Medicine and Health Sciences Commons^™

B1 Cell Ige Impedes Mast Cell-Mediated Enhancement Of Parasite Expulsion Through B2 Ige Blockade, Rebecca K. Martin, Sheela R. Damle, Yolander A. Valentine, Matthew P. Zellner, Briana N. James, Joseph C. Lownik, Andrea J. Luker, Elijah H. Davis, Martha M. Demeules, Laura M. Khandjian, Fred D. Finkelman, Joseph F. Urban Jr., Daniel H. Conrad

Microbiology and Immunology Publications

Helminth infection is known for generating large amounts of poly-specific IgE. Here we demonstrate that innate-like B1 cells are responsible for this IgE production during infection with the nematode parasites Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. In vitro analysis of B1 cell immunoglobulin class switch recombination to IgE demonstrated a requirement for anti-CD40 and IL-4 that was further enhanced when IL-5 was added or when the B1 source was helminth infected mice. An IL-25-induced upregulation of IgE in B1 cells was also demonstrated. In T cell-reconstituted RAG1^−/− mice, N. brasiliensis clearance was enhanced with the addition of B2 …

Structural Modeling And Functional Analysis Of The Essential Ribosomal Processing Protease Prp From Staphylococcus Aureus, Erin A. Wall, Adam L. Johnson, Darrell L. Peterson, Gail E. Christie

Microbiology and Immunology Publications

In Firmicutes and related bacteria, ribosomal large subunit protein L27 is encoded with a conserved N-terminal extension that is removed to expose residues critical for ribosome function. Bacteria encoding L27 with this N-terminal extension also encode a sequence-specific cysteine protease, Prp, which carries out this cleavage. In this work, we demonstrate that L27 variants with an un-cleavable N-terminal extension, or lacking the extension (pre-cleaved), are unable to complement an L27 deletion in Staphylococcus aureus. This indicates that N-terminal processing of L27 is not only essential but possibly has a regulatory role. Prp represents a new clade of previously uncharacterized cysteine …

Tetr Family Regulator Brpt Modulates Biofilm Formation In Streptococcus Sanguinis, Jinlin Liu, Victoria N. Stone, Xiuchun Ge, Madison Tang, Fadi Elrami, Ping Xu

Microbiology and Immunology Publications

Biofilms are a key component in bacterial communities providing protection and contributing to infectious diseases. However, mechanisms involved in S. sanguinis biofilm formation have not been clearly elucidated. Here, we report the identification of a novel S. sanguinis TetR repressor, brpT (Biofilm Regulatory Protein TetR), involved in biofilm formation. Deletion of brpT resulted in a significant increase in biofilm formation. Interestingly, the mutant accumulated more water soluble and water insoluble glucans in its biofilm compared to the wild-type and the complemented mutant. The brpT mutation led to an altered biofilm morphology and structure exhibiting a rougher appearance, uneven …

Identification Of Naegleria Fowleri Proteins Linked To Primary Amoebic Meningoencephalitis, Melissa Jamerson, Jacqueline A. Schmoyer, Jay Park, Francine Marciano-Cabral, Guy A. Cabral

Microbiology and Immunology Publications

Naegleria fowleri (N. fowleri) causes primary amoebic meningoencephalitis, a rapidly fatal disease of the central nervous system. N. fowleri can exist in cyst, flagellate or amoebic forms, depending on environmental conditions. The amoebic form can invade the brain following introduction into the nasal passages. When applied intranasally to a mouse model, cultured N. fowleri amoebae exhibit low virulence. However, upon serial passage in mouse brain, the amoebae acquire a highly virulent state. In the present study, a proteomics approach was applied to the identification of N. fowleri amoeba proteins whose expression was associated with the highly virulent state …

Saikosaponins Induced Hepatotoxicity In Mice Via Lipid Metabolism Dysregulation And Oxidative Stress: A Proteomic Study, Xiaoyu Li, Xiaojiaoyang Li, Junxian Lu, Youyi Huang, Lili Lv, Yongfu Luan, Runping Liu, Rong Sun

Microbiology and Immunology Publications

Background

Radix Bupleuri (RB) has been popularly used for treating many liver diseases such as chronic hepatic inflammation and viral Hepatitis in China. Increasing clinical and experimental evidence indicates the potential hepatotoxicity of RB or prescriptions containing RB. Recently, Saikosaponins (SS) have been identified as major bioactive compounds isolated from RB, which may be also responsible for RB-induced liver injury.

