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Session 8: T4 Effectors 08:00 - 09:50 Tuesday, 11Th June, 2019 Anasazi Ballroom Presentation Type Oral

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Session 8: T4 Effectors 08:00 - 09:50 Tuesday, 11Th June, 2019 Anasazi Ballroom Presentation Type Oral Session 8: T4 Effectors 08:00 - 09:50 Tuesday, 11th June, 2019 Anasazi Ballroom Presentation type Oral 4 Identification and characterization of T4SS substrates in Wolbachia pipientis Irene Newton, Kathy Sheehan, Danny Rice, MaryAnn Martin Indiana University, Bloomington, USA Abstract Wolbachia are alpha-proteobacteria, part of the anciently intracellular Anaplasmataceae, and related to the important human pathogens Anaplasma, Rickettsia and Ehrlichia. However, Wolbachia do not infect mammals, but instead are well known for their reproductive manipulations of insect populations. In order for Wolbachia to establish itself in an insect population it must invade host cells, persist during infection, and be transmitted to the next generation. Like all intracellular bacteria, Wolbachia need to manipulate the host cell to invade and persist. Many microbes accomplish this via secretion systems. All Wolbachia symbionts encode a functional type IV secretion system (T4SS), which is expressed by Wolbachia within its native host. What has eluded researchers until recently is the identification of proteins secreted by Wolbachia. These proteins, referred to as effectors, often act to manipulate or usurp host cell processes in order to promote bacterial infection. We used a polyphasic approach to identify and characterize Wolbachia effectors. We identified candidate Wolbachia effectors using bioinformatics, then, we expressed the effectors in the model eukaryote (Saccharomyces), identifying proteins that induce a growth defect upon overexpression. We discovered that predicted effectors are coregulated with the T4SS using RNA-seq in the native host. Finally, we show that one of these predicted effectors is secreted via a heterologous assay, is found in the host cytosol, binds to host proteins, and facilitates maternal transmission. Our results pave the way for future work on mechanisms of symbiosis in this enigmatic symbiont. 14 A conserved, potential nucleomodulin in Rickettsia species Hema P. Narra, Sandhya R. Golla, Abha Sahni, Krishna M. Sepuru, Sanjeev K. Sahni University of Texas Medical Branch, Galveston, USA Abstract Pathogenic bacteria employ specialized molecular secretion systems to deliver virulence factors and/or effectors to subvert host defense strategies. Despite a pattern of evolution via genome reduction, Rickettsia species encode and maintain effector delivery mechanisms, including components of a VirB/D-based type IV secretion system, yet only a few rickettisal effectors have so far been recognized and functionally characterized. By RNA sequencing and quantitative RT-PCR, we have identified abundant expression of RC0103, currently annotated as a hypothetical protein, during in vitro infection of human microvascular endothelial cells (HMECs) with R. conorii and significant upregulation of RC0103 expression at 24h when compared to 3h post-infection (38±5 copies versus 11±4 copies/bacterium). Sequence analysis revealed the presence of a bona fide bipartite nuclear translocation signal and existence of RC0103 homologs in all Rickettsia species. Circular dichroism spectroscopy of recombinant RC0103 suggested a unique antiparallel β- sheet secondary structure with approximately 28% left-twisted and 25% right-twisted sheets. Ectopic expression of RC0103 in HMECs revealed its translocation into the nucleus, yielding first evidence for its potential functional roles as a nucleomodulin. We next investigated the downstream effects of RC0103 nuclear translocation on the expression of 84 genes using an endothelial-specific PCR array and follow-up validation by quantitative RT-PCR. Our initial findings suggest increased expression of matrix metalloproteinases MMP1 and MMP2 and down-regulation of the tissue inhibitor of MMPs TIMP-1 in HMECs stably transfected with RC0103, suggesting a potential virulence factor-like activity involved in vascular dysfunction. Further in-depth studies into RC0103 secretion mechanisms and host transcriptome regulation are ongoing. 