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Massive platelet activation and thrombotic events characterize severe COVID-19, highlighting their critical role in SARS-CoV-2-induced immunopathology. Since there is a well-described expansion of myeloid-derived suppressor cells (MDSC) in severe COVID-19, we evaluated their possible role in platelet activation during SARS-CoV-2 infection. During COVID-19, a lower plasmatic L-arginine level was observed compared to healthy donors, which correlated with MDSC frequency. Additionally, activated GPIIb/IIIa complex (PAC-1) expression was higher on platelets from severe COVID-19 patients compared to healthy controls and inversely correlated with L-arginine plasmatic concentration. Notably, MDSC were able to induce PAC-1 expression in vitro by reducing L-arginine concentration, indicating a direct role of PMN-MDSC in platelet activation. Accordingly, we found a positive correlation between ex vivo platelet PAC-1 expression and PMN-MDSC frequency. Overall, our data demonstrate the involvement of PMN-MDSC in triggering platelet activation during COVID-19, highlighting a novel role of MDSC in driving COVID-19 pathogenesis.
Alessandra Sacchi; Germana Grassi; Stefania Notari; Simona Gili; Veronica Bordoni; Eleonora Tartaglia; Rita Casetti; Eleonora Cimini; Davide Mariotti; Gabriele Garotto; Alessia Beccacece; Luisa Marchioni; Michele Bibas; Emanuele Nicastri; Giuseppe Ippolito; Chiara Agrati. Expansion of Myeloid Derived Suppressor Cells Contributes to Platelet Activation by L-Arginine Deprivation during SARS-CoV-2 Infection. Cells 2021, 10, 2111 .
AMA StyleAlessandra Sacchi, Germana Grassi, Stefania Notari, Simona Gili, Veronica Bordoni, Eleonora Tartaglia, Rita Casetti, Eleonora Cimini, Davide Mariotti, Gabriele Garotto, Alessia Beccacece, Luisa Marchioni, Michele Bibas, Emanuele Nicastri, Giuseppe Ippolito, Chiara Agrati. Expansion of Myeloid Derived Suppressor Cells Contributes to Platelet Activation by L-Arginine Deprivation during SARS-CoV-2 Infection. Cells. 2021; 10 (8):2111.
Chicago/Turabian StyleAlessandra Sacchi; Germana Grassi; Stefania Notari; Simona Gili; Veronica Bordoni; Eleonora Tartaglia; Rita Casetti; Eleonora Cimini; Davide Mariotti; Gabriele Garotto; Alessia Beccacece; Luisa Marchioni; Michele Bibas; Emanuele Nicastri; Giuseppe Ippolito; Chiara Agrati. 2021. "Expansion of Myeloid Derived Suppressor Cells Contributes to Platelet Activation by L-Arginine Deprivation during SARS-CoV-2 Infection." Cells 10, no. 8: 2111.
In severe COVID-19, which is characterized by blood clots and neutrophil-platelet aggregates in the circulating blood and different tissues, an increased incidence of cardiovascular complications and venous thrombotic events has been reported. The inflammatory storm that characterizes severe infections may act as a driver capable of profoundly disrupting the complex interplay between platelets, endothelium, and leukocytes, thus contributing to the definition of COVID-19-associated coagulopathy. In this frame, P-selectin represents a key molecule expressed on endothelial cells and on activated platelets, and contributes to endothelial activation, leucocyte recruitment, rolling, and tissue migration. Briefly, we describe the current state of knowledge about P-selectin involvement in COVID-19 pathogenesis, its possible use as a severity marker and as a target for host-directed therapeutic intervention.
Chiara Agrati; Alessandra Sacchi; Eleonora Tartaglia; Alessandra Vergori; Roberta Gagliardini; Alessandra Scarabello; Michele Bibas. The Role of P-Selectin in COVID-19 Coagulopathy: An Updated Review. International Journal of Molecular Sciences 2021, 22, 7942 .
AMA StyleChiara Agrati, Alessandra Sacchi, Eleonora Tartaglia, Alessandra Vergori, Roberta Gagliardini, Alessandra Scarabello, Michele Bibas. The Role of P-Selectin in COVID-19 Coagulopathy: An Updated Review. International Journal of Molecular Sciences. 2021; 22 (15):7942.