Methods

Serum AST, ALT and LDH levels were determined to evaluate SS-induced liver injury in mice. Serum and liver total triglyceride and cholesterol were used to indicate lipid metabolism homeostasis. Liver ROS, GSH, MDA and iNOS were used to examine …

The Pathogen-Occupied Vacuoles Of Anaplasma Phagocytophilum And Anaplasma Marginale Interact With The Endoplasmic Reticulum, Hilary K. Truchan, Chelsea L. Cockburn, Kathryn S. Hebert, Forgivemore Magunda, Susan M. Noh, Jason A. Carlyon

Microbiology and Immunology Publications

The genus Anaplasma consists of tick-transmitted obligate intracellular bacteria that invade white or red blood cells to cause debilitating and potentially fatal infections. A. phagocytophilum, a human and veterinary pathogen, infects neutrophils to cause granulocytic anaplasmosis. A. marginale invades bovine erythrocytes. Evidence suggests that both species may also infect endothelial cells in vivo. In mammalian and arthropod host cells, A. phagocytophilum and A. marginale reside in host cell derived pathogen-occupied vacuoles (POVs). While it was recently demonstrated that the A. phagocytophilum-occupied vacuole (ApV) intercepts membrane traffic from the trans-Golgi network, it is unclear if it or …

Involvement Of Nadh Oxidase In Biofilm Formation In Streptococcus Sanguinis, Xiuchun Ge, Xiaoli Shi, Limei Shi, Jinlin Liu, Victoria Stone, Fanxiang Kong, Todd Kitten, Ping Xu

Microbiology and Immunology Publications

Biofilms play important roles in microbial communities and are related to infectious diseases. Here, we report direct evidence that a bacterial nox gene encoding NADH oxidase is involved in biofilm formation. A dramatic reduction in biofilm formation was observed in a Streptococcus sanguinis nox mutant under anaerobic conditions without any decrease in growth. The membrane fluidity of the mutant bacterial cells was found to be decreased and the fatty acid composition altered, with increased palmitic acid and decreased stearic acid and vaccenic acid. Extracellular DNA of the mutant was reduced in abundance and bacterial competence was suppressed. Gene expression analysis …

Impaired Immunological Synapse In Sperm Associated Antigen 6 (Spag6) Deficient Mice, Lauren Folgosa Cooley, Mohey Eldin El Shikh, Wei Li, Rebecca C. Keim, Zhengang Zhang, Jerome F. Strauss, Zhibing Zhang, Daniel H. Conrad

Microbiology and Immunology Publications

Sperm associated antigen 6 (SPAG6), a component of the central apparatus of the “9 + 2” axoneme, plays a central role in ciliary and flagellar motility; but, its contribution to adaptive immunity and immune system development is completely unknown. While immune cells lack a cilium, the immunological synapse is a surrogate cilium as it utilizes the same machinery as ciliogenesis including the nucleation of microtubules at the centrosome. This prompted our hypothesis that SPAG6 critically regulates the formation and function of immunological synapses. Using bone marrow reconstitution studies of adult WT mice, we demonstrate that SPAG6 is expressed in primary …

Interaction Between Cannabinoid System And Toll-Like Receptors Controls Inflammation, Kathleen L. Mccoy

Microbiology and Immunology Publications

Since the discovery of the endocannabinoid system consisting of cannabinoid receptors, endogenous ligands, and biosynthetic and metabolizing enzymes, interest has been renewed in investigating the promise of cannabinoids as therapeutic agents. Abundant evidence indicates that cannabinoids modulate immune responses. An inflammatory response is triggered when innate immune cells receive a danger signal provided by pathogen- or damage-associated molecular patterns engaging pattern-recognition receptors. Toll-like receptor family members are prominent pattern-recognition receptors expressed on innate immune cells. Cannabinoids suppress Toll-like receptor-mediated inflammatory responses. However, the relationship between the endocannabinoid system and innate immune system may not be one-sided. Innate immune cells express …

