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Resolution of Gastric Cancer-Promoting Inflammation: A Novel Strategy for Anti-cancer Therapy.
Piazuelo MB, Riechelmann RP, Wilson KT, Algood HMS
(2019) Curr Top Microbiol Immunol 421: 319-359
MeSH Terms: Cytokines, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation, Stomach Neoplasms, Tumor Microenvironment
Show Abstract · Added June 6, 2019
The connection between inflammation and cancer was initially recognized by Rudolf Virchow in the nineteenth century. During the last decades, a large body of evidence has provided support to his hypothesis, and now inflammation is recognized as one of the hallmarks of cancer, both in etiopathogenesis and ongoing tumor growth. Infection with the pathogen Helicobacter pylori is the primary causal factor in 90% of gastric cancer (GC) cases. As we increase our understanding of how chronic inflammation develops in the stomach and contributes to carcinogenesis, there is increasing interest in targeting cancer-promoting inflammation as a strategy to treat GC. Moreover, once cancer develops and anti-cancer immune responses are suppressed, there is evidence of a substantial shift in the microenvironment and new targets for immune therapy emerge. In this chapter, we provide insight into inflammation-related factors, including T lymphocytes, macrophages, pro-inflammatory chemokines, and cytokines, which promote H. pylori-associated GC initiation and growth. While intervening with chronic inflammation is not a new practice in rheumatology or gastroenterology, this approach has not been fully explored for its potential to prevent carcinogenesis or to contribute to the treatment of GC. This review highlights current and possible strategies for therapeutic intervention including (i) targeting pro-inflammatory mediators, (ii) targeting growth factors and pathways involved in angiogenesis in the gastric tumor microenvironment, and (iii) enhancing anti-tumor immunity. In addition, we highlight a significant number of clinical trials and discuss the importance of individual tumor characterization toward offering personalized immune-related therapy.
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8 MeSH Terms
VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection.
Altobelli A, Bauer M, Velez K, Cover TL, Müller A
(2019) MBio 10:
MeSH Terms: Animals, Bacterial Proteins, Cell Differentiation, Dendritic Cells, Disease Models, Animal, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Immune Evasion, Interleukin-10, Interleukin-23, Lung, Macrophages, Mice, Mucous Membrane, Myeloid Cells, T-Lymphocytes, Regulatory, Transforming Growth Factor beta
Show Abstract · Added April 11, 2019
The gastric bacterium causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the -host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the immunomodulator VacA to -specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3) regulatory T cells that are neuropilin negative and express RORγt. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-β expression in macrophages. Taken together, the results are consistent with the idea that creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors persistence, and affects immunity at distant sites. has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.
Copyright © 2019 Altobelli et al.
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18 MeSH Terms
Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of .
Grunenwald CM, Choby JE, Juttukonda LJ, Beavers WN, Weiss A, Torres VJ, Skaar EP
(2019) MBio 10:
MeSH Terms: Animals, Cation Transport Proteins, Disease Models, Animal, Gene Expression Regulation, Bacterial, Homeostasis, Iron, Manganese, Mice, Inbred BALB C, Microbial Viability, Oxidative Stress, Staphylococcal Infections, Staphylococcus aureus, Transcription Factors, Transcription, Genetic, Virulence
Show Abstract · Added April 2, 2019
