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1. Tocilizumab-treated convalescent COVID-19 patients retain the cross-neutralization potential against SARS-CoV-2 variants

Author

Chauvin, Camille, Levillayer, Laurine, Roumier, Mathilde, Nielly, Hubert, Roth, Claude, Karnam, Anupama, Bonam, Srinivasa Reddy, Bourgarit, Anne, Dubost, Clément, Bousquet, Aurore, Le Burel, Sébastien, Mestiri, Raphaële, Sene, Damien, Galland, Joris, Vasse, Marc, Groh, Matthieu, Le Marchand, Mathilde, Vassord-Dang, Camille, Gautier, Jean-François, Pham-Thi, Nhan, Verny, Christiane, Pitard, Bruno, Planchais, Cyril, Mouquet, Hugo, Paul, Richard, Simon-Loriere, Etienne, Bayry, Jagadeesh, Gilardin, Laurent, and Sakuntabhai, Anavaj

Published
2023
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11. IL-3 produced by T cells is crucial for basophil extravasation in hapten-induced allergic contact dermatitis.

Author

El Hachem, Carole, Marschall, Pierre, Hener, Pierre, Karnam, Anupama, Bonam, Srinivasa Reddy, Meyer, Pierre, Flatter, Eric, Birling, Marie-Christine, Bayry, Jagadeesh, and Mei Li

Subjects
BASOPHILS, T cells, CONTACT dermatitis, EXTRAVASATION, VASCULAR endothelium, SKIN aging
Abstract

Basophils have been recognized as a characterized cellular player for Th2 immune responses implicated in allergic diseases, but the mechanisms responsible for basophil recruitment to allergic skin remain not well understood. Using a hapten fluorescein isothiocyanate (FITC)-induced allergic contact dermatitis (ACD) mouse model, we show that basophils in FITC-treated IL-3-knockout mice are defective in crossing the vascular endothelium to enter the inflamed skin. By generating mice in which IL-3 is selectively ablated in T cells, we further demonstrate that IL-3 produced by T cells mediates basophil extravasation. Moreover, basophils sorted from FITC-treated IL-3-knockout mice exhibit a decreased expression of integrins Itgam, Itgb2, Itga2b and Itgb7, which are potentially implicated in extravasation process. Interestingly, we observed that these basophils had a reduced expression of retinaldehyde dehydrogenase 1 family member A2 (Aldh1a2), an enzyme responsible for the production of retinoic acid (RA), and administration of all-trans RA restored partially the extravasation of basophils in IL-3-knockout mice. Finally, we validate that IL-3 induces the expression of ALDH1A2 in primary human basophils, and provide further evidence that IL-3 stimulation induces the expression of integrins particularly ITGB7 in an RA-dependent manner. Together, our data propose a model that IL-3 produced by T cells activates ALDH1A2 expression by basophils, leading to the production of RA, which subsequently induces the expression of integrins crucially implicated in basophil extravasation to inflamed ACD skin. [ABSTRACT FROM AUTHOR]

Published
2023
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12. Wnt-β-Catenin Signaling in Human Dendritic Cells Mediates Regulatory T-Cell Responses to Fungi via the PD-L1 Pathway

Author

Karnam, Anupama, Bonam, Srinivasa Reddy, Rambabu, Naresh, Wong, Sarah Sze Wah, Aimanianda, Vishukumar, Bayry, Jagadeesh, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Indian Institut of Technology [Palakkad] (ITT Palakkad), We acknowledge financial support from Agence Nationale de la Recherche, France (ANR-19-CE17-0021 [BASIN]) and a research fellowship to A.K. from La Fondation pour la Recherche Médicale (no. FDT201805005552)., ANR-19-CE17-0021,BASIN,Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires(2019), HAL-SU, Gestionnaire, Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires - - BASIN2019 - ANR-19-CE17-0021 - AAPG2019 - VALID, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and École Pratique des Hautes Études (EPHE)

