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Article ; Online: Citrulline protects Streptococcus pyogenes from acid stress using the arginine deiminase pathway and the F1Fo-ATPase.

Cusumano, Zachary T / Caparon, Michael G

2015 Volume 197, Issue 7, Page(s) 1288–1296

Abstract: Unlabelled: A common stress encountered by both pathogenic and environmental bacteria is exposure to a low-pH environment, which can inhibit cell growth and lead to cell death. One major defense mechanism against this stress is the arginine deiminase ( ... ...

Abstract	Unlabelled: A common stress encountered by both pathogenic and environmental bacteria is exposure to a low-pH environment, which can inhibit cell growth and lead to cell death. One major defense mechanism against this stress is the arginine deiminase (ADI) pathway, which catabolizes arginine to generate two ammonia molecules and one molecule of ATP. While this pathway typically relies on the utilization of arginine, citrulline has also been shown to enter into the pathway and contribute to protection against acid stress. In the pathogenic bacterium Streptococcus pyogenes, the utilization of citrulline has been demonstrated to contribute to pathogenesis in a murine model of soft tissue infection, although the mechanism underlying its role in infection is unknown. To gain insight into this question, we analyzed a panel of mutants defective in different steps in the ADI pathway to dissect how arginine and citrulline protect S. pyogenes in a low-pH environment. While protection provided by arginine utilization occurred through the buffering of the extracellular environment, citrulline catabolism protection was pH independent, requiring the generation of ATP via the ADI pathway and a functional F1Fo-ATP synthase. This work demonstrates that arginine and citrulline catabolism protect against acid stress through distinct mechanisms and have unique contributions to virulence during an infection. Importance: An important aspect of bacterial pathogenesis is the utilization of host-derived nutrients during an infection for growth and virulence. Previously published work from our lab identified a unique role for citrulline catabolism in Streptococcus pyogenes during a soft tissue infection. The present article probes the role of citrulline utilization during this infection and its contribution to protection against acid stress. This work reveals a unique and concerted action between the catabolism of citrulline and the F1Fo-ATPase that function together to provide protection for bacteria in a low-pH environment. Dissection of these collaborative pathways highlights the complexity of bacterial infections and the contribution of atypical nutrients, such as citrulline, to pathogenesis.
MeSH term(s)	Acids ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Citrulline/pharmacology ; Culture Media ; Gene Expression Regulation, Bacterial/physiology ; Hydrogen-Ion Concentration ; Hydrolases/genetics ; Hydrolases/metabolism ; Mutation ; Proton-Translocating ATPases/genetics ; Proton-Translocating ATPases/metabolism ; Streptococcus pyogenes/drug effects ; Streptococcus pyogenes/genetics ; Streptococcus pyogenes/metabolism ; Stress, Physiological/drug effects
Chemical Substances	Acids ; Bacterial Proteins ; Culture Media ; Citrulline (29VT07BGDA) ; Hydrolases (EC 3.-) ; arginine deiminase (EC 3.5.3.6) ; Proton-Translocating ATPases (EC 3.6.3.14)
Language	English
Publishing date	2015-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2968-3
ISSN	1098-5530 ; 0021-9193
ISSN (online)	1098-5530
ISSN	0021-9193
DOI	10.1128/JB.02517-14
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Article ; Online: The FLRT3-UNC5B checkpoint pathway inhibits T cell-based cancer immunotherapies.

Prajapati, Kushal / Yan, Chuan / Yang, Qiqi / Arbitman, Steven / Fitzgerald, Daniel P / Sharee, Sasan / Shaik, Jahangheer / Bosiacki, Jason / Myers, Kayla / Paucarmayta, Ana / Johnson, Dorothy M / O'Neill, Thomas / Kundu, Subhadip / Cusumano, Zachary / Langermann, Solomon / Langenau, David M / Patel, Shashank / Flies, Dallas B

Science advances

2024 Volume 10, Issue 9, Page(s) eadj4698

Abstract: Cancers exploit coinhibitory receptors on T cells to escape tumor immunity, and targeting such mechanisms has shown remarkable clinical benefit, but in a limited subset of patients. We hypothesized that cancer cells mimic noncanonical mechanisms of early ...

