradfield, Bae-Hoon Kim, John D Macmicking

  Cell host & microbe. 11(3):221-3.

  Rubicon is a protein known to engage the Beclin-1/Vps34-PI3K/UVRAG complex and inhibit endosome and autophagosomal fusion with lysosomes. Yang et al. (2012) uncover new roles for this adaptor proteinRubicon is a protein known to engage the Beclin-1/Vps34-PI3K/UVRAG complex and inhibit endosome and autophagosomal fusion with lysosomes. Yang et al. (2012) uncover new roles for this adaptor protein within noncanonical p22(phox) or CARD9 complexes that regulate oxidative and cytokine responses in activated macrophages, respectively. Both complexes impact pathogen-specific host defense.

• Zinc sequestration by the neutrophil protein calprotectin enhances salmonella growth in the inflamed gut.

  Authors: Janet Z Liu, Stefan Jellbauer, Adam J Poe, Vivian Ton, Michele Pesciaroli, Thomas E Kehl-Fie, Nicole A Restrepo, Martin P Hosking, Robert A Edwards, Andrea Battistoni, Paolo Pasquali, Thomas E Lane, Walter J Chazin, Thomas Vogl, Johannes Roth, Eric P Skaar, Manuela Raffatellu

  Cell host & microbe. 11(3):227-39.

  Neutrophils are innate immune cells that counter pathogens by many mechanisms, including release of antimicrobial proteins such as calprotectin to inhibit bacterial growth. Calprotectin sequestersNeutrophils are innate immune cells that counter pathogens by many mechanisms, including release of antimicrobial proteins such as calprotectin to inhibit bacterial growth. Calprotectin sequesters essential micronutrient metals such as zinc, thereby limiting their availability to microbes, a process termed nutritional immunity. We find that while calprotectin is induced by neutrophils during infection with the gut pathogen Salmonella Typhimurium, calprotectin-mediated metal sequestration does not inhibit S. Typhimurium proliferation. Remarkably, S. Typhimurium overcomes calprotectin-mediated zinc chelation by expressing a high affinity zinc transporter (ZnuABC). A S. Typhimurium znuA mutant impaired for growth in the inflamed gut was rescued in the absence of calprotectin. ZnuABC was also required to promote the growth of S. Typhimurium over that of competing commensal bacteria. Thus, our findings indicate that Salmonella thrives in the inflamed gut by overcoming the zinc sequestration of calprotectin and highlight the importance of zinc acquisition in bacterial intestinal colonization.

• Disruption of PAMP-Induced MAP Kinase Cascade by a Pseudomonas syringae Effector Activates Plant Immunity Mediated by the NB-LRR Protein SUMM2.

  Authors: Zhibin Zhang, Yaling Wu, Minghui Gao, Jie Zhang, Qing Kong, Yanan Liu, Hongping Ba, Jianmin Zhou, Yuelin Zhang

  Cell host & microbe. 11(3):253-63.

  Pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) serves as a primary plant defense response against microbial pathogens, with MEKK1, MKK1/MKK2, and MPK4 functioning as a MAPPathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) serves as a primary plant defense response against microbial pathogens, with MEKK1, MKK1/MKK2, and MPK4 functioning as a MAP kinase cascade downstream of PAMP receptors. Plant Resistance (R) proteins sense specific pathogen effectors to initiate a second defense mechanism, termed effector-triggered immunity (ETI). In a screen for suppressors of the mkk1 mkk2 autoimmune phenotype, we identify the nucleotide-binding leucine-rich repeat (NB-LRR) protein SUMM2 and find that the MEKK1-MKK1/MKK2-MPK4 cascade negatively regulates SUMM2-mediated immunity. Further, the MEKK1-MKK1/MKK2-MPK4 cascade positively regulates basal defense targeted by the Pseudomonas syringae pathogenic effector HopAI1, which inhibits MPK4 kinase activity. Inactivation of MPK4 by HopAI1 results in activation of SUMM2-mediated defense responses. Our data suggest that SUMM2 is an R protein that becomes active when the MEKK1-MKK1/MKK2-MPK4 cascade is disrupted by pathogens, supporting the hypothesis that R proteins evolved to protect plants when microbial effectors suppress basal resistance.

• The Autophagy Regulator Rubicon Is a Feedback Inhibitor of CARD9-Mediated Host Innate Immunity.

  Authors: Chul-Su Yang, Mary Rodgers, Chan-Ki Min, Jong-Soo Lee, Lara Kingeter, June-Yong Lee, Ambrose Jong, Igor Kramnik, Xin Lin, Jae U Jung

  Cell host & microbe. 11(3):277-89.