Chicago/Turabian StyleChiara Agrati; Alessandra Sacchi; Eleonora Tartaglia; Alessandra Vergori; Roberta Gagliardini; Alessandra Scarabello; Michele Bibas. 2021. "The Role of P-Selectin in COVID-19 Coagulopathy: An Updated Review." International Journal of Molecular Sciences 22, no. 15: 7942.
Complex systems are inherently multilevel and multiscale systems. The infectious disease system is considered a complex system resulting from the interaction between three sub-systems (host, pathogen, and environment) organized into a hierarchical structure, ranging from the cellular to the macro-ecosystem level, with multiscales. Therefore, to describe infectious disease phenomena that change through time and space and at different scales, we built a model framework where infectious disease must be considered the set of biological responses of human hosts to pathogens, with biological pathways shared with other pathologies in an ecological interaction context. In this paper, we aimed to design a framework for building a disease model for COVID-19 based on current literature evidence. The model was set up by identifying the molecular pathophysiology related to the COVID-19 phenotypes, collecting the mechanistic knowledge scattered across scientific literature and bioinformatic databases, and integrating it using a logical/conceptual model systems biology. The model framework building process began from the results of a domain-based literature review regarding a multiomics approach to COVID-19. This evidence allowed us to define a framework of COVID-19 conceptual model and to report all concepts in a multilevel and multiscale structure. The same interdisciplinary working groups that carried out the scoping review were involved. The conclusive result is a conceptual method to design multiscale models of infectious diseases. The methodology, applied in this paper, is a set of partially ordered research and development activities that result in a COVID-19 multiscale model.
Francesco Messina; Chiara Montaldo; Isabella Abbate; Manuela Antonioli; Veronica Bordoni; Giulia Matusali; Alessandra Sacchi; Emanuela Giombini; Gian Fimia; Mauro Piacentini; Maria Capobianchi; Francesco Lauria; Giuseppe Ippolito; on behalf of COVID-19 Scoping Review Working Group. Rationale and Criteria for a COVID-19 Model Framework. Viruses 2021, 13, 1309 .
AMA StyleFrancesco Messina, Chiara Montaldo, Isabella Abbate, Manuela Antonioli, Veronica Bordoni, Giulia Matusali, Alessandra Sacchi, Emanuela Giombini, Gian Fimia, Mauro Piacentini, Maria Capobianchi, Francesco Lauria, Giuseppe Ippolito, on behalf of COVID-19 Scoping Review Working Group. Rationale and Criteria for a COVID-19 Model Framework. Viruses. 2021; 13 (7):1309.
Chicago/Turabian StyleFrancesco Messina; Chiara Montaldo; Isabella Abbate; Manuela Antonioli; Veronica Bordoni; Giulia Matusali; Alessandra Sacchi; Emanuela Giombini; Gian Fimia; Mauro Piacentini; Maria Capobianchi; Francesco Lauria; Giuseppe Ippolito; on behalf of COVID-19 Scoping Review Working Group. 2021. "Rationale and Criteria for a COVID-19 Model Framework." Viruses 13, no. 7: 1309.
Vaccination is the main public health measure to reduce SARS-CoV-2 transmission and hospitalization, and a massive worldwide scientific effort resulted in the rapid development of effective vaccines. This work aimed to define the dynamics of humoral and cell-mediated immune response in a cohort of health care workers (HCWs) who received a two-dose BNT162b2-mRNA vaccination. The serological response was evaluated by quantifying the anti-RBD and neutralizing antibodies. The cell-mediated response was performed by a whole blood test quantifying Th1 cytokines (IFN-γ, TNF-α, IL-2), produced in response to spike peptides. The BNT162b2-mRNA vaccine induced both humoral and cell-mediated immune responses against spike peptides in virtually all HCWs without previous SARS-CoV-2 infection, with a moderate inverse relation with age in the anti-RBD response. Spike-specific T cells produced several Th1 cytokines (IFN-γ, TNF-α, and IL-2), which correlated with the specific-serological response. Overall, our study describes the ability of the BNT162b2 mRNA vaccine to elicit a coordinated neutralizing humoral and spike-specific T cell response in HCWs. Assessing the dynamics of these parameters by an easy immune monitoring protocol can allow for the evaluation of the persistence of the vaccine response in order to define the optimal vaccination strategy.