Manganese (Mn) is an essential micronutrient critical for the pathogenesis of , a significant cause of human morbidity and mortality. Paradoxically, excess Mn is toxic; therefore, maintenance of intracellular Mn homeostasis is required for survival. Here we describe a Mn exporter in , MntE, which is a member of the cation diffusion facilitator (CDF) protein family and conserved among Gram-positive pathogens. Upregulation of transcription in response to excess Mn is dependent on the presence of MntR, a transcriptional repressor of the Mn uptake system. Inactivation of or leads to reduced growth in media supplemented with Mn, demonstrating MntE is required for detoxification of excess Mn. Inactivation of results in elevated levels of intracellular Mn, but reduced intracellular iron (Fe) levels, supporting the hypothesis that MntE functions as a Mn efflux pump and Mn efflux influences Fe homeostasis. Strains inactivated for are more sensitive to the oxidants NaOCl and paraquat, indicating Mn homeostasis is critical for resisting oxidative stress. Furthermore, and are required for full virulence of during infection, suggesting experiences Mn toxicity Combined, these data support a model in which MntR controls Mn homeostasis by balancing transcriptional repression of and induction of , both of which are critical for pathogenesis. Thus, Mn efflux contributes to bacterial survival and virulence during infection, establishing MntE as a potential antimicrobial target and expanding our understanding of Mn homeostasis. Manganese (Mn) is generally viewed as a critical nutrient that is beneficial to pathogenic bacteria due to its function as an enzymatic cofactor and its capability of acting as an antioxidant; yet paradoxically, high concentrations of this transition metal can be toxic. In this work, we demonstrate utilizes the cation diffusion facilitator (CDF) family protein MntE to alleviate Mn toxicity through efflux of excess Mn. Inactivation of leads to a significant reduction in resistance to oxidative stress and mediated mortality within a mouse model of systemic infection. These results highlight the importance of MntE-mediated Mn detoxification in intracellular Mn homeostasis, resistance to oxidative stress, and virulence. Therefore, this establishes MntE as a potential target for development of anti- therapeutics.
Copyright © 2019 Grunenwald et al.
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Assessing Acinetobacter baumannii Virulence and Persistence in a Murine Model of Lung Infection.
Palmer LD, Green ER, Sheldon JR, Skaar EP
(2019) Methods Mol Biol 1946: 289-305
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Acute Disease, Animals, Bacterial Load, Biopsy, Disease Models, Animal, Flow Cytometry, Immunity, Immunohistochemistry, Mice, Pneumonia, Bacterial, Virulence
Show Abstract · Added April 2, 2019
Acinetobacter baumannii is a Gram-negative opportunistic pathogen and a leading cause of ventilator-associated pneumonia. Murine models of A. baumannii lung infection allow researchers to experimentally assess A. baumannii virulence and host response. Intranasal administration of A. baumannii models acute lung infection. This chapter describes the methods to test A. baumannii virulence in a murine model of lung infection, including assessing the competitive index of a bacterial mutant and the associated inflammatory responses.
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13 MeSH Terms
Intracellular Degradation of Helicobacter pylori VacA Toxin as a Determinant of Gastric Epithelial Cell Viability.
Foegeding NJ, Raghunathan K, Campbell AM, Kim SW, Lau KS, Kenworthy AK, Cover TL, Ohi MD
(2019) Infect Immun 87:
MeSH Terms: Autophagy, Bacterial Proteins, Cell Line, Cell Survival, Epithelial Cells, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Hydrogen-Ion Concentration, Muramidase, Protein Stability, Protein Transport, Proteolysis
Show Abstract · Added February 7, 2019
VacA is a secreted pore-forming toxin that induces cell vacuolation and contributes to the pathogenesis of gastric cancer and peptic ulcer disease. We observed that purified VacA has relatively little effect on the viability of AGS gastric epithelial cells, but the presence of exogenous weak bases such as ammonium chloride (NHCl) enhances the susceptibility of these cells to VacA-induced vacuolation and cell death. Therefore, we tested the hypothesis that NHCl augments VacA toxicity by altering the intracellular trafficking of VacA or inhibiting intracellular VacA degradation. We observed VacA colocalization with LAMP1- and LC3-positive vesicles in both the presence and absence of NHCl, indicating that NHCl does not alter VacA trafficking to lysosomes or autophagosomes. Conversely, we found that supplemental NHCl significantly increases the intracellular stability of VacA. By conducting experiments using chemical inhibitors, stable ATG5 knockdown cell lines, and ATG16L1 knockout cells (generated using CRISPR/Cas9), we show that VacA degradation is independent of autophagy and proteasome activity but dependent on lysosomal acidification. We conclude that weak bases like ammonia, potentially generated during infection by urease and other enzymes, enhance VacA toxicity by inhibiting toxin degradation.
