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Article ; Online: Schnurri 3 promotes Th2 cytokine production during the late phase of T-cell antigen stimulation.

Cunha, Christina / Koike, Toru / Seki, Yoichi / Yamamoto, Mutsumi / Iwashima, Makio

2022 Volume 52, Issue 7, Page(s) 1077–1094

Abstract: Th1 and Th2 polarization is determined by the coordination of numerous factors including the affinity and strength of the antigen-receptor interaction, predominant cytokine environment, and costimulatory molecules present. Here, we show that Schnurri ( ... ...

Abstract	Th1 and Th2 polarization is determined by the coordination of numerous factors including the affinity and strength of the antigen-receptor interaction, predominant cytokine environment, and costimulatory molecules present. Here, we show that Schnurri (SHN) proteins have distinct roles in Th1 and Th2 polarization. SHN2 was previously found to block the induction of GATA3 and Th2 differentiation. We found that, in contrast to SHN2, SHN3 is critical for IL-4 production and Th2 polarization. Strength of stimulation controls SHN2 and SHN3 expression patterns, where higher doses of antigen receptor stimulation promoted SHN3 expression and IL-4 production, along with repression of SHN2 expression. SHN3-deficient T cells showed a substantial defect in IL-4 production and expression of AP-1 components, particularly c-Jun and Jun B. This loss of early IL-4 production led to reduced GATA3 expression and impaired Th2 differentiation. Together, these findings uncover SHN3 as a novel, critical regulator of Th2 development.
MeSH term(s)	Cell Differentiation ; Cytokines/metabolism ; DNA-Binding Proteins/metabolism ; GATA3 Transcription Factor/genetics ; GATA3 Transcription Factor/metabolism ; Interleukin-4/metabolism ; Th1 Cells ; Th2 Cells
Chemical Substances	Cytokines ; DNA-Binding Proteins ; GATA3 Transcription Factor ; Interleukin-4 (207137-56-2)
Language	English
Publishing date	2022-05-11
Publishing country	Germany
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202149633
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 85: Show issues

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Article ; Online: Polyamine-Linked Cholesterol Incorporation in Rift Valley Fever Virus Particles Promotes Infectivity.

Mastrodomenico, Vincent / LoMascolo, Natalie J / Cruz-Pulido, Yazmin E / Cunha, Christina R / Mounce, Bryan C

ACS infectious diseases

2022 Volume 8, Issue 8, Page(s) 1439–1448

Abstract: Viruses rely on an array of cellular metabolites to replicate and form progeny virions. One set of these molecules, polyamines, are small aliphatic molecules, which are abundant in most cells, that support virus infection; however, the precise roles of ... ...

Abstract	Viruses rely on an array of cellular metabolites to replicate and form progeny virions. One set of these molecules, polyamines, are small aliphatic molecules, which are abundant in most cells, that support virus infection; however, the precise roles of polyamines in virus infection remain incompletely understood. Recent work demonstrated that polyamine metabolism supports cellular cholesterol synthesis through translation of the key transcription factor SREBP2. Here, we show that the bunyavirus Rift Valley fever virus (RVFV) relies on both cholesterol and polyamines for virus infection. Depletion of cellular cholesterol or interruption of cholesterol trafficking negatively impacts RVFV infection. Cholesterol is incorporated into RVFV virions and mediates their infectivity in a polyamine-dependent manner; we find that the virus derived from polyamine-depleted cells lacks cholesterol within the virion membrane. Conversely, we find that virion-associated cholesterol is linked to the incorporation of spermidine within the virion. Our prior work demonstrated that polyamines facilitate pH-mediated fusion and genome release, which may be a consequence of cholesterol depletion within virions. Thus, our work highlights the metabolic connection between polyamines and cholesterol synthesis to impact bunyavirus infection. These data demonstrate the connectedness between cellular metabolic pathways and reveal potential avenues of therapeutic intervention.
MeSH term(s)	Animals ; Cholesterol ; Polyamines ; Rift Valley fever virus/genetics ; Virion/genetics
Chemical Substances	Polyamines ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2022-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.2c00071
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Article ; Online: Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity.

Tate, Patrick M / Mastrodomenico, Vincent / Cunha, Christina / McClure, Joshua / Barron, Annelise E / Diamond, Gill / Mounce, Bryan C / Kirshenbaum, Kent

ACS infectious diseases

2023 Volume 9, Issue 8, Page(s) 1508–1522

Abstract: The development of durable new antiviral therapies is challenging, as viruses can evolve rapidly to establish resistance and attenuate therapeutic efficacy. New compounds that selectively target conserved viral features are attractive therapeutic ... ...