Chiara Agrati; Concetta Castilletti; Delia Goletti; Silvia Meschi; Alessandra Sacchi; Giulia Matusali; Veronica Bordoni; Linda Petrone; Daniele Lapa; Stefania Notari; Valentina Vanini; Francesca Colavita; Alessandra Aiello; Alessandro Agresta; Chiara Farroni; Germana Grassi; Sara Leone; Francesco Vaia; Maria Capobianchi; Giuseppe Ippolito; Vincenzo Puro; on behalf of the INMI COVID-190 Vaccine Study Group. Coordinate Induction of Humoral and Spike Specific T-Cell Response in a Cohort of Italian Health Care Workers Receiving BNT162b2 mRNA Vaccine. Microorganisms 2021, 9, 1315 .
AMA StyleChiara Agrati, Concetta Castilletti, Delia Goletti, Silvia Meschi, Alessandra Sacchi, Giulia Matusali, Veronica Bordoni, Linda Petrone, Daniele Lapa, Stefania Notari, Valentina Vanini, Francesca Colavita, Alessandra Aiello, Alessandro Agresta, Chiara Farroni, Germana Grassi, Sara Leone, Francesco Vaia, Maria Capobianchi, Giuseppe Ippolito, Vincenzo Puro, on behalf of the INMI COVID-190 Vaccine Study Group. Coordinate Induction of Humoral and Spike Specific T-Cell Response in a Cohort of Italian Health Care Workers Receiving BNT162b2 mRNA Vaccine. Microorganisms. 2021; 9 (6):1315.
Chicago/Turabian StyleChiara Agrati; Concetta Castilletti; Delia Goletti; Silvia Meschi; Alessandra Sacchi; Giulia Matusali; Veronica Bordoni; Linda Petrone; Daniele Lapa; Stefania Notari; Valentina Vanini; Francesca Colavita; Alessandra Aiello; Alessandro Agresta; Chiara Farroni; Germana Grassi; Sara Leone; Francesco Vaia; Maria Capobianchi; Giuseppe Ippolito; Vincenzo Puro; on behalf of the INMI COVID-190 Vaccine Study Group. 2021. "Coordinate Induction of Humoral and Spike Specific T-Cell Response in a Cohort of Italian Health Care Workers Receiving BNT162b2 mRNA Vaccine." Microorganisms 9, no. 6: 1315.
The immunological mechanisms underlying the clinical presentation of SARS-CoV-2 infection and those influencing the disease outcome remain to be defined. Myeloid-derived suppressor cells (MDSC) have been described to be highly increased during COVID-19, however, their role remains elusive. We performed an in depth analysis of MDSC in 128 SARS-CoV-2 infected patients. Polymorphonuclear (PMN)-MDSC expanded during COVID-19, in particular in patients who required intensive care treatments, and correlated with IL-1β, IL-6, IL-8, and TNF-α plasma levels. PMN-MDSC inhibited T-cells IFN-γ production upon SARS-CoV-2 peptides stimulation, through TGF-β- and iNOS-mediated mechanisms, possibly contrasting virus elimination. Accordingly, a multivariate regression analysis found a strong association between PMN-MDSC percentage and fatal outcome of the disease. The PMN-MDSC frequency was higher in non-survivors than survivors at the admission time, followed by a decreasing trend. Interestingly, this trend was associated with IL-6 increase in non-survivors but not in survivors. In conclusion, this study indicates PMN-MDSC as a novel factor in the pathogenesis of SARS-CoV2 infection, and open up to new therapeutic options.
Alessandra Sacchi; Germana Grassi; Veronica Bordoni; Patrizia Lorenzini; Eleonora Cimini; Rita Casetti; Eleonora Tartaglia; Luisa Marchioni; Nicola Petrosillo; Fabrizio Palmieri; Gianpiero D’Offizi; Stefania Notari; Massimo Tempestilli; Maria Rosaria Capobianchi; Emanuele Nicastri; Markus Maeurer; Alimuddin Zumla; Franco Locatelli; Andrea Antinori; Giuseppe Ippolito; Chiara Agrati. Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome. Cell Death & Disease 2020, 11, 1 -9.