The Prostaglandin E2-Ep3 Receptor Axis Regulates Anaplasma Phagocytophilum-Mediated Nlrc4 Inflammasome Activation, Xiaowei Wang, Dana K. Shaw, Holly L. Hammond, Fayyaz S. Sutterwala, Manira Rayamajhi, Kari Ann Shirey, Darren J. Perkins, Joseph V. Bonventre, Thangam S. Velayutham, Sean M. Evans, Kyle G. Rodino, Lauren Viebrock, Karen M. Scanlon, Nicholas H. Carbonetti, Jason A. Carlyon, Edward A. Miao, Jere W. Mcbride, Michail Kotsyfakis, Joao H. F. Pedra

Microbiology and Immunology Publications

Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads …

Interaction Between Cannabinoid System And Toll-Like Receptors Controls Inflammation, Kathleen L. Mccoy

Microbiology and Immunology Publications

Since the discovery of the endocannabinoid system consisting of cannabinoid receptors, endogenous ligands, and biosynthetic and metabolizing enzymes, interest has been renewed in investigating the promise of cannabinoids as therapeutic agents. Abundant evidence indicates that cannabinoids modulate immune responses. An inflammatory response is triggered when innate immune cells receive a danger signal provided by pathogen- or damage-associated molecular patterns engaging pattern-recognition receptors. Toll-like receptor family members are prominent pattern-recognition receptors expressed on innate immune cells. Cannabinoids suppress Toll-like receptor-mediated inflammatory responses. However, the relationship between the endocannabinoid system and innate immune system may not be one-sided. Innate immune cells express …

Widely Used Herpes Simplex Virus 1 Icp0 Deletion Mutant Strain Dl1403 And Its Derivative Viruses Do Not Express Glycoprotein C Due To A Secondary Mutation In The Gc Gene, Cristina W. Cunha, Kathryne E. Taylor, Suzanne M. Pritchard, Mark G. Delboy, Tri Komala Sari, Hector C. Aguilar, Karen L. Mossman, Anthony V. Nicola

Microbiology and Immunology Publications

Herpes simplex virus 1 (HSV-1) ICP0 is a multi-functional phosphoprotein expressed with immediate early kinetics. An ICP0 deletion mutant, HSV-1 dl1403, has been widely used to study the roles of ICP0 in the HSV-1 replication cycle including gene expression, latency, entry and assembly. We show that HSV-1 dl1403 virions lack detectable levels of envelope protein gC, and that gC is not synthesized in infected cells. Sequencing of the gC gene from HSV-1dl1403 revealed a single amino acid deletion that results in a frameshift mutation. The HSV-1dl1403 gC gene is predicted to encode a polypeptide …

Turning Over A New Leaf: Cannabinoid And Endocannabinoid Modulation Of Immune Function, Guy A. Cabral, Thomas J. Rogers, Aron H. Lichtman

Microbiology and Immunology Publications

Cannabis is a complex substance that harbors terpenoid-like compounds referred to as phytocannabinoids. The major psychoactive phytocannabinoid found in cannabis ∆9-tetrahydrocannabinol (THC) produces the majority of its pharmacological effects through two cannabinoid receptors, termed CB1 and CB2. The discovery of these receptors as linked functionally to distinct biological effects of THC, and the subsequent development of synthetic cannabinoids, precipitated discovery of the endogenous cannabinoid (or endocannabinoid) system. This system consists of the endogenous lipid ligands N- arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB1 and CB2 receptors that they activate. Endocannabinoids have been …

Hiv Protease Inhibitors Sensitize Human Head And Neck Squamous Carcinoma Cells To Radiation By Activating Endoplasmic Reticulum Stress, Runping Liu, Luyong Zhang, Jing Yang, Xiaoxuan Zhang, Ross B. Mikkelsen, Shiyu Song, Huiping Zhou