Abstract	The development of durable new antiviral therapies is challenging, as viruses can evolve rapidly to establish resistance and attenuate therapeutic efficacy. New compounds that selectively target conserved viral features are attractive therapeutic candidates, particularly for combating newly emergent viral threats. The innate immune system features a sustained capability to combat pathogens through production of antimicrobial peptides (AMPs); however, these AMPs have shortcomings that can preclude clinical use. The essential functional features of AMPs have been recapitulated by peptidomimetic oligomers, yielding effective antibacterial and antifungal agents. Here, we show that a family of AMP mimetics, called peptoids, exhibit direct antiviral activity against an array of enveloped viruses, including the key human pathogens Zika, Rift Valley fever, and chikungunya viruses. These data suggest that the activities of peptoids include engagement and disruption of viral membrane constituents. To investigate how these peptoids target lipid membranes, we used liposome leakage assays to measure membrane disruption. We found that liposomes containing phosphatidylserine (PS) were markedly sensitive to peptoid treatment; in contrast, liposomes formed exclusively with phosphatidylcholine (PC) showed no sensitivity. In addition, chikungunya virus containing elevated envelope PS was more susceptible to peptoid-mediated inactivation. These results indicate that peptoids mimicking the physicochemical characteristics of AMPs act through a membrane-specific mechanism, most likely through preferential interactions with PS. We provide the first evidence for the engagement of distinct viral envelope lipid constituents, establishing an avenue for specificity that may enable the development of a new family of therapeutics capable of averting the rapid development of resistance.
MeSH term(s)	Animals ; Humans ; Antiviral Agents/pharmacology ; Peptidomimetics/pharmacology ; Phosphatidylserines ; Liposomes ; Peptoids/pharmacology ; Peptoids/chemistry ; Zika Virus ; Zika Virus Infection
Chemical Substances	Antiviral Agents ; Peptidomimetics ; Phosphatidylserines ; Liposomes ; Peptoids
Language	English
Publishing date	2023-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.3c00063
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Article ; Online: TGF-β suppresses RasGRP1 expression and supports regulatory T cell resistance against p53-induced CD28-dependent T-cell apoptosis.

Takami, Mariko / Cunha, Christina / Motohashi, Shinichiro / Nakayama, Toshinori / Iwashima, Makio

European journal of immunology

2018 Volume 48, Issue 12, Page(s) 1938–1943

Abstract: Thymus-derived regulatory T cells (tTregs) play pivotal roles in immunological self-tolerance and homeostasis. A majority of tTregs are reactive to self-antigens and are constantly exposed to antigenic stimulation. Despite this continuous stimulation, ... ...

Abstract	Thymus-derived regulatory T cells (tTregs) play pivotal roles in immunological self-tolerance and homeostasis. A majority of tTregs are reactive to self-antigens and are constantly exposed to antigenic stimulation. Despite this continuous stimulation, tTreg and conventional T-cell populations remain balanced during homeostasis, but the mechanisms controlling this balance are unknown. We previously reported a form of activation-induced cell death, which is dependent on p53 (p53-induced CD28-dependent T-cell apoptosis, PICA). Under PICA-inducing conditions, tTregs survive while a majority of conventional T cells undergo apoptosis, suggesting there is a survival mechanism that protects tTregs. Here, we report that the expression of RasGRP1 (Ras guanyl-releasing protein 1) is required for PICA, as conventional T cells isolated from RasGRP1-deficient mice become resistant to PICA. After continuous stimulation, tTregs express a substantially lower amount of RasGRP1 compared to conventional T cells. This reduced expression of RasGRP1 is dependent on TGF-β, as addition of TGF-β to conventional T cells reduces RasGRP1 expression. Conversely, RasGRP1 expression in tTregs increases when TGF-β signaling is inhibited. Together, these data show that RasGRP1 expression is repressed in tTregs by TGF-β signaling and suggests that reduced RasGRP1 expression is critical for tTregs to resist apoptosis caused by continuous antigen exposure.
MeSH term(s)	Animals ; Apoptosis ; CD28 Antigens/metabolism ; Cell Differentiation ; Cells, Cultured ; Gene Expression Regulation ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Receptor Cross-Talk ; Receptors, Antigen, T-Cell/metabolism ; Signal Transduction ; T-Lymphocytes, Regulatory/immunology ; Thymus Gland/immunology ; Transforming Growth Factor beta/metabolism ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	CD28 Antigens ; Guanine Nucleotide Exchange Factors ; Rasgrp1 protein, mouse ; Receptors, Antigen, T-Cell ; Transforming Growth Factor beta ; Tumor Suppressor Protein p53
Language	English
Publishing date	2018-10-24
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201847587
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 85: Show issues