AMA StyleAlessandra Sacchi, Germana Grassi, Veronica Bordoni, Patrizia Lorenzini, Eleonora Cimini, Rita Casetti, Eleonora Tartaglia, Luisa Marchioni, Nicola Petrosillo, Fabrizio Palmieri, Gianpiero D’Offizi, Stefania Notari, Massimo Tempestilli, Maria Rosaria Capobianchi, Emanuele Nicastri, Markus Maeurer, Alimuddin Zumla, Franco Locatelli, Andrea Antinori, Giuseppe Ippolito, Chiara Agrati. Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome. Cell Death & Disease. 2020; 11 (10):1-9.
Chicago/Turabian StyleAlessandra Sacchi; Germana Grassi; Veronica Bordoni; Patrizia Lorenzini; Eleonora Cimini; Rita Casetti; Eleonora Tartaglia; Luisa Marchioni; Nicola Petrosillo; Fabrizio Palmieri; Gianpiero D’Offizi; Stefania Notari; Massimo Tempestilli; Maria Rosaria Capobianchi; Emanuele Nicastri; Markus Maeurer; Alimuddin Zumla; Franco Locatelli; Andrea Antinori; Giuseppe Ippolito; Chiara Agrati. 2020. "Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome." Cell Death & Disease 11, no. 10: 1-9.
An expansion of effector/activated Vδ2 T-cells was recently described in acute Zika virus (ZIKV)-infected patients, but their role in the protective immune response was not clarified. The aim of this study was to define the antiviral activity of Vδ2 T-cells against ZIKV-infected cells. The Vδ2 T-cells expansion and their cytotoxic activity against ZIKV-infected cells were tested in vitro and analyzed by RT-PCR and flow cytometry. We found that ZIKV infection was able to induce Vδ2 T-cells expansion and sensitized A549 cells to Vδ2-mediated killing. Indeed, expanded Vδ2 T-cells killed ZIKV-infected cells through degranulation and perforin release. Moreover, ZIKV infection was able to increase the expression on A549 cells of NKG2D ligands (NKG2DLs), namely MICA, MICB, and ULBP2, at both the mRNA and protein levels, suggesting the possible involvement of these molecules in the recognition by NKG2D-expressing Vδ2 T-cells. Indeed, the killing of ZIKV-infected cells by expanded Vδ2 T-cells was mediated by NKG2D/NKG2DL interaction as NKG2D neutralization abrogated Vδ2 cytotoxicity. Our data showed a strong antiviral activity of Vδ2 T-cells against ZIKV-infected cells, suggesting their involvement in the protective immune response. Other studies are necessary to investigate whether the lack of Vδ2 T-cells expansion in vivo may be associated with disease complications.
Eleonora Cimini; Alessandra Sacchi; Sara De Minicis; Veronica Bordoni; Rita Casetti; Germana Grassi; Francesca Colavita; Concetta Castilletti; Maria Rosaria Capobianchi; Giuseppe Ippolito; Maria Giovanna Desimio; Margherita Doria; Chiara Agrati. Vδ2 T-Cells Kill ZIKV-Infected Cells by NKG2D-Mediated Cytotoxicity. Microorganisms 2019, 7, 350 .
AMA StyleEleonora Cimini, Alessandra Sacchi, Sara De Minicis, Veronica Bordoni, Rita Casetti, Germana Grassi, Francesca Colavita, Concetta Castilletti, Maria Rosaria Capobianchi, Giuseppe Ippolito, Maria Giovanna Desimio, Margherita Doria, Chiara Agrati. Vδ2 T-Cells Kill ZIKV-Infected Cells by NKG2D-Mediated Cytotoxicity. Microorganisms. 2019; 7 (9):350.
Chicago/Turabian StyleEleonora Cimini; Alessandra Sacchi; Sara De Minicis; Veronica Bordoni; Rita Casetti; Germana Grassi; Francesca Colavita; Concetta Castilletti; Maria Rosaria Capobianchi; Giuseppe Ippolito; Maria Giovanna Desimio; Margherita Doria; Chiara Agrati. 2019. "Vδ2 T-Cells Kill ZIKV-Infected Cells by NKG2D-Mediated Cytotoxicity." Microorganisms 7, no. 9: 350.