Abstract	Cancers exploit coinhibitory receptors on T cells to escape tumor immunity, and targeting such mechanisms has shown remarkable clinical benefit, but in a limited subset of patients. We hypothesized that cancer cells mimic noncanonical mechanisms of early development such as axon guidance pathways to evade T cell immunity. Using gain-of-function genetic screens, we profiled axon guidance proteins on human T cells and their cognate ligands and identified fibronectin leucine-rich transmembrane protein 3 (FLRT3) as a ligand that inhibits T cell activity. We demonstrated that FLRT3 inhibits T cells through UNC5B, an axon guidance receptor that is up-regulated on activated human T cells. FLRT3 expressed in human cancers favored tumor growth and inhibited CAR-T and BiTE + T cell killing and infiltration in humanized cancer models. An FLRT3 monoclonal antibody that blocked FLRT3-UNC5B interactions reversed these effects in an immune-dependent manner. This study supports the concept that axon guidance proteins mimic T cell checkpoints and can be targeted for cancer immunotherapy.
MeSH term(s)	Humans ; T-Lymphocytes ; Neoplasms/genetics ; Neoplasms/therapy ; Immunotherapy ; Membrane Glycoproteins ; Netrin Receptors
Chemical Substances	FLRT3 protein, human ; Membrane Glycoproteins ; UNC5B protein, human ; Netrin Receptors
Language	English
Publishing date	2024-03-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adj4698
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Article ; Online: Adaptive evolution of the Streptococcus pyogenes regulatory aldolase LacD.1.

Cusumano, Zachary / Caparon, Michael

Journal of bacteriology

2013 Volume 195, Issue 6, Page(s) 1294–1304

Abstract: In the human-pathogenic bacterium Streptococcus pyogenes, the tagatose bisphosphate aldolase LacD.1 likely originated through a gene duplication event and was adapted to a role as a metabolic sensor for regulation of virulence gene transcription. ... ...

Abstract	In the human-pathogenic bacterium Streptococcus pyogenes, the tagatose bisphosphate aldolase LacD.1 likely originated through a gene duplication event and was adapted to a role as a metabolic sensor for regulation of virulence gene transcription. Although LacD.1 retains enzymatic activity, its ancestral metabolic function resides in the LacD.2 aldolase, which is required for the catabolism of galactose. In this study, we compared these paralogous proteins to identify characteristics correlated with divergence and novel function. Surprisingly, despite the fact that these proteins have identical active sites and 82% similarity in amino acid sequence, LacD.1 was less efficient at cleaving both fructose and tagatose bisphosphates. Analysis of kinetic properties revealed that LacD.1's adaptation was associated with a decrease in k(cat) and an increase in K(m). Construction and analysis of enzyme chimeras indicated that non-active-site residues previously associated with the variable activities of human aldolase isoenzymes modulated LacD.1's affinity for substrate. Mutant LacD.1 proteins engineered to have LacD.2-like levels of enzymatic efficiency lost the ability to function as regulators, suggesting that an alteration in efficiency was required for adaptation. In competition under growth conditions that mimic a deep-tissue environment, LacD.1 conferred a significant gain in fitness that was associated with its regulatory activity. Taken together, these data suggest that LacD.1's adaptation represents a form of neofunctionalization in which duplication facilitated the gain of regulatory function important for growth in tissue and pathogenesis.
MeSH term(s)	Aldehyde-Lyases/chemistry ; Aldehyde-Lyases/genetics ; Aldehyde-Lyases/metabolism ; Amino Acid Sequence ; Biological Evolution ; Catalytic Domain ; Evolution, Molecular ; Fructose/metabolism ; Fructose-Bisphosphate Aldolase/metabolism ; Gene Expression Regulation, Bacterial ; Genetic Variation ; Hexosediphosphates/metabolism ; Isoenzymes/chemistry ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Streptococcus pyogenes/enzymology ; Streptococcus pyogenes/genetics ; Streptococcus pyogenes/metabolism
Chemical Substances	Hexosediphosphates ; Isoenzymes ; Fructose (30237-26-4) ; D-tagatose 1,6-diphosphate (55529-38-9) ; Aldehyde-Lyases (EC 4.1.2.-) ; tagatose 1,6-diphosphate aldolase (EC 4.1.2.-) ; Fructose-Bisphosphate Aldolase (EC 4.1.2.13)
Language	English
Publishing date	2013-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2968-3
ISSN	1098-5530 ; 0021-9193
ISSN (online)	1098-5530
ISSN	0021-9193
DOI	10.1128/JB.01997-12
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Article: Adaptive Evolution of the Streptococcus pyogenes Regulatory Aldolase LacD.1