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Article ; Online: Activated human Foxp3

Nelson, Alexander / Cunha, Christina / Nishimura, Michael I / Iwashima, Makio

Cytokine

2018 Volume 111, Page(s) 454–459

Abstract: TNF is a multifunctional cytokine that is critical to host defense against pathogens but can also drive the pathophysiology of inflammatory diseases. Inhibition of TNF occasionally causes exacerbation of some autoimmune diseases, suggesting a role for ... ...

Abstract	TNF is a multifunctional cytokine that is critical to host defense against pathogens but can also drive the pathophysiology of inflammatory diseases. Inhibition of TNF occasionally causes exacerbation of some autoimmune diseases, suggesting a role for TNF in the regulation of immune homeostasis. Here, we demonstrate that human peripheral blood CD4
MeSH term(s)	Autoimmune Diseases/immunology ; CD4-Positive T-Lymphocytes/immunology ; Cell Line ; Cell Proliferation/physiology ; Endothelial Cells/immunology ; Forkhead Transcription Factors/immunology ; Humans ; Interleukin-2/immunology ; Interleukin-2 Receptor alpha Subunit/immunology ; Receptors, Tumor Necrosis Factor, Type II/immunology ; T-Lymphocytes, Regulatory/immunology ; Tumor Necrosis Factor-alpha/immunology
Chemical Substances	FOXP3 protein, human ; Forkhead Transcription Factors ; Interleukin-2 ; Interleukin-2 Receptor alpha Subunit ; Receptors, Tumor Necrosis Factor, Type II ; TNF protein, human ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2018-06-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1018055-2
ISSN	1096-0023 ; 1043-4666
ISSN (online)	1096-0023
ISSN	1043-4666
DOI	10.1016/j.cyto.2018.05.036
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Zs.A 2840: Show issues

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Article ; Online: Human CD36

Lee, Jessica G / Jaeger, Kathleen E / Seki, Yoichi / Wei Lim, Yi / Cunha, Christina / Vuchkovska, Aleksandra / Nelson, Alexander J / Nikolai, Anya / Kim, Dan / Nishimura, Michael / Knight, Katherine L / White, Paula / Iwashima, Makio

Immunology

2021 Volume 163, Issue 3, Page(s) 293–309

Abstract: The fetal and neonatal immune systems are uniquely poised to generate tolerance to self, maternal and environmental antigens encountered in the womb and shortly after birth. However, the tolerogenic nature of fetal and neonatal immunity can be ... ...

Abstract	The fetal and neonatal immune systems are uniquely poised to generate tolerance to self, maternal and environmental antigens encountered in the womb and shortly after birth. However, the tolerogenic nature of fetal and neonatal immunity can be detrimental in the context of pathogens, leading to overwhelming bacterial infections or chronic viral infections. A variety of mechanisms contribute to fetal and neonatal tolerance, including a propensity to generate Foxp3
MeSH term(s)	Adult ; CD36 Antigens/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Differentiation ; Cells, Cultured ; Fetal Blood/cytology ; Fetus ; Forkhead Transcription Factors/metabolism ; Graft vs Host Disease/immunology ; Humans ; Immune Tolerance ; Immunosuppression Therapy ; Lymphocyte Activation ; Monocytes/immunology ; T-Box Domain Proteins/genetics ; T-Lymphocytes, Regulatory/immunology ; Transplantation, Heterologous
Chemical Substances	CD36 Antigens ; FOXP3 protein, human ; Forkhead Transcription Factors ; T-Box Domain Proteins ; T-box transcription factor TBX21
Language	English
Publishing date	2021-03-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/imm.13316
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Ud II Zs.181: Show issues

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Article: Malignant catarrhal fever: Understanding molecular diagnostics in context of epidemiology

Li, Hong / Cunha, Christina W / Taus, Naomi S

International Journal of Molecular Sciences. 2011, v. 12, no. 10

2011

Abstract: Malignant catarrhal fever (MCF) is a frequently fatal disease, primarily of ruminants, caused by a group of gammaherpesviruses. Due to complexities of pathogenesis and epidemiology in various species, which are either clinically-susceptible or reservoir ... ...