Copyright © 2019 American Society for Microbiology.
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14 MeSH Terms
Structural basis of a potent human monoclonal antibody against Zika virus targeting a quaternary epitope.
Long F, Doyle M, Fernandez E, Miller AS, Klose T, Sevvana M, Bryan A, Davidson E, Doranz BJ, Kuhn RJ, Diamond MS, Crowe JE, Rossmann MG
(2019) Proc Natl Acad Sci U S A 116: 1591-1596
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cryoelectron Microscopy, Disease Models, Animal, Epitopes, Humans, Male, Mice, Mice, Inbred C57BL, Vaccination, Viral Envelope Proteins, Zika Virus, Zika Virus Infection
Show Abstract · Added March 31, 2019
Zika virus (ZIKV) is a major human pathogen and member of the genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-resolution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.
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Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate Colitis while Dysregulating the Inflammatory Response.
Maseda D, Zackular JP, Trindade B, Kirk L, Roxas JL, Rogers LM, Washington MK, Du L, Koyama T, Viswanathan VK, Vedantam G, Schloss PD, Crofford LJ, Skaar EP, Aronoff DM
(2019) MBio 10:
MeSH Terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, CD4-Positive T-Lymphocytes, Clostridium Infections, Gastrointestinal Microbiome, Indomethacin, Intestinal Mucosa, Mice, Neutrophils, Prostaglandins, Survival Analysis
Show Abstract · Added April 7, 2019
infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and the intestinal pathology associated with CDI in mice. We demonstrated that in -infected animals, indomethacin treatment led to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by increased recruitment of intestinal neutrophils and CD4 cells and also by a perturbation of the gut microbiota. Together, these data implicate NSAIDs in the disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses. infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.
Copyright © 2019 Maseda et al.
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11 MeSH Terms
Current Understanding of Humoral Immunity to Enterovirus D68.
Vogt MR, Crowe JE
(2018) J Pediatric Infect Dis Soc 7: S49-S53
MeSH Terms: Animals, Antibodies, Neutralizing, Disease Models, Animal, Enterovirus D, Human, Enterovirus Infections, Epitopes, Humans, Immunity, Humoral, Nervous System Diseases, Respiratory Tract Infections, Seroepidemiologic Studies, Vaccination, Viral Vaccines
Show Abstract · Added March 31, 2019
Enterovirus D68 (EV-D68) is a pathogen that causes outbreaks of respiratory illness across the world, mostly in children, and can be especially severe in those with asthma. Clusters of acute flaccid myelitis, a poliomyelitis-like neuromuscular weakness syndrome, often occur concurrent with EV-D68 respiratory outbreaks. Seroepidemiologic studies have found that the serum of nearly everyone older than 2 to 5 years contains anti-EV-D68 neutralizing antibodies, which suggests that EV-D68 is a ubiquitous pathogen of childhood. However, knowledge of the viral epitopes against which the humoral immune response is directed is only inferred from previous studies of related viruses. Although neutralizing antibodies protect newborn mice from lethal EV-D68 inoculation via nonphysiologic routes, cotton rats have a mixed phenotype of both benefit and possible exacerbation when inoculated intranasally. The human antibody response to EV-D68 needs to be studied further to clarify the role of antibodies in protection versus pathogenesis, which might differ among respiratory and neurologic disease phenotypes.
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Heme sensing and detoxification by HatRT contributes to pathogenesis during Clostridium difficile infection.