Microbiology and Immunology Publications

Background

Human head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. Despite significant advances in the delivery of treatment and surgical reconstruction, there is no significant improvement of mortality rates for this disease in the past decades. Radiotherapy is the core component of the clinical combinational therapies for HNSCC. However, the tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear. Our previous study has shown that …

Comparison Of Effectiveness Of Cefovecin, Doxycycline, And Amoxicillin For The Treatment Of Experimentally Induced Early Lyme Borreliosis In Dogs, Bettina Wagner, John Johnson, David Garcia-Tapia, Nicole Honsberger, Vickie King, Catherine Strietzel, John M. Hardham, Thomas J. Heinz, Richard T. Marconi, Patrick F.M. Meeus

Microbiology and Immunology Publications

Background

While Koch’s postulates have been fulfilled for Lyme disease; causing transient fever, anorexia and arthritis in young dogs; treatment of sero-positive dogs, especially asymptomatic animals, remains a topic of debate. To complicate this matter the currently recommended antibiotic treatments of Lyme Disease in dogs caused by Borrelia burgdorferi require daily oral administrations for 31 days or longer, which makes non-compliance a concern. Additionally, there is no approved veterinary antimicrobial for the treatment of Lyme Disease in dogs in the USA and few recommended treatments have been robustly tested.

In vitro testing of cefovecin, a novel extended-spectrum cephalosporin, demonstrated inhibition …

Widely Used Herpes Simplex Virus 1 Icp0 Deletion Mutant Strain Dl1403 And Its Derivative Viruses Do Not Express Glycoprotein C Due To A Secondary Mutation In The Gc Gene, Cristina W. Cunha, Kathryne E. Taylor, Suzanne M. Pritchard, Mark Delboy, Tri Komala Sari, Hector C. Aguilar, Karen L. Mossman, Anthony V. Nicola

Microbiology and Immunology Publications

Herpes simplex virus 1 (HSV-1) ICP0 is a multi-functional phosphoprotein expressed with immediate early kinetics. An ICP0 deletion mutant, HSV-1 dl1403, has been widely used to study the roles of ICP0 in the HSV-1 replication cycle including gene expression, latency, entry and assembly. We show that HSV-1dl1403 virions lack detectable levels of envelope protein gC, and that gC is not synthesized in infected cells. Sequencing of the gC gene from HSV-1 dl1403 revealed a single amino acid deletion that results in a frameshift mutation. The HSV-1 dl1403 gC gene is predicted to encode a polypeptide …

Epigenetic Modifications Of The Pgc-1Α Promoter During Exercise Induced Expression In Mice, Timothy L. Lochmann, Ravindar R. Thomas, James P. Bennett Jr., Shirley M. Taylor

Microbiology and Immunology Publications

The transcriptional coactivator, PGC-1α, is known for its role in mitochondrial biogenesis. Although originally thought to exist as a single protein isoform, recent studies have identified additional promoters which produce multiple mRNA transcripts. One of these promoters (promoter B), approximately 13.7kb upstream of the canonical PGC-1α promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1α mRNA transcript. In skeletal muscle, exercise resulted in a substantial, rapid increase of mRNA of these alternative PGC-1α transcripts. Although the β2-adrenergic receptor was identified as a signaling pathway that activates transcription from PGC-1α promoter B, it is not …

Essential Domains Of Anaplasma Phagocytophilum Invasins Utilized To Infect Mammalian Host Cells, David Seidman, Kathryn S. Hebert, Hilary K. Truchan, Daniel P. Miller, Brittney K. Tegels, Richard T. Marconi, Jason A. Carlyon

Microbiology and Immunology Publications

Anaplasma phagocytophilum causes granulocytic anaplasmosis, an emerging disease of humans and domestic animals. The obligate intracellular bacterium uses its invasins OmpA, Asp14, and AipA to infect myeloid and non-phagocytic cells. Identifying the domains of these proteins that mediate binding and entry, and determining the molecular basis of their interactions with host cell receptors would significantly advance understanding of A. phagocytophilum infection. Here, we identified the OmpA binding domain as residues 59 to 74. Polyclonal antibody generated against a peptide spanning OmpA residues 59 to 74 inhibited A. phagocytophilum infection of host cells and binding to its receptor, sialyl Lewis x …