Cusumano, Zachary / Caparon, Michael

Journal of bacteriology. 2013 Mar. 15, v. 195, no. 6

2013

Abstract	In the human-pathogenic bacterium Streptococcus pyogenes, the tagatose bisphosphate aldolase LacD.1 likely originated through a gene duplication event and was adapted to a role as a metabolic sensor for regulation of virulence gene transcription. Although LacD.1 retains enzymatic activity, its ancestral metabolic function resides in the LacD.2 aldolase, which is required for the catabolism of galactose. In this study, we compared these paralogous proteins to identify characteristics correlated with divergence and novel function. Surprisingly, despite the fact that these proteins have identical active sites and 82% similarity in amino acid sequence, LacD.1 was less efficient at cleaving both fructose and tagatose bisphosphates. Analysis of kinetic properties revealed that LacD.1's adaptation was associated with a decrease in kcat and an increase in Km. Construction and analysis of enzyme chimeras indicated that non-active-site residues previously associated with the variable activities of human aldolase isoenzymes modulated LacD.1's affinity for substrate. Mutant LacD.1 proteins engineered to have LacD.2-like levels of enzymatic efficiency lost the ability to function as regulators, suggesting that an alteration in efficiency was required for adaptation. In competition under growth conditions that mimic a deep-tissue environment, LacD.1 conferred a significant gain in fitness that was associated with its regulatory activity. Taken together, these data suggest that LacD.1's adaptation represents a form of neofunctionalization in which duplication facilitated the gain of regulatory function important for growth in tissue and pathogenesis.
Keywords	Streptococcus pyogenes ; active sites ; amino acid sequences ; bacteria ; bacteriology ; chimerism ; enzyme activity ; evolution ; fructose ; fructose-bisphosphate aldolase ; galactose ; gene duplication ; humans ; isozymes ; metabolism ; mutants ; pathogenesis ; proteins ; transcription (genetics) ; virulence
Language	English
Dates of publication	2013-0315
Size	p. 1294-1304.
Publishing place	American Society for Microbiology
Document type	Article
ZDB-ID	2968-3
ISSN	1098-5530 ; 0021-9193
ISSN (online)	1098-5530
ISSN	0021-9193
DOI	10.1128/JB.01997-12
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Article ; Online: Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections.

Cusumano, Zachary T / Klein, Roger D / Hultgren, Scott J

Microbiology spectrum

2016 Volume 4, Issue 2

Abstract: Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial ... ...

Abstract	Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.
MeSH term(s)	Animals ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Bacteria/cytology ; Bacteria/drug effects ; Bacteria/enzymology ; Bacteria/genetics ; Bacterial Adhesion/drug effects ; Bacterial Infections/drug therapy ; Bacterial Infections/microbiology ; Bacterial Infections/prevention & control ; Biofilms/drug effects ; Drug Resistance, Bacterial ; Humans ; Molecular Targeted Therapy
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2016-05-17
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2165-0497
ISSN (online)	2165-0497
DOI	10.1128/microbiolspec.VMBF-0023-2015
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Article: Citrulline Protects Streptococcus pyogenes from Acid Stress Using the Arginine Deiminase Pathway and the F₁Fₒ-ATPase

Cusumano, Zachary T / Caparon, Michael G

Journal of bacteriology. 2015 Apr. 1, v. 197, no. 7

2015

Abstract: A common stress encountered by both pathogenic and environmental bacteria is exposure to a low-pH environment, which can inhibit cell growth and lead to cell death. One major defense mechanism against this stress is the arginine deiminase (ADI) pathway, ... ...