Myeloid derived suppressor cells (MDSC) is a heterogeneous subset of immature and mature cells of the myeloid lineage, undergoing expansion during pathologic conditions, and able to perform strong immune suppressive functions. It has been shown that cryopreservation selectively impacts the polimorphonuclear (PMN) MDSC viability and recovery, and alters the correct analysis of MDSC subsets. In laboratory practice, cryopreservation is often inevitable, in particular in multicenter studies where samples have to be shipped to a centralized laboratory. Aim of the present work was to set out a new protocol to evaluate the frequency of PMN-MDSC in thawed cells by flow-cytometry. PBMC were isolated from HIV+ patients and healthy donors, and were cryopreserved for at least ten days. After thawing, two different protocols were used: 1. standard protocol (SP) consisting of staining with the antibodies mix and then fixing with formalin 1%; 2. thawed protocol (TP) in which fixation foregoes the staining with the antibodies mix. Results showed that PMN-MDSC frequency in ex vivo PBMC evaluated by means TP was comparable to that analysed by SP, indicating that the protocol did not alter PMN-MDSC quantification in ex vivo cells. We then demonstrated that PMN-MDSC frequency in thawed PBMC tested by TP was almost identical to the frequency obtained in ex vivo cells evaluated by using SP. However, we observed that after three hours of culture post-thawing, PMN-MDSC were not assessable anymore with both SP and TP. In conclusion, we herein demonstrated that fixing PBMC soon after thawing and before antibody staining allows preservation of PMN-MDSC integrity and a reliable cells quantification. Thus, it is possible to phenotipically identify PMN-MDSC in cryopreserved PBMC, consenting adequate test precision and accuracy as well as making multicentre research more feasible.
Alessandra Sacchi; Nicola Tumino; Germana Grassi; Rita Casetti; Eleonora Cimini; Veronica Bordoni; Adriana Ammassari; Andrea Antinori; Chiara Agrati. A new procedure to analyze polymorphonuclear myeloid derived suppressor cells in cryopreserved samples cells by flow cytometry. PLoS ONE 2018, 13, e0202920 .
AMA StyleAlessandra Sacchi, Nicola Tumino, Germana Grassi, Rita Casetti, Eleonora Cimini, Veronica Bordoni, Adriana Ammassari, Andrea Antinori, Chiara Agrati. A new procedure to analyze polymorphonuclear myeloid derived suppressor cells in cryopreserved samples cells by flow cytometry. PLoS ONE. 2018; 13 (8):e0202920.
Chicago/Turabian StyleAlessandra Sacchi; Nicola Tumino; Germana Grassi; Rita Casetti; Eleonora Cimini; Veronica Bordoni; Adriana Ammassari; Andrea Antinori; Chiara Agrati. 2018. "A new procedure to analyze polymorphonuclear myeloid derived suppressor cells in cryopreserved samples cells by flow cytometry." PLoS ONE 13, no. 8: e0202920.
The impact of early antiretroviral therapy (ART) during Primary HIV Infection (PHI) on the hematopoietic progenitor cells (HPCs) homeostasis is not available. This study aimed to characterize HPCs and their relationship with cytokines regulating progenitors function in ART-treated patients with PHI. We enrolled HIV infected patients treated with ART during PHI. Circulating HPCs, Lymphoid-HPCs (L-HPCs) frequency and plasmatic concentrations of IL-7, IL-18 and Stem Cell Factor (SCF) were analysed at baseline and after 6 months of therapy. ART introduction during PHI restored the decline of L-HPCs, induced a decrease in the level of pro-inflammatory IL-18 cytokine and a parallel increase of SCF. Moreover, L-HPCs frequency positively correlated with IL-18 at baseline, and with SCF after 6 months of therapy, suggesting that different signals impact L-HPCs expansion and maintenance before and after treatment. Finally, the SCF receptor expression on HPCs decreased after early ART initiation. These insights may open new perspectives for the evaluation of cytokine-driven L-HPCs expansion and their impact on the homeostasis of hematopoietic compartment during HIV infection.