Intracellular Uropathogenic E. Coli Exploits Host Rab35 For Iron Acquisition And Survival Within Urinary Bladder Cells, Neha Dikshit, Pradeep Bist, Shannon N. Fenlon, Niyas Kudukkil Pulloor, Christelle En Lin Chua, Marci A. Scidmore, Jason A. Carlyon, Bor Luen Tang, Swaine L. Chen, Bindu Sukumaran

Microbiology and Immunology Publications

Recurrent urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC) are common and morbid infections with limited therapeutic options. Previous studies have demonstrated that persistent intracellular infection of bladder epithelial cells (BEC) by UPEC contributes to recurrent UTI in mouse models of infection. However, the mechanisms employed by UPEC to survive within BEC are incompletely understood. In this study we aimed to understand the role of host vesicular trafficking proteins in the intracellular survival of UPEC. Using a cell culture model of intracellular UPEC infection, we found that the small GTPase Rab35 facilitates UPEC survival in UPEC-containing vacuoles …

Intracellular Uropathogenic E. Coli Exploits Host Rab35 For Iron Acquisition And Survival Within Urinary Bladder Cells, Neha Dikshit, Pradeep Bist, Shannon N. Fenlon, Niyas Kudukkil Pulloor, Christelle En Lin Chua, Marci A. Scidmore, Jason A. Carlyon, Bor Len Tang, Swaine L. Chen, Bindu Sukumaran

Microbiology and Immunology Publications

Recurrent urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC) are common and morbid infections with limited therapeutic options. Previous studies have demonstrated that persistent intracellular infection of bladder epithelial cells (BEC) by UPEC contributes to recurrent UTI in mouse models of infection. However, the mechanisms employed by UPEC to survive within BEC are incompletely understood. In this study we aimed to understand the role of host vesicular trafficking proteins in the intracellular survival of UPEC. Using a cell culture model of intracellular UPEC infection, we found that the small GTPase Rab35 facilitates UPEC survival in UPEC-containing vacuoles …

Orientia Tsutsugamushi Ankyrin Repeat-Containing Protein Family Members Are Type 1 Secretion System Substrates That Traffic To The Host Cell Endoplasmic Reticulum, Lauren Viebrock, Sean M. Evans, Andrea R. Beyer, Charles L. Larson, Paul A. Beare, Hong Ge, Smita Singh, Kyle G. Rodino, Robert A. Heinzen, Allen L. Richards, Jason A. Carlyon

Microbiology and Immunology Publications

Scrub typhus is an understudied, potentially fatal infection that threatens one billion persons in the Asia-Pacific region. How the causative obligate intracellular bacterium, Orientia tsutsugamushi, facilitates its intracellular survival and pathogenesis is poorly understood. Many intracellular bacterial pathogens utilize the Type 1 (T1SS) or Type 4 secretion system (T4SS) to translocate ankyrin repeat-containing proteins (Anks) that traffic to distinct subcellular locations and modulate host cell processes. The O. tsutsugamushi genome encodes one of the largest known bacterial Ank repertoires plus T1SS and T4SS components. Whether these potential virulence factors are expressed during infection, how the Anks are potentially secreted, and …

Increased B Cell Adam10 In Allergic Patients And Th2 Prone Mice, Lauren Folgosa Cooley, Rebecca K. Martin, Hannah B. Zellner, Anne-Marie Irani, Cora Uram-Tuculescu, Mohey Eldin El Shikh, Daniel H. Conrad

Microbiology and Immunology Publications

ADAM10, as the sheddase of the low affinity IgE receptor (CD23), promotes IgE production and thus is a unique target for attenuating allergic disease. Herein, we describe that B cell levels of ADAM10, specifically, are increased in allergic patients and Th2 prone WT mouse strains (Balb/c and A/J). While T cell help augments ADAM10 expression, Balb WT B cells exhibit increased ADAM10 in the naïve state and even more dramatically increased ADAM10 after anti-CD40/IL4 stimulation compared C57 (Th1 prone) WT B cells. Furthermore, ADAM17 and TNF are reduced in allergic patients and Th2 prone mouse strains (Balb/c and A/J) compared …