Abstract	A common stress encountered by both pathogenic and environmental bacteria is exposure to a low-pH environment, which can inhibit cell growth and lead to cell death. One major defense mechanism against this stress is the arginine deiminase (ADI) pathway, which catabolizes arginine to generate two ammonia molecules and one molecule of ATP. While this pathway typically relies on the utilization of arginine, citrulline has also been shown to enter into the pathway and contribute to protection against acid stress. In the pathogenic bacterium Streptococcus pyogenes , the utilization of citrulline has been demonstrated to contribute to pathogenesis in a murine model of soft tissue infection, although the mechanism underlying its role in infection is unknown. To gain insight into this question, we analyzed a panel of mutants defective in different steps in the ADI pathway to dissect how arginine and citrulline protect S. pyogenes in a low-pH environment. While protection provided by arginine utilization occurred through the buffering of the extracellular environment, citrulline catabolism protection was pH independent, requiring the generation of ATP via the ADI pathway and a functional F ₁F ₒ-ATP synthase. This work demonstrates that arginine and citrulline catabolism protect against acid stress through distinct mechanisms and have unique contributions to virulence during an infection. IMPORTANCE An important aspect of bacterial pathogenesis is the utilization of host-derived nutrients during an infection for growth and virulence. Previously published work from our lab identified a unique role for citrulline catabolism in Streptococcus pyogenes during a soft tissue infection. The present article probes the role of citrulline utilization during this infection and its contribution to protection against acid stress. This work reveals a unique and concerted action between the catabolism of citrulline and the F ₁F ₒ-ATPase that function together to provide protection for bacteria in a low-pH environment. Dissection of these collaborative pathways highlights the complexity of bacterial infections and the contribution of atypical nutrients, such as citrulline, to pathogenesis.
Keywords	Streptococcus pyogenes ; adenosine triphosphate ; ammonia ; animal models ; arginine ; arginine deiminase ; bacteria ; bacterial infections ; cell death ; cell growth ; citrulline ; metabolism ; mutants ; nutrients ; pathogenesis ; virulence
Language	English
Dates of publication	2015-0401
Size	p. 1288-1296.
Publishing place	American Society for Microbiology
Document type	Article
ZDB-ID	2968-3
ISSN	1098-5530 ; 0021-9193
ISSN (online)	1098-5530
ISSN	0021-9193
DOI	10.1128/JB.02517-14
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in

Port, Gary C / Cusumano, Zachary T / Tumminello, Paul R / Caparon, Michael G

mBio

2017 Volume 8, Issue 2

Abstract: SpxA is a unique transcriptional regulator highly conserved among members of the ... ...

Abstract	SpxA is a unique transcriptional regulator highly conserved among members of the phylum
MeSH term(s)	Aerobiosis ; Animals ; Bacterial Toxins/metabolism ; Disease Models, Animal ; Gene Deletion ; Mice ; Streptococcal Infections/microbiology ; Streptococcal Infections/pathology ; Streptococcus pyogenes/genetics ; Streptococcus pyogenes/pathogenicity ; Streptococcus pyogenes/physiology ; Stress, Physiological ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Virulence
Chemical Substances	Bacterial Toxins ; Transcription Factors
Language	English
Publishing date	2017-03-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.00288-17
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Article ; Online: Mannose-derived FimH antagonists: a promising anti-virulence therapeutic strategy for urinary tract infections and Crohn's disease.

Mydock-McGrane, Laurel K / Cusumano, Zachary T / Janetka, James W

Expert opinion on therapeutic patents

2016 Volume 26, Issue 2, Page(s) 175–197

Abstract: Introduction: Type 1 pili are utilized by Gram-negative bacteria to adhere to host tissue and thus are a key virulence factor in urinary tract infections (UTIs) and Crohn's disease (CD). This adhesion is mediated through specific binding of the terminal ...