Abstract	Malignant catarrhal fever (MCF) is a frequently fatal disease, primarily of ruminants, caused by a group of gammaherpesviruses. Due to complexities of pathogenesis and epidemiology in various species, which are either clinically-susceptible or reservoir hosts, veterinary clinicians face significant challenges in laboratory diagnostics. The recent development of specific assays for viral DNA and antibodies has expanded and improved the inventory of laboratory tests and opened new opportunities for use of MCF diagnostics. Issues related to understanding and implementing appropriate assays for specific diagnostic needs must be addressed in order to take advantage of molecular diagnostics in the laboratory.
Keywords	DNA ; antibodies ; assays ; disease diagnosis ; disease reservoirs ; inventories ; malignant catarrhal fever ; molecular epidemiology ; pathogenesis ; ruminants
Language	English
Size	p. 6881-6893.
Document type	Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1661-6596
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms12106881
Database	NAL-Catalogue (AGRICOLA)

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Article: Identification of Plant Extracts that Inhibit the Formation of Diabetes-Linked IAPP Amyloid.

Fuentes, Ana Lucia / Hennessy, Kathleen / Pascual, Jacob / Pepe, Nicole / Wang, In / Santiago, Alexander / Chaggan, Cynthia / Martinez, Jessica / Rivera, Evelyn / Cota, Paola / Cunha, Christina / Nogaj, Luiza A / Moffet, David A

Journal of herbal medicine

2016 Volume 6, Issue 1, Page(s) 37–41

Abstract: The extracts of 27 vegetables, spices and herbs were screened for their functional ability to inhibit the aggregation of islet amyloid polypeptide (IAPP, amylin) into toxic amyloid aggregates. The aggregation of IAPP has been directly linked to the death ...

Abstract	The extracts of 27 vegetables, spices and herbs were screened for their functional ability to inhibit the aggregation of islet amyloid polypeptide (IAPP, amylin) into toxic amyloid aggregates. The aggregation of IAPP has been directly linked to the death of pancreatic β-islet cells in type 2 diabetes. Inhibiting the aggregation of IAPP is believed to have the potential to slow, if not prevent entirely, the progression of this disease. As vegetables, spices and herbs are known to possess many different positive health effects, the extracts of 27 plants (abundant within the United States and spanning several plant families) were screened for their ability to inhibit the formation of toxic IAPP aggregates. Their anti-amyloid activities were assessed through (1) thioflavin T binding assays, (2) visualization of amyloid fibers using atomic force microscopy and (3) cell rescue studies. From this research, mint, peppermint, red bell pepper and thyme emerged as possessing the greatest anti-amyloid activity.
Language	English
Publishing date	2016-02-05
Publishing country	Netherlands
Document type	Journal Article
ISSN	2210-8033
ISSN	2210-8033
DOI	10.1016/j.hermed.2015.11.001
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Article: Identification of plant extracts that inhibit the formation of diabetes-linked IAPP amyloid

Journal of herbal medicine. 2016 Mar., v. 6, no. 1

2016

Abstract	The extracts of 27 vegetables, spices and herbs were screened for their functional ability to inhibit the aggregation of islet amyloid polypeptide (IAPP, amylin) into toxic amyloid aggregates. The aggregation of IAPP has been directly linked to the death of pancreatic β-islet cells in type 2 diabetes. Inhibiting the aggregation of IAPP is believed to have the potential to slow, if not prevent entirely, the progression of this disease. As vegetables, spices and herbs are known to possess many different positive health effects, the extracts of 27 plants (abundant within the United States and Europe and spanning several plant families) were screened for their ability to inhibit the formation of toxic IAPP aggregates. Their anti-amyloid activities were assessed through (1) thioflavin T binding assays, (2) visualization of amyloid fibers using atomic force microscopy and (3) cell rescue studies. From this research, mint, peppermint, red bell pepper and thyme emerged as possessing the greatest anti-amyloid activity.
Keywords	Mentha piperita nothosubsp. piperita ; amyloid ; atomic force microscopy ; death ; health effects assessments ; herbal medicines ; mint ; noninsulin-dependent diabetes mellitus ; polypeptides ; spices ; sweet peppers ; thyme ; toxicity ; Europe ; United States
Language	English
Dates of publication	2016-03
Size	p. 37-41.
Publishing place	Elsevier GmbH
Document type	Article
ISSN	2210-8033
DOI	10.1016/j.hermed.2015.11.001
Database	NAL-Catalogue (AGRICOLA)

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