Essential Domains Of Anaplasma Phagocytophilum Invasins Utilized To Infect Mammalian Host Cells, David Seidman, Kathryn S. Hebert, Hilary K. Truchan, Daniel P. Miller, Brittney K. Tegels, Richard T. Marconi, Jason A. Carlyon

Microbiology and Immunology Publications

Anaplasma phagocytophilum causes granulocytic anaplasmosis, an emerging disease of humans and domestic animals. The obligate intracellular bacterium uses its invasins OmpA, Asp14, and AipA to infect myeloid and non-phagocytic cells. Identifying the domains of these proteins that mediate binding and entry, and determining the molecular basis of their interactions with host cell receptors would significantly advance understanding of A. phagocytophilum infection. Here, we identified the OmpA binding domain as residues 59 to 74. Polyclonal antibody generated against a peptide spanning OmpA residues 59 to 74 inhibited A. phagocytophilum infection of host cells and binding to its receptor, sialyl Lewis x …

Identification Of Small-Molecule Inhibitors Against Meso-2, 6-Diaminopimelate Dehydrogenase From Porphyromonas Gingivalis, Victoria N. Stone, Hardik I. Parikh, Fadi El-Rami, Xiuchun Ge, Weihau Chen, Yan Zhang, Glen E. Kellogg, Ping Xu

Microbiology and Immunology Publications

Species-specific antimicrobial therapy has the potential to combat the increasing threat of antibiotic resistance and alteration of the human microbiome. We therefore set out to demonstrate the beginning of a pathogen-selective drug discovery method using the periodontal pathogen Porphyromonas gingivalis as a model. Through our knowledge of metabolic networks and essential genes we identified a “druggable” essential target, meso-diaminopimelate dehydrogenase, which is found in a limited number of species. We adopted a highthroughput virtual screen method on the ZINC chemical library to select a group of potential small-molecule inhibitors. Meso-diaminopimelate dehydrogenase from P. gingivalis was first expressed and purified in …

Phylogenetic And Syntenic Data Support A Single Horizontal Transference To Atrypanosoma Ancestor Of A Prokaryotic Proline Racemase Implicated In Parasite Evasion From Host Defences, Zuleima C. Caballero, Andre G. Costa-Martins, Robson C. Ferreira, João M P Alves, Myrna G. Serrano, Erney P. Camargo, Gregory A. Buck, Paola Minoprio, Marata M G Teixeira

Microbiology and Immunology Publications

Background

Proline racemase (PRAC) enzymes of Trypanosoma cruzi (TcPRAC), the agent of Chagas disease, and Trypanosoma vivax (TvPRAC), the agent of livestock trypanosomosis, have been implicated in the B-cells polyclonal activation contributing to immunosuppression and the evasion of host defences. The similarity to prokaryotic PRAC and the absence in Trypanosoma brucei andTrypanosoma congolense have raised many questions about the origin, evolution, and functions of trypanosome PRAC (TryPRAC) enzymes.

Findings

We identified TryPRAC homologs as single copy genes per haploid genome in 12 of 15Trypanosoma species, including T. cruzi and T. cruzi …

Hiv Protease Inhibitors Sensitize Human Head And Neck Squamous Carcinoma Cells To Radiation By Activating Endoplasmic Reticulum Stress, Runping Liu, Luyong Zhang, Jing Yang, Xiaoxuan Zhang, Ross Mikkelsen, Shiyu Song, Huiping Zhou

Microbiology and Immunology Publications

Background

Human head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. Despite significant advances in the delivery of treatment and surgical reconstruction, there is no significant improvement of mortality rates for this disease in the past decades. Radiotherapy is the core component of the clinical combinational therapies for HNSCC. However, the tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear. Our previous study has shown that …

Sjl Mice Infected With Acanthamoeba Castellanii Develop Central Nervous System Autoimmunity Through The Generation Of Cross-Reactive T Cells For Myelin Antigens, Chandirasegaran Massilamany, Francine Marciano-Cabral, Bruno Da Rocha-Azevedo, Melissa Jamerson, Arunakumar Gangaplara, David Steffen, Rana Zabad, Zsolt Illes, Raymond A. Sobel, Jay Reddy