Veronica Bordoni; Domenico Viola; Alessandra Sacchi; Carmela Pinnetti; Rita Casetti; Eleonora Cimini; Nicola Tumino; Andrea Antinori; Adriana Ammassari; Chiara Agrati. IL-18 and Stem Cell Factor affect hematopoietic progenitor cells in HIV-infected patients treated during primary HIV infection. Cytokine 2018, 103, 34 -37.
AMA StyleVeronica Bordoni, Domenico Viola, Alessandra Sacchi, Carmela Pinnetti, Rita Casetti, Eleonora Cimini, Nicola Tumino, Andrea Antinori, Adriana Ammassari, Chiara Agrati. IL-18 and Stem Cell Factor affect hematopoietic progenitor cells in HIV-infected patients treated during primary HIV infection. Cytokine. 2018; 103 ():34-37.
Chicago/Turabian StyleVeronica Bordoni; Domenico Viola; Alessandra Sacchi; Carmela Pinnetti; Rita Casetti; Eleonora Cimini; Nicola Tumino; Andrea Antinori; Adriana Ammassari; Chiara Agrati. 2018. "IL-18 and Stem Cell Factor affect hematopoietic progenitor cells in HIV-infected patients treated during primary HIV infection." Cytokine 103, no. : 34-37.
Hepatitis C virus (HCV) persistence results from inefficiencies of both innate and adaptive immune responses to eradicate the infection. A functional impairment of circulating Vγ9Vδ2 T-cells was described but few data are available on Vγ9Vδ2 T-cells in the liver that, however, represents the battlefield in the HCV/host interaction. Aim of this work was to compare circulating and intrahepatic Vγ9Vδ2 T-cells in chronic HCV-infected patients (HCV(pos)) and in HCV-negative (HCV(neg)) subjects. Phenotypic and functional analysis was performed by flow cytometry. Anti-HCV activity was analyzed by using an in vitro autologous liver culture system. Independently from HCV infection, the liver was enriched of Vγ9Vδ2 T-cells expressing an effector/activated phenotype. In contrast, an enrichment of PD-1 expressing Vγ9Vδ2 T-cells was observed both in the peripheral blood and in the liver of HCV(pos) patients, probably due to a persistent antigenic stimulation. Moreover, a lower frequency of IFN-γ producing Vγ9Vδ2 T-cells was observed in the liver of HCV(pos) patients, suggesting a functional impairment in the cytokine production in HCV(pos) liver. Despite this hypo-responsiveness, intrahepatic Vγ9Vδ2 T-cells are able to exert an anti-HCV activity after specific stimulation. Altogether, our data show that HCV infection induced a dysregulation of intrahepatic Vγ9Vδ2 T cells that maintain their anti-HCV activity after specific stimulation. A study aimed to evaluate the mechanisms of the antiviral activity may be useful to identify new pathways able to improve Vγ9Vδ2 T-cells intrahepatic function during HCV infection.
E. Cimini; V. Bordoni; A. Sacchi; U. Visco-Comandini; M. Montalbano; C. Taibi; R. Casetti; Eleonora Lalle; G. D’Offizi; M.R. Capobianchi; C. Agrati. Intrahepatic Vγ9Vδ2 T-cells from HCV-infected patients show an exhausted phenotype but can inhibit HCV replication. Virus Research 2018, 243, 31 -35.
AMA StyleE. Cimini, V. Bordoni, A. Sacchi, U. Visco-Comandini, M. Montalbano, C. Taibi, R. Casetti, Eleonora Lalle, G. D’Offizi, M.R. Capobianchi, C. Agrati. Intrahepatic Vγ9Vδ2 T-cells from HCV-infected patients show an exhausted phenotype but can inhibit HCV replication. Virus Research. 2018; 243 ():31-35.
Chicago/Turabian StyleE. Cimini; V. Bordoni; A. Sacchi; U. Visco-Comandini; M. Montalbano; C. Taibi; R. Casetti; Eleonora Lalle; G. D’Offizi; M.R. Capobianchi; C. Agrati. 2018. "Intrahepatic Vγ9Vδ2 T-cells from HCV-infected patients show an exhausted phenotype but can inhibit HCV replication." Virus Research 243, no. : 31-35.