  Assembly of a scaffold consisting of CARD9, BCL10, and MALT1 (CBM complex) is critical for effective signaling by multiple pattern recognition receptors (PRRs) including Dectin and RIG-I. The RUNAssembly of a scaffold consisting of CARD9, BCL10, and MALT1 (CBM complex) is critical for effective signaling by multiple pattern recognition receptors (PRRs) including Dectin and RIG-I. The RUN domain Beclin-1-interacting cysteine-rich-containing Rubicon protein associates constitutively with the Beclin-UVRAG-Vps34 complex under normal conditions to regulate autophagy. Rubicon also interacts with the phagocytic NADPH-oxidase complex upon TLR stimulation to induce potent antimicrobial responses. Here, we show Rubicon is a physiological feedback inhibitor of CBM-mediated PRR signaling, preventing unbalanced proinflammatory responses. Upon Dectin-1- or RIG-I-mediated activation, Rubicon dynamically exchanges binding partners from 14-3-3β to CARD9 in a stimulation-specific and phosphorylation-dependent manner, disassembling the CBM signaling complex and ultimately terminating PRR-induced cytokine production. Remarkably, Rubicon's actions in the autophagy complex, phagocytosis complex, and CBM complex are functionally and genetically separable. Rubicon thus differentially targets signaling complexes, depending on environmental stimuli, and may function to coordinate various immune responses against microbial infection.

• Pancreatic acinar cell-specific autophagy disruption reduces coxsackievirus replication and pathogenesis in vivo.

  Authors: Mehrdad Alirezaei, Claudia T Flynn, Malcolm R Wood, J Lindsay Whitton

  Cell host & microbe. 11(3):298-305.

  Autophagy protects against many infections by inducing the lysosomal-mediated degradation of invading pathogens. However, previous in vitro studies suggest that some enteroviruses not only evadeAutophagy protects against many infections by inducing the lysosomal-mediated degradation of invading pathogens. However, previous in vitro studies suggest that some enteroviruses not only evade these protective effects but also exploit autophagy to facilitate their replication. We generated Atg5(f/f)/Cre(+) mice, in which the essential autophagy gene Atg5 is specifically deleted in pancreatic acinar cells, and show that coxsackievirus B3 (CVB3) requires autophagy for optimal infection and pathogenesis. Compared to Cre(-) littermates, Atg5(f/f)/Cre(+) mice had an ∼2,000-fold lower CVB3 titer in the pancreas, and pancreatic pathology was greatly diminished. Both in vivo and in vitro, Atg5(f/f)/Cre(+) acinar cells had reduced intracellular viral RNA and proteins. Furthermore, intracellular structural elements induced upon CVB3 infection, such as compound membrane vesicles and highly geometric paracrystalline arrays, which may represent viral replication platforms, were infrequently observed in infected Atg5(f/f)/Cre(+) cells. Thus, CVB3-induced subversion of autophagy not only benefits the virus but also exacerbates pancreatic pathology.

• The Ability of Primate Lentiviruses to Degrade the Monocyte Restriction Factor SAMHD1 Preceded the Birth of the Viral Accessory Protein Vpx.

  Authors: Efrem S Lim, Oliver I Fregoso, Connor O McCoy, Frederick A Matsen, Harmit S Malik, Michael Emerman

  Cell host & microbe. 11(2):194-204.

  The human SAMHD1 protein potently restricts lentiviral infection in dendritic cells and monocyte/macrophages but is antagonized by the primate lentiviral protein Vpx, which targets SAMHD1 forThe human SAMHD1 protein potently restricts lentiviral infection in dendritic cells and monocyte/macrophages but is antagonized by the primate lentiviral protein Vpx, which targets SAMHD1 for degradation. However, only two of eight primate lentivirus lineages encode Vpx, whereas its paralog, Vpr, is conserved across all extant primate lentiviruses. We find that not only multiple Vpx but also some Vpr proteins are able to degrade SAMHD1, and such antagonism led to dramatic positive selection of SAMHD1 in the primate subfamily Cercopithecinae. Residues that have evolved under positive selection precisely determine sensitivity to Vpx/Vpr degradation and alter binding specificity. By overlaying these functional analyses on a phylogenetic framework of Vpr and Vpx evolution, we can decipher the chronology of acquisition of SAMHD1-degrading abilities in lentiviruses. We conclude that vpr neofunctionalized to degrade SAMHD1 even prior to the birth of a separate vpx gene, thereby initiating an evolutionary arms race with SAMHD1.

• A PIP Gets the plasmodium protein export pathway going.

  Authors: Rays H Y Jiang, Matthias Marti

  Cell host & microbe. 11(2):99-100.

  Survival of blood stage malaria parasites requires extensive host cell remodeling, which is facilitated by secretion of parasite proteins via a dedicated protein export pathway. In a recent CellSurvival of blood stage malaria parasites requires extensive host cell remodeling, which is facilitated by secretion of parasite proteins via a dedicated protein export pathway. In a recent Cell paper, Bhattacharjee et al., (2012) describe PI(3)P binding as one of the first steps in targeting parasite proteins to the host cell.

• SAMHD1 Joins the red Queen's court.

  Authors: Vicente Planelles

  Cell host & microbe. 11(2):103-5.

  The host restriction factor SAMHD1 hinders lentiviral infection of myeloid cells, a function counteracted by the viral protein Vpx. Two papers in this issue of Cell Host & Microbe document theThe host restriction factor SAMHD1 hinders lentiviral infection of myeloid cells, a function counteracted by the viral protein Vpx. Two papers in this issue of Cell Host & Microbe document the genetic conflict between SAMHD1 and the Vpr/Vpx proteins, which has subjected SAMHD1 to intense periods of diversifying selection through primate evolution.

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