Knippel RJ, Zackular JP, Moore JL, Celis AI, Weiss A, Washington MK, DuBois JL, Caprioli RM, Skaar EP
(2018) PLoS Pathog 14: e1007486
MeSH Terms: Animals, Bacterial Proteins, Clostridium Infections, Clostridium difficile, Genes, Bacterial, Heme, Male, Mice, Mice, Inbred C57BL, Operon, Virulence
Show Abstract · Added April 7, 2019
Clostridium difficile is a Gram-positive, spore-forming anaerobic bacterium that infects the colon, causing symptoms ranging from infectious diarrhea to fulminant colitis. In the last decade, the number of C. difficile infections has dramatically risen, making it the leading cause of reported hospital acquired infection in the United States. Bacterial toxins produced during C. difficile infection (CDI) damage host epithelial cells, releasing erythrocytes and heme into the gastrointestinal lumen. The reactive nature of heme can lead to toxicity through membrane disruption, membrane protein and lipid oxidation, and DNA damage. Here we demonstrate that C. difficile detoxifies excess heme to achieve full virulence within the gastrointestinal lumen during infection, and that this detoxification occurs through the heme-responsive expression of the heme activated transporter system (HatRT). Heme-dependent transcriptional activation of hatRT was discovered through an RNA-sequencing analysis of C. difficile grown in the presence of a sub-toxic concentration of heme. HatRT is comprised of a TetR family transcriptional regulator (hatR) and a major facilitator superfamily transporter (hatT). Strains inactivated for hatR or hatT are more sensitive to heme toxicity than wild-type. HatR binds heme, which relieves the repression of the hatRT operon, whereas HatT functions as a heme efflux pump. In a murine model of CDI, a strain inactivated for hatT displayed lower pathogenicity in a toxin-independent manner. Taken together, these data suggest that HatR senses intracellular heme concentrations leading to increased expression of the hatRT operon and subsequent heme efflux by HatT during infection. These results describe a mechanism employed by C. difficile to relieve heme toxicity within the host, and set the stage for the development of therapeutic interventions to target this bacterial-specific system.
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Increased breadth of HIV-1 neutralization achieved by diverse antibody clones each with limited neutralization breadth.
Chukwuma VU, Kose N, Sather DN, Sapparapu G, Falk R, King H, Singh V, Lampley R, Malherbe DC, Ditto NT, Sullivan JT, Barnes T, Doranz BJ, Labranche CC, Montefiori DC, Kalams SA, Haigwood NL, Crowe JE
(2018) PLoS One 13: e0209437
MeSH Terms: Antibodies, Neutralizing, Antibody Diversity, B-Lymphocytes, Cells, Cultured, Epitope Mapping, Epitopes, HIV Antibodies, HIV Infections, HIV-1, Humans, Hybridomas, Neutralization Tests, env Gene Products, Human Immunodeficiency Virus
Show Abstract · Added March 31, 2019
Broadly neutralizing antibodies (bNAbs) are rarely elicited by current human immunodeficiency virus type 1 (HIV-1) vaccine designs, but the presence of bNAbs in naturally infected individuals may be associated with high plasma viral loads, suggesting that the magnitude, duration, and diversity of viral exposure may contribute to the development of bNAbs. Here, we report the isolation and characterization of a panel of human monoclonal antibodies (mAbs) from two subjects who developed broadly neutralizing autologous antibody responses during HIV-1 infection. In both subjects, we identified collections of mAbs that exhibited specificity only to a few autologous envelopes (Envs), with some mAbs exhibiting specificity only to a subset of Envs within the quasispecies of a particular sample at one time point. Neutralizing antibodies (NAbs) isolated from these subjects mapped mostly to epitopes in the Env V3 loop region and the CD4 binding site. None of the individual neutralizing mAbs recovered exhibited the cumulative breadth of neutralization present in the serum of the subjects. Surprisingly, however, the activity of polyclonal mixtures comprising individual mAbs that each possessed limited neutralizing activity, could achieve increased breadth of neutralizing activity against autologous isolates. While a single broadly neutralizing antibody targeting one epitope can mediate neutralization breadth, the findings presented here suggest that a cooperative polyclonal process mediated by diverse antibodies with more limited breadth targeting multiple epitopes also can achieve neutralization breadth against HIV-1.
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13 MeSH Terms