First anti-HCV treatments, that include protease inhibitors in conjunction with IFN-α and Ribavirin, increase the sustained virological response (SVR) up to 80% in patients infected with HCV genotype 1. The effects of triple therapies on dendritic cell (DC) compartment have not been investigated. In this study we evaluated the effect of telaprevir-based triple therapy on DC phenotype and function, and their possible association with treatment outcome. HCV+ patients eligible for telaprevir-based therapy were enrolled, and circulating DC frequency, phenotype, and function were evaluated by flow-cytometry. The antiviral activity of plasmacytoid DC was also tested. In SVR patients, myeloid DC frequency transiently decreased, and returned to baseline level when telaprevir was stopped. Moreover, an up-regulation of CD80 and CD86 on mDC was observed in SVR patients as well as an improvement of IFN-α production by plasmacytoid DC, able to inhibit in vitro HCV replication.
Alessandra Sacchi; Nicola Tumino; Federica Turchi; Giulia Refolo; Gianmaria Fimia; Fabiola Ciccosanti; Marzia Montalbano; Raffaella Lionetti; Chiara Taibi; Gianpiero D'offizi; Rita Casetti; Veronica Bordoni; Eleonora Cimini; Federico Martini; Chiara Agrati. Dendritic cells activation is associated with sustained virological response to telaprevir treatment of HCV-infected patients. Clinical Immunology 2017, 183, 82 -90.
AMA StyleAlessandra Sacchi, Nicola Tumino, Federica Turchi, Giulia Refolo, Gianmaria Fimia, Fabiola Ciccosanti, Marzia Montalbano, Raffaella Lionetti, Chiara Taibi, Gianpiero D'offizi, Rita Casetti, Veronica Bordoni, Eleonora Cimini, Federico Martini, Chiara Agrati. Dendritic cells activation is associated with sustained virological response to telaprevir treatment of HCV-infected patients. Clinical Immunology. 2017; 183 ():82-90.
Chicago/Turabian StyleAlessandra Sacchi; Nicola Tumino; Federica Turchi; Giulia Refolo; Gianmaria Fimia; Fabiola Ciccosanti; Marzia Montalbano; Raffaella Lionetti; Chiara Taibi; Gianpiero D'offizi; Rita Casetti; Veronica Bordoni; Eleonora Cimini; Federico Martini; Chiara Agrati. 2017. "Dendritic cells activation is associated with sustained virological response to telaprevir treatment of HCV-infected patients." Clinical Immunology 183, no. : 82-90.
The definition of the immunological response to Zika (ZIKV) infection in humans represents a key issue to identify protective profile useful for vaccine development and for pathogenesis studies. No data are available on the cellular immune response in the acute phase of human ZIKV infection, and its role in the protection and/or pathogenesis needs to be clarified. We studied and compared the phenotype and functionality of T-cells in patients with acute ZIKV and Dengue viral (DENV) infections. A significant activation of T-cells was observed during both ZIKV and DENV infections. ZIKV infection was characterized by a CD4 T cell differentiation toward effector cells and by a lower frequency of IFN-γ producing CD4 T cells. Moreover, a substantial expansion of CD3+CD4−CD8− T-cell subset expressing Vδ2 TCR was specifically observed in ZIKV patients. Vδ2 T cells presented a terminally differentiated profile, expressed granzyme B and maintained their ability to produce IFN-γ. These findings provide new knowledge on the immune response profile during self-limited infection that may help in vaccine efficacy definition, and in identifying possible immuno-pathogenetic mechanisms of severe infection.
Eleonora Cimini; Concetta Castilletti; Alessandra Sacchi; Rita Casetti; Veronica Bordoni; Antonella Romanelli; Federica Turchi; Federico Martini; Nicola Tumino; Emanuele Nicastri; Angela Corpolongo; Antonino Di Caro; Gary Kobinger; Professor Sir Alimuddin Zumla; Maria Rosaria Capobianchi; Giuseppe Ippolito; Chiara Agrati. Human Zika infection induces a reduction of IFN-γ producing CD4 T-cells and a parallel expansion of effector Vδ2 T-cells. Scientific Reports 2017, 7, 1 -10.