Subjects
CD4-Positive T-Lymphocytes, PD-L1, [SDV]Life Sciences [q-bio], chemical and pharmacologic phenomena, CD8-Positive T-Lymphocytes, Wnt-β-catenin, T-Lymphocytes, Regulatory, Microbiology, DC-SIGN, B7-H1 Antigen, regulatory T cells, Aspergillosis, Humans, dendritic cells, human, Wnt Signaling Pathway, beta Catenin, Tumor Necrosis Factor-alpha, Aspergillus fumigatus, hemic and immune systems, Wnt-b-catenin, Wnt signaling, QR1-502, Interleukin-10, [SDV] Life Sciences [q-bio], dectin-2, dectin-1, Research Article
Abstract

The signaling pathways activated following interaction between dendritic cells (DCs) and a pathogen determine the polarization of effector T-cell and regulatory T-cell (Treg) responses to the infection. Several recent studies, mostly in the context of bacterial infections, have shown that the Wnt/β-catenin pathway plays a major role in imparting tolerogenic features in DCs and in promotion of Treg responses. However, the significance of the Wnt/β-catenin pathway’s involvement in regulating the immune response to the fungal species is not known. Using Aspergillus fumigatus, a ubiquitous airborne opportunistic fungal species, we show here that fungi activate the Wnt/β-catenin pathway in human DCs and are critical for mediating the immunosuppressive Treg responses. Pharmacological inhibition of this pathway in DCs led to inhibition of maturation-associated molecules and interleukin 10 (IL-10) secretion without affecting the majority of the inflammatory cytokines. Furthermore, blockade of Wnt signaling in DCs suppressed DC-mediated Treg responses in CD4+ T cells and downregulated both tumor necrosis factor alpha (TNF-α) and IL-10 responses in CD8+ T cells. Mechanistically, induction of β-catenin pathway by A. fumigatus required C-type lectin receptors and promoted Treg polarization via the induction of programmed death-ligand 1 on DCs. Further investigation on the identity of fungal molecular patterns has revealed that the cell wall polysaccharides β-(1, 3)-glucan and α-(1, 3)-glucan, but not chitin, possess the capacity to activate the β-catenin pathway. Our data suggest that the Wnt/β-catenin pathway is a potential therapeutic target to selectively suppress the Treg response and to sustain the protective Th1 response in the context of invasive aspergillosis caused by A. fumigatus. IMPORTANCE The balance between effector CD4+ T-cell and immunosuppressive regulatory T-cell (Treg) responses determines the outcome of an infectious disease. The signaling pathways that regulate human CD4+ T-effector versus Treg responses to the fungi are not completely understood. By using Aspergillus fumigatus, a ubiquitous opportunistic fungal species, we show that fungi activate the Wnt/β-catenin pathway in human dendritic cells (DCs) that promotes Treg responses via induction of immune checkpoint molecule programmed death ligand 1 on DCs. Blockade of the Wnt/β-catenin pathway in DCs led to the selective inhibition of Treg without affecting the Th1 response. Dissection of the identity of A. fumigatus pathogen-associated molecular patterns (PAMPs) revealed that cell wall polysaccharides exhibit selectivity in their capacity to activate the β-catenin pathway in DCs. Our data thus provide a pointer that Wnt/β-catenin pathway represents potential therapeutic target to selectively suppress Treg responses and to sustain protective a Th1 response against invasive fungal diseases.

Published
2021
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13. Species-Specific Immunological Reactivities Depend on the Cell-Wall Organization of the Two Aspergillus, Aspergillus fumigatus and A. flavus