Abstract	Introduction: Type 1 pili are utilized by Gram-negative bacteria to adhere to host tissue and thus are a key virulence factor in urinary tract infections (UTIs) and Crohn's disease (CD). This adhesion is mediated through specific binding of the terminal adhesin, FimH, to mannosylated host glycoproteins. FimH is essential for UTI pathogenesis and thus is a promising therapeutic target. Areas covered: Herein, we review the structural frameworks of FimH antagonists disclosed in the patent literature. X-ray crystallographic binding studies of D-mannose and early FimH antagonists have uncovered key molecular interactions. Exploiting this knowledge, mannosides with extraordinarily high binding affinities have been designed. Structure-activity relationships (SAR) and structure-property relationship (SPR) studies have resulted in the rapid development of orally bioavailable FimH antagonists with promising therapeutic potential for UTI and CD. Expert opinion: It is our opinion that biaryl or 'two-ring' mannosides, which represent the largest and most thoroughly tested class of FimH antagonists, also hold the most promise as a novel treatment for UTIs. These antagonists have also been shown to have efficacy in treating CD. Judging from the strong preclinical data, we predict that one or more FimH antagonists will be entering the clinic within the next 1-2 years.
MeSH term(s)	Adhesins, Escherichia coli ; Animals ; Anti-Bacterial Agents/administration & dosage ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Crohn Disease/drug therapy ; Crohn Disease/microbiology ; Drug Design ; Fimbriae Proteins/antagonists & inhibitors ; Gram-Negative Bacteria/drug effects ; Gram-Negative Bacteria/pathogenicity ; Gram-Negative Bacterial Infections/drug therapy ; Gram-Negative Bacterial Infections/microbiology ; Humans ; Mannose/chemistry ; Patents as Topic ; Structure-Activity Relationship ; Urinary Tract Infections/drug therapy ; Urinary Tract Infections/microbiology
Chemical Substances	Adhesins, Escherichia coli ; Anti-Bacterial Agents ; fimH protein, E coli ; Fimbriae Proteins (147680-16-8) ; Mannose (PHA4727WTP)
Language	English
Publishing date	2016
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1186201-4
ISSN	1744-7674 ; 0962-2594 ; 1354-3776
ISSN (online)	1744-7674
ISSN	0962-2594 ; 1354-3776
DOI	10.1517/13543776.2016.1131266
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Article ; Online: Development of an immunohistochemical assay for Siglec-15.

Shafi, Saba / Aung, Thazin Nwe / Robbins, Charles / Zugazagoitia, Jon / Vathiotis, Ioannis / Gavrielatou, Niki / Yaghoobi, Vesal / Fernandez, Aileen / Niu, Shuqiong / Liu, Linda N / Cusumano, Zachary T / Leelatian, Nalin / Cole, Kimberley / Wang, He / Homer, Robert / Herbst, Roy S / Langermann, Sol / Rimm, David L

Laboratory investigation; a journal of technical methods and pathology

2022 Volume 102, Issue 7, Page(s) 771–778

Abstract: Siglec-15, a member of sialic-acid binding immunoglobulin type lectins, is normally expressed by myeloid cells and upregulated in some human cancers and represents a promising new target for immunotherapy. While PD-L1 blockade is an important strategy ... ...