AMA StyleEleonora Cimini, Concetta Castilletti, Alessandra Sacchi, Rita Casetti, Veronica Bordoni, Antonella Romanelli, Federica Turchi, Federico Martini, Nicola Tumino, Emanuele Nicastri, Angela Corpolongo, Antonino Di Caro, Gary Kobinger, Professor Sir Alimuddin Zumla, Maria Rosaria Capobianchi, Giuseppe Ippolito, Chiara Agrati. Human Zika infection induces a reduction of IFN-γ producing CD4 T-cells and a parallel expansion of effector Vδ2 T-cells. Scientific Reports. 2017; 7 (1):1-10.
Chicago/Turabian StyleEleonora Cimini; Concetta Castilletti; Alessandra Sacchi; Rita Casetti; Veronica Bordoni; Antonella Romanelli; Federica Turchi; Federico Martini; Nicola Tumino; Emanuele Nicastri; Angela Corpolongo; Antonino Di Caro; Gary Kobinger; Professor Sir Alimuddin Zumla; Maria Rosaria Capobianchi; Giuseppe Ippolito; Chiara Agrati. 2017. "Human Zika infection induces a reduction of IFN-γ producing CD4 T-cells and a parallel expansion of effector Vδ2 T-cells." Scientific Reports 7, no. 1: 1-10.
Immunological nonresponse represents the Achilles heel in the combination antiretroviral therapy (cART) effectiveness, and increases risk of clinical events and death. CD8 T cells play a crucial role in controlling HIV replication, and polyfunctional HIV-specific CD8 T cells have been associated with nonprogressive HIV infection. However, the possible role of polyfunctional CD8 T cells in predicting posttreatment immune reconstitution has not yet been explored. The aim of this study was to identify functional markers predictive of immunological response to cART in chronic HIV-infected patients. A cohort of chronic HIV-infected individuals naive to cART were enrolled in the ALPHA study. CD4/CD8 T-cell subsets, their differentiation/activation, as well as susceptibility to apoptosis were analyzed before and after 12 months of cART. Moreover, CD8 T cells polyfunctional response after HIV antigenic stimulation was also assessed. Results showed a significant correlation between worse CD4 T-cell restoration and low frequency of naive CD4 T cells, high frequency of effector memory CD4 T cells, and high susceptibility to apoptosis of CD4 T cells all before cART. Moreover, CD8 functional subsets expressing total C-C motif chemokine ligand 4 (CCL-4) or in combination with CD107a and interferon gamma (IFNγ) were negatively associated with immune reconstitution. In conclusion, our study shows that a more differentiated phenotype of CD4 T cells and CCL-4–producing CD8 T cells could represent valuable predictors of worse immune reconstitution. These parameters may be used as tools for identifying patients at risk of immunological failure during cART and eventually represent the basis for innovative therapeutic strategies.
Rita Casetti; Carmela Pinnetti; Alessandra Sacchi; Gabriele De Simone; Veronica Bordoni; Eleonora Cimini; Nicola Tumino; Francesca Besi; Domenico Viola; Federica Turchi; Valentina Mazzotta; Andrea Antinori; Federico Martini; Adriana Ammassari; Chiara Agrati. HIV-Specific CD8 T Cells Producing CCL-4 Are Associated With Worse Immune Reconstitution During Chronic Infection. JAIDS Journal of Acquired Immune Deficiency Syndromes 2017, 75, 338 -344.
AMA StyleRita Casetti, Carmela Pinnetti, Alessandra Sacchi, Gabriele De Simone, Veronica Bordoni, Eleonora Cimini, Nicola Tumino, Francesca Besi, Domenico Viola, Federica Turchi, Valentina Mazzotta, Andrea Antinori, Federico Martini, Adriana Ammassari, Chiara Agrati. HIV-Specific CD8 T Cells Producing CCL-4 Are Associated With Worse Immune Reconstitution During Chronic Infection. JAIDS Journal of Acquired Immune Deficiency Syndromes. 2017; 75 (3):338-344.
Chicago/Turabian StyleRita Casetti; Carmela Pinnetti; Alessandra Sacchi; Gabriele De Simone; Veronica Bordoni; Eleonora Cimini; Nicola Tumino; Francesca Besi; Domenico Viola; Federica Turchi; Valentina Mazzotta; Andrea Antinori; Federico Martini; Adriana Ammassari; Chiara Agrati. 2017. "HIV-Specific CD8 T Cells Producing CCL-4 Are Associated With Worse Immune Reconstitution During Chronic Infection." JAIDS Journal