Author

Wong, Sarah Sze Wah, Venugopalan, Lakshmi Prabha, Beaussart, Audrey, Karnam, Anupama, Mohammed, Mohammed Razeeth Shait, Jayapal, Jeya Maheshwari, Bretagne, Stéphane, Bayry, Jagadeesh, Prajna, Lalitha, Kuppamuthu, Dharmalingam, Latgé, Jean-Paul, Aimanianda, Vishukumar, Mycologie moléculaire - Molecular Mycology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Aspergillus, Institut Pasteur [Paris], Aravind Medical Research Foundation (AMRF), Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), This work, including a postdoctoral fellowship to SW and a project assistantship to LV, was supported by the Centre Franco-Indien pour la Promotion de la Recherche Avancée (CEFIPRA) grant No. 5403-1. VA was also supported by ANR-FUNHYDRO (ANR-16S-CE110020-01) grant., ANR-16-CE11-0020,FUNHYDRO,Amyloïdes fonctionnels formés par les hydrophobines du pathogène fongique Aspergillus fumigatus(2016), HAL-SU, Gestionnaire, Amyloïdes fonctionnels formés par les hydrophobines du pathogène fongique Aspergillus fumigatus - - FUNHYDRO2016 - ANR-16-CE11-0020 - AAPG2016 - VALID, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and École Pratique des Hautes Études (EPHE)

Subjects
fungi, polysaccharides, conidia, bacterial infections and mycoses, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, drug susceptibility, Aspergillus, cell-wall organization, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, skin and connective tissue diseases, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, immunoreactivity, antifungal, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

International audience; Although belong to the same genus, Aspergillus fumigatus is primarily involved in invasive pulmonary infection, whereas Aspergillus flavus is a common cause of superficial infection. In this study, we compared conidia (the infective propagules) of these two Aspergillus species. In immunocompetent mice, intranasal inoculation with conidia of A. flavus resulted in significantly higher inflammatory responses in the lungs compared to mice inoculated with A. fumigatus conidia. In vitro assays revealed that the dormant conidia of A. flavus, unlike A. fumigatus dormant conidia, are immunostimulatory. The conidial surface of A. fumigatus was covered by a rodlet-layer, while that of A. flavus were presented with exposed polysaccharides. A. flavus harbored significantly higher number of proteins in its conidial cell wall compared to A. fumigatus conidia. Notably, β-1,3-glucan in the A. flavus conidial cell-wall showed significantly higher percentage of branching compared to that of A. fumigatus. The polysaccharides ensemble of A. flavus conidial cell wall stimulated the secretion of proinflammatory cytokines, and conidial cell wall associated proteins specifically stimulated IL-8 secretion from the host immune cells. Furthermore, the two species exhibited different sensitivities to antifungal drugs targeting cell wall polysaccharides, proposing the efficacy of species-specific treatment strategies. Overall, the species-specific organization of the conidial cell wall could be important in establishing infection by the two Aspergillus species.

Published
2021
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15. The Role of RodA-Conserved Cysteine Residues in the Aspergillus fumigatus Conidial Surface Organization

Author

Valsecchi, Isabel, primary, Stephen-Victor, Emmanuel, additional, Wong, Sarah Sze Wah, additional, Karnam, Anupama, additional, Sunde, Margaret, additional, Guijarro, J. Iñaki, additional, Rodríguez de Francisco, Borja, additional, Krüger, Thomas, additional, Kniemeyer, Olaf, additional, Brown, Gordon D., additional, Willment, Janet A., additional, Latgé, Jean-Paul, additional, Brakhage, Axel A., additional, Bayry, Jagadeesh, additional, and Aimanianda, Vishukumar, additional

Published
2020
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17. Intravenous immunoglobulin induces IL-4 in human basophils by signaling through 1 surface-bound IgE

Author

Galeotti, Caroline, Stephen-Victor, Emmanuel, Karnam, Anupama, Das, Mrinmoy, Gilardin, Laurent, Maddur, Mohan, Wymann, Sandra, Vonarburg, Cédric, Chevailler, Alain, Dimitrov, Jordan, Benveniste, Olivier, Bruhns, Pierre, Kaveri, Srini, Bayry, Jagadeesh, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Immunopathologie et immunointervention thérapeutique (CRC - Inserm U1138), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de médecine interne et d'immunologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), CLS Behring AG, Bern, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), LabEX IGO Immunothérapie Grand Ouest, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie, Université Paris Descartes and CSL Behring, Switzerland. CG is a recipient of fellowship from La Fondation pour la Recherche Médicale (FDM20150633674), France, ESV and AK are recipient of fellowships from Indo-French Center for Promotion of Advanced Research (CEFIPRA)., École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), Centre de recherche en Myologie – U974 SU-INSERM, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Gestionnaire, Hal Sorbonne Université