40 A Rickettsia typhi phosphatidylinositol 3-kinase, RT0135, is an rvh type IV secretion system effector that modulates plasma membrane phosphoinositide metabolism during invasion and subverts cellular autophagy to establish its intracellular niche Oliver H. Voss1, Joseph J. Gillespie1, Stephanie S. Lehman2, Sherri A. Rennoll1, Magda Beier-Sexton1, M. Sayeedur Rahman1, Abdu F. Azad1 1Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, USA. 2Department of Microbiology and Immunology, University of Maryland School of Medicine, Balimore, USA Abstract Many invasive bacteria repurpose host phosphoinositide (PI) metabolism to induce phagocytosis, subvert intracellular trafficking, delay endosomal-lysosomal fusion, or avoid autolysosomal killing. These manipulative processes are often mediated by secretion system effectors. For Rickettsia typhi, the etiological agent of murine typhus, we previously characterized two rvh type IV secretion system (T4SS) effectors: RARP-2 targets the host endoplasmic reticulum, while RalF activates host Arf6 at the plasma membrane to facilitate PI 4- phosphate-5 kinase-mediated generation of PI 4,5-bisphosphate (PIP2). PIP2 accumulation at early phagocytic cup formation leads to downstream PI shifts throughout phagocytosis: class I PI3-kinase (PI3K)-mediated phosphorylation of PIP2 to PI (3,4,5)-trisphosphate (PIP3) for phagocytic cup closure, and ultimately class III PI3K-mediated generation of PI 3-phosphate (PI3P), the dominant PI on early endosomes. Accordingly, we hypothesized that additional rickettsial effectors might target host PI metabolism for its survival and pathogenesis. Indeed, immunoprecipitation of R. typhi lysate using an anti-RvhD4 (the rvhT4SS signal recognition protein) antibody revealed a novel PI3K domain-containing effector (RT0135). In vitro assays with recombinant RT0135 revealed both class I (PIP2 to PIP3) and class III (PI to PI3P) PI3K activities, a unique feature among characterized bacterial PI3Ks. R. typhi secretes RT0135 during host cell infection, with neutralization of RT0135 PI3K activity diminishing PIP2-PIP3 conversion and significantly reducing invasion. Furthermore, RT0135 binds Beclin-1 on autophagosomes later in infection, a likely safeguard against autophagolysosomal destruction. Collectively, our data suggest that R. typhi secretes a PI3K effector, RT0135, that facilitates intracellular growth by repurposing plasma membrane PI metabolism during invasion and subverting cellular autophagy later in infection. 52 Inhibition of Ehrlichia chaffeensis Infection by Cell-permeable Bicyclic Peptides that Bind Ehrlichial Type IV Secretion Effector Etf-1 Mingqun Lin, Amritendu Koley, Wenqing Zhang, Dehua Pei, Yasuko Rikihisa The Ohio State University, Columbus, OH, USA Abstract Ehrlichia chaffeensis is an obligatory intracellular bacterium that causes human monocytic ehrlichiosis (HME), an emerging life-threatening infectious disease worldwide. E. chaffeensis encodes a type IV secretion effector protein, Ehrlichial translocated factor-1 (Etf-1), which is abundantly produced and secreted into infected cells. Etf-1 is critical for Ehrlichia infection of human monocytes by subverting and manipulating two important innate immune defense mechanisms against intracellular infection, cellular apoptosis and autophagy. Therefore, Etf-1 can serve as a potential therapeutic target for HME, since currently, the only drug is the broad- spectrum antibiotic doxycycline and no vaccine exists. In this study, we screened a combinatorial library of cell-permeable bicyclic peptides (bicyclic CPPs), which feature an ensemble of random peptide sequences in the first ring and a family of cell-penetrating peptides in the second ring, for binding to Etf-1. Two rounds of screening of over 320,000 bicyclic CPPs identified 30 hits that bound to Etf-1, and among them, two peptides (B7 and 174-5) interacted with Etf-1 with relatively high affinity (Kd of 5.3 and 1.5 mM, respectively) by fluorescence anisotropy assays. Treatment of E. chaffeensis infected THP-1 cells showed that peptides B7 and 174-5 significantly blocked Ehrlichia infection in a dose-dependent manner, but a control peptide C17, which did not bind to Etf-1, had no effect on bacterial infection. Our results demonstrate the feasibility of developing cell-permeable macrocyclic peptides as Etf-1 inhibitors for potential treatment of diseases caused by obligatory intracellular bacteria. 99 Modulation of NF-kB signalling by a Coxiella burnetii eukaryotic-like effector protein Melanie Burette, Julie Allombert, Ghizlane Maarifi, Sebastien Nisole, Karine Lambou, Matteo Bonazzi CNRS, Montpellier, France Abstract Coxiella burnetii, the etiological agent of the worldwide emerging zoonosis Q fever, replicates inside host cells in large autolysosome-like compartments and persists by protecting infected cells from apoptosis and silencing the innate immune response to infection. Recent bioinformatics analysis let to the identification of 7 Coxiella effector proteins containing eukaryotic-like domains, potentially involved in protein-protein interactions, post- translational modification and chromatin rearrangements. Among these, NopA (for Nucleolar protein A), displays 4 regulation of chromatin condensation (RCC) domains, which are found in the eukaryotic Ran GEF RCC1. Similar to RCC1, NopA localizes at the nucleus of infected or transfected cells, it is found associated with the chromatin nuclear fraction, and uses the RCC domains to interact with Ran,
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