Microbiology and Immunology Publications

We recently reported that Acanthamoeba castellanii (ACA), an opportunistic pathogen of the central nervous system (CNS) possesses mimicry epitopes for proteolipid protein (PLP) 139–151 and myelin basic protein 89–101, and that the epitopes induce experimental autoimmune encephalomyelitis (EAE) in SJL mice reminiscent of the diseases induced with their corresponding cognate peptides. We now demonstrate that mice infected with ACA also show the generation of cross-reactive T cells, predominantly for PLP 139–151, as evaluated by T cell proliferation and IAs/dextramer staining. We verified that PLP 139–151-sensitized lymphocytes generated in infected mice contained a high proportion of T helper 1 cytokine-producing cells, …

Reduction Of The Hiv Protease Inhibitor-Induced Er Stress And Inflammatory Response By Raltegravir In Macrophages, Xiaoxuan Zhang, Risheng Cao, Ruping Liu, Renping Zhao, Yi Huang, Emily C. Gurley, Phillip B. Hylemon, William M. Pandak, Guangji Wang, Luyong Zhang, Xiaokun Li, Huiping Zhou

Microbiology and Immunology Publications

Background

HIV protease inhibitor (PI), the core component of highly active antiretroviral treatment (HAART) for HIV infection, has been implicated in HAART-associated cardiovascular complications. Our previous studies have demonstrated that activation of endoplasmic reticulum (ER) stress is linked to HIV PI-induced inflammation and foam cell formation in macrophages. Raltegravir is a first-in-its-class HIV integrase inhibitor, the newest class of anti-HIV agents. We have recently reported that raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting ER stress. However, little information is available as to whether raltegravir would also prevent HIV PI-induced inflammatory …

Phase Variation Of Poly-N-Acetylglucosamine Expression In Staphylococcus Aureus, Jamie L. Brooks, Kimberly K. Jefferson

Microbiology and Immunology Publications

Polysaccharide intercellular adhesin (PIA), also known as poly-N-acetyl-β-(1–6)-glucosamine (PIA/PNAG) is an important component of Staphylococcus aureus biofilms and also contributes to resistance to phagocytosis. The proteins IcaA, IcaD, IcaB, and IcaC are encoded within the intercellular adhesin (ica) operon and synthesize PIA/PNAG. We discovered a mechanism of phase variation in PIA/PNAG expression that appears to involve slipped-strand mispairing. The process is reversible and RecA-independent, and involves the expansion and contraction of a simple tetranucleotide tandem repeat within icaC. Inactivation of IcaC results in a PIA/PNAG-negative phenotype. A PIA/PNAG-hyperproducing strain gained a fitness advantage in vitro following the …

P. Aeruginosa Sgnh Hydrolase-Like Proteins Algj And Algx Have Similar Topology But Separate And Distinct Roles In Alginate Acetylation, Perrin Baker, Tyler Ricer, Patrick J. Moynihan, Elena N. Kitova, Marthe T. C. Walvoort, Dustin J. Little, John C. Whitney, Karen Dawson, Joel T. Weadge, Howard Robinson, Dennis E. Ohman, Jeroen D. C. Codee, John S. Klassen, Anthony J. Clarke, P. Lynne Howell

Microbiology and Immunology Publications

The O-acetylation of polysaccharides is a common modification used by pathogenic organisms to protect against external forces. Pseudomonas aeruginosa secretes the anionic, O-acetylated exopolysaccharide alginate during chronic infection in the lungs of cystic fibrosis patients to form the major constituent of a protective biofilm matrix. Four proteins have been implicated in the O-acetylation of alginate, AlgIJF and AlgX. To probe the biological function of AlgJ, we determined its structure to 1.83 Å resolution. AlgJ is a SGNH hydrolase-like protein, which while structurally similar to the N-terminal domain of AlgX exhibits a distinctly different electrostatic surface potential. Consistent with other SGNH …