Subjects
FcγRIIB, DCIR, hemic and lymphatic diseases, FcεRI, Anti-IgE IgG, chemical and pharmacologic phenomena, hemic and immune systems, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Antisynthetase syndrome, DC-SIGN, Dermatomyositis, Polymyositis
Abstract

International audience; BACKGROUND: Therapeutic normal IgG or intravenous immunoglobulin (IVIG) exerts anti-inflammatory effects through several mutually nonexclusive mechanisms. Recent data in mouse models of autoimmune disease suggest that IVIG induces IL-4 in basophils by enhancing IL-33 in SIGN-related 1-positive innate cells. However, translational insight on these data is lacking.OBJECTIVE: We sought to investigate the effect of IVIG on human basophil functions.METHODS: Isolated circulating basophils from healthy donors were cultured in the presence of IL-3, IL-33, GM-CSF, thymic stromal lymphopoietin, or IL-25. The effect of IVIG and F(ab')2 and Fc IVIG fragments was examined based on expression of various surface molecules, phosphorylation of spleen tyrosine kinase, induction of cytokines, and histamine release. Basophil phenotypes were also analyzed from IVIG-treated patients with myopathy. Approaches, such as depletion of anti-IgE reactivity from IVIG, blocking antibodies, or inhibitors, were used to investigate the mechanisms.RESULTS: We report that IVIG directly induces activation of IL-3-primed human basophils, but IL-33 and other cytokines were dispensable for this effect. Activation of basophils by IVIG led to enhanced expression of CD69 and secretion of IL-4, IL-6, and IL-8. IVIG-treated patients with myopathy displayed enhanced expression of CD69 on basophils. The spleen tyrosine kinase pathway is implicated in these functions of IVIG and were mediated by F(ab')2 fragments. Mechanistically, IVIG induced IL-4 in human basophils by interacting with basophil surface-bound IgE but independent of FcγRII, type II Fc receptors, C-type lectin receptors, and sialic acid-binding immunoglobulin-like lectins.CONCLUSION: These results uncovered a pathway of promoting the TH2 response by IVIG through direct interaction of IgG with human basophils.

Published
2019
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21. Two Aspergillus species, A. flavus and A. fumigatus - a comparative study of their conidial surface properties and immunological reactivities

Author

Aimanianda, Vishukumar, Wong, Sarah S. W., L. Prabha, Venugopalan, Karnam, Anupama, Beaussart, Audrey, Bayry, Jagadeesh, J. Maheshwari, Jayapal, D, Kuppamuthu, Latgé, Jean-Paul, L, Prajna, Lassailly-Bondaz, Anne, Aspergillus, Institut Pasteur [Paris], Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Aravind Medical Research Foundation (AMRF), Institut Pasteur [Paris] (IP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), and Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)

Subjects
fungi, skin and connective tissue diseases, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

International audience; Though belonging to the Aspergillus genus, Aspergillus fumigatus is the major causative agent of fatal invasive aspergillosis, the systemic infection in immunocompromised, while A. flavus causes keratitis, a superficial health hazardous infection in immunocompetent individuals. In the present study, we have been exploring these two Aspergillus species in understanding differences in their preferred sites of infection. Structurally, there was a difference in their conidial sizes. A. fumigatus conidia were uniformly labelled by calcofluor white, negative for FITC conjugated Concanavalin-A or wheat-germ agglutinin labelling, while A. flavus conidia showed heterogenous labelling. The A. fumigatus conidia surface was covered by a uniform rodlet layer whereas A. flavus conidia showed heterogeneity; some conidia showing rodlet layer, but others with additional amorphous structure. A. flavus conidial cell wall contained significantly higher amount of chitin and lower amount of glucan in the alkali-insoluble fraction compared to A. fumigatus conidial cell wall. Whereas, in the mycelial morphotype, the A. flavus cell wall showed a significantly lower amount of glucan in cell wall and higher amounts of chitin and galactosamine containing polysaccharide in the alkali-insoluble fraction. A. fumigatus condia failed to activate human monocyte derived macrophages, dendritic cells and isolated neutrophils, but A. flavus conidia were immuno-stimulatory in their effect. Interestingly, though macrophages secreted both pro- and anti-inflammatory cytokines, dendritic cells and neutrophils secreted only IL-8 upon A. flavus conidial interaction. These observations may reason for their preferred mode and thus the site of infection