Abstract	Siglec-15, a member of sialic-acid binding immunoglobulin type lectins, is normally expressed by myeloid cells and upregulated in some human cancers and represents a promising new target for immunotherapy. While PD-L1 blockade is an important strategy for immunotherapy, its effectiveness is limited. The expression of Siglec-15 has been demonstrated to be predominantly mutually exclusive to PD-L1 in certain cancer histologies. Thus, there is significant opportunity for Siglec-15 as an immunotherapeutic target for patients that do not respond to PD-1/PD-L1 inhibition. The aim of this study was to prospectively develop an immunohistochemical (IHC) assay for Siglec-15 to be used as a companion diagnostic for future clinical trials. Here, we create and validate an IHC assay with a novel recombinant antibody to the cytoplasmic domain of Siglec-15. To find an enriched target, this antibody was first used in a quantitative fluorescence (QIF) assay to screen a broad range of tumor histologies to determine tumor types where Siglec-15 demonstrated high expression. Based on this and previous data, we focused on development of a chromogenic IHC assay for lung cancer. Then we developed a scoring system for this assay that has high concordance amongst pathologist readers. We then use this chromogenic IHC assay to test the expression of Siglec-15 in two cohorts of NSCLC. We found that this assay shows a higher level of staining in both tumor and immune cells compared to previous QIF assays utilizing a polyclonal antibody. However, similar to that study, only a small percentage of positive Siglec-15 cases showed high expression for PD-L1. This validated assay for Siglec-15 expression may support development of a companion diagnostic assay to enrich for patients expressing the Siglec-15 target for therapy.
MeSH term(s)	Antibodies, Monoclonal/therapeutic use ; B7-H1 Antigen/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Humans ; Immunohistochemistry ; Lung Neoplasms/metabolism ; Sialic Acid Binding Immunoglobulin-like Lectins/therapeutic use
Chemical Substances	Antibodies, Monoclonal ; B7-H1 Antigen ; Sialic Acid Binding Immunoglobulin-like Lectins
Language	English
Publishing date	2022-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	80178-1
ISSN	1530-0307 ; 0023-6837
ISSN (online)	1530-0307
ISSN	0023-6837
DOI	10.1038/s41374-022-00785-9
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Article ; Online: Streptococcus pyogenes arginine and citrulline catabolism promotes infection and modulates innate immunity.

Cusumano, Zachary T / Watson, Michael E / Caparon, Michael G

Infection and immunity

2013 Volume 82, Issue 1, Page(s) 233–242

Abstract: A bacterium's ability to acquire nutrients from its host during infection is an essential component of pathogenesis. For the Gram-positive pathogen Streptococcus pyogenes, catabolism of the amino acid arginine via the arginine deiminase (ADI) pathway ... ...

Abstract	A bacterium's ability to acquire nutrients from its host during infection is an essential component of pathogenesis. For the Gram-positive pathogen Streptococcus pyogenes, catabolism of the amino acid arginine via the arginine deiminase (ADI) pathway supplements energy production and provides protection against acid stress in vitro. Its expression is enhanced in murine models of infection, suggesting an important role in vivo. To gain insight into the function of the ADI pathway in pathogenesis, the virulence of mutants defective in each of its enzymes was examined. Mutants unable to use arginine (ΔArcA) or citrulline (ΔArcB) were attenuated for carriage in a murine model of asymptomatic mucosal colonization. However, in a murine model of inflammatory infection of cutaneous tissue, the ΔArcA mutant was attenuated but the ΔArcB mutant was hyperattenuated, revealing an unexpected tissue-specific role for citrulline metabolism in pathogenesis. When mice defective for the arginine-dependent production of nitric oxide (iNOS(-/-)) were infected with the ΔArcA mutant, cutaneous virulence was rescued, demonstrating that the ability of S. pyogenes to utilize arginine was dispensable in the absence of nitric oxide-mediated innate immunity. This work demonstrates the importance of arginine and citrulline catabolism and suggests a novel mechanism of virulence by which S. pyogenes uses its metabolism to modulate innate immunity through depletion of an essential host nutrient.
MeSH term(s)	Animals ; Arginine/metabolism ; Citrulline/metabolism ; Disease Models, Animal ; Gene Expression Regulation, Bacterial/physiology ; Hydrolases/physiology ; Immunity, Innate/physiology ; Macrophages/microbiology ; Mice ; Nitric Oxide Synthase Type II/deficiency ; Streptococcus pyogenes/growth & development ; Streptococcus pyogenes/immunology ; Streptococcus pyogenes/metabolism ; Streptococcus pyogenes/pathogenicity ; Virulence/physiology
Chemical Substances	Citrulline (29VT07BGDA) ; Arginine (94ZLA3W45F) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Hydrolases (EC 3.-) ; arginine deiminase (EC 3.5.3.6)
Language	English
Publishing date	2013-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/IAI.00916-13
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