Published
2018

25. MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection

Author

Holla, Sahana, primary, Prakhar, Praveen, additional, Singh, Vikas, additional, Karnam, Anupama, additional, Mukherjee, Tanushree, additional, Mahadik, Kasturi, additional, Parikh, Pankti, additional, Singh, Amit, additional, Rajmani, R. S., additional, Ramachandra, Subbaraya G., additional, and Balaji, Kithiganahalli Narayanaswamy, additional

Published
2016
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26. IL-1β, But Mot Programed Death-1 and Programed Death ligand Pathway, is Critical for the Human Th17 Response to Mycobacterium tuberculosis.

Author

Stephen-Victor, Emmanuel, Sharma, Varun Kumar, Das, Mrinmoy, Karnam, Anupama, Saha, Chaitrali, Lecerf, Maxime, Galeotti, Caroline, Kaveri, Srinivas V., and Bayry, Jagadeesh

Subjects
MYCOBACTERIUM tuberculosis, DENDRITIC cells, LIGANDS (Biochemistry)
Abstract

The programed death-1 (PD-1)-programed death ligand-1 (PD-L1) and PD-L2 co-inhibitory pathway has been implicated in the evasion strategies of Mycobacterium tuberculosis. Specifically, M. tuberculosis-induced PD-L1 orchestrates expansion of regulatory T cells and suppression of Th1 response. However, the role of PD pathway in regulating Th17 response to M. tuberculosis has not been investigated. In the present report, we demonstrate that M. tuberculosis and M. tuberculosis-derived antigen fractions have differential abilities to mediate human monocyte- and dendritic cell (DC)-mediated Th17 response and were independent of expression of PD-L1 or PD-L2 on aforementioned antigen-presenting cells. Importantly, we observed that blockade of PD-L1 or PD-1 did not significantly modify either the frequencies of Th17 cells or the production of IL-17 from CD4+ T cells though IFN-γ response was significantly enhanced. On the contrary, IL-1β from monocytes and DCs were critical for the Th17 response to M. tuberculosis. Together, our results indicate that IL-1β, but not members of the programed death pathway, is critical for human Th17 response to M. tuberculosis. [ABSTRACT FROM AUTHOR]

Published
2016
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27. Wnt-β-Catenin Signaling in Human Dendritic Cells Mediates Regulatory T-Cell Responses to Fungi via the PD-L1 Pathway.

Author

Karnam A, Bonam SR, Rambabu N, Wong SSW, Aimanianda V, and Bayry J

Subjects
Aspergillosis genetics, Aspergillosis microbiology, B7-H1 Antigen genetics, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Humans, Interleukin-10 genetics, Interleukin-10 immunology, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha immunology, Wnt Signaling Pathway, beta Catenin genetics, Aspergillosis immunology, Aspergillus fumigatus physiology, B7-H1 Antigen immunology, Dendritic Cells immunology, T-Lymphocytes, Regulatory immunology, beta Catenin immunology
Abstract

The signaling pathways activated following interaction between dendritic cells (DCs) and a pathogen determine the polarization of effector T-cell and regulatory T-cell (Treg) responses to the infection. Several recent studies, mostly in the context of bacterial infections, have shown that the Wnt/β-catenin pathway plays a major role in imparting tolerogenic features in DCs and in promotion of Treg responses. However, the significance of the Wnt/β-catenin pathway's involvement in regulating the immune response to the fungal species is not known. Using Aspergillus fumigatus, a ubiquitous airborne opportunistic fungal species, we show here that fungi activate the Wnt/β-catenin pathway in human DCs and are critical for mediating the immunosuppressive Treg responses. Pharmacological inhibition of this pathway in DCs led to inhibition of maturation-associated molecules and interleukin 10 (IL-10) secretion without affecting the majority of the inflammatory cytokines. Furthermore, blockade of Wnt signaling in DCs suppressed DC-mediated Treg responses in CD4 + T cells and downregulated both tumor necrosis factor alpha (TNF-α) and IL-10 responses in CD8 + T cells. Mechanistically, induction of β-catenin pathway by A. fumigatus required C-type lectin receptors and promoted Treg polarization via the induction of programmed death-ligand 1 on DCs. Further investigation on the identity of fungal molecular patterns has revealed that the cell wall polysaccharides β-(1, 3)-glucan and α-(1, 3)-glucan, but not chitin, possess the capacity to activate the β-catenin pathway. Our data suggest that the Wnt/β-catenin pathway is a potential therapeutic target to selectively suppress the Treg response and to sustain the protective Th1 response in the context of invasive aspergillosis caused by A. fumigatus. IMPORTANCE The balance between effector CD4 + T-cell and immunosuppressive regulatory T-cell (Treg) responses determines the outcome of an infectious disease. The signaling pathways that regulate human CD4 + T-effector versus Treg responses to the fungi are not completely understood. By using Aspergillus fumigatus, a ubiquitous opportunistic fungal species, we show that fungi activate the Wnt/β-catenin pathway in human dendritic cells (DCs) that promotes Treg responses via induction of immune checkpoint molecule programmed death ligand 1 on DCs. Blockade of the Wnt/β-catenin pathway in DCs led to the selective inhibition of Treg without affecting the Th1 response. Dissection of the identity of A. fumigatus pathogen-associated molecular patterns (PAMPs) revealed that cell wall polysaccharides exhibit selectivity in their capacity to activate the β-catenin pathway in DCs. Our data thus provide a pointer that Wnt/β-catenin pathway represents potential therapeutic target to selectively suppress Treg responses and to sustain protective a Th1 response against invasive fungal diseases.

Published
2021
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28. Species-Specific Immunological Reactivities Depend on the Cell-Wall Organization of the Two Aspergillus , Aspergillus fumigatus and A. flavus .

Author

Wong SSW, Venugopalan LP, Beaussart A, Karnam A, Mohammed MRS, Jayapal JM, Bretagne S, Bayry J, Prajna L, Kuppamuthu D, Latgé JP, and Aimanianda V

Subjects
Animals, Aspergillus flavus, Cell Wall, Mice, Spores, Fungal, Aspergillus, Aspergillus fumigatus
Abstract

Although belong to the same genus, Aspergillus fumigatus is primarily involved in invasive pulmonary infection, whereas Aspergillus flavus is a common cause of superficial infection. In this study, we compared conidia (the infective propagules) of these two Aspergillus species. In immunocompetent mice, intranasal inoculation with conidia of A. flavus resulted in significantly higher inflammatory responses in the lungs compared to mice inoculated with A. fumigatus conidia. In vitro assays revealed that the dormant conidia of A. flavus , unlike A. fumigatus dormant conidia, are immunostimulatory. The conidial surface of A. fumigatus was covered by a rodlet-layer, while that of A. flavus were presented with exposed polysaccharides. A. flavus harbored significantly higher number of proteins in its conidial cell wall compared to A. fumigatus conidia. Notably, β-1,3-glucan in the A. flavus conidial cell-wall showed significantly higher percentage of branching compared to that of A. fumigatus . The polysaccharides ensemble of A. flavus conidial cell wall stimulated the secretion of proinflammatory cytokines, and conidial cell wall associated proteins specifically stimulated IL-8 secretion from the host immune cells. Furthermore, the two species exhibited different sensitivities to antifungal drugs targeting cell wall polysaccharides, proposing the efficacy of species-specific treatment strategies. Overall, the species-specific organization of the conidial cell wall could be important in establishing infection by the two Aspergillus species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wong, Venugopalan, Beaussart, Karnam, Mohammed, Jayapal, Bretagne, Bayry, Prajna, Kuppamuthu, Latgé and Aimanianda.)

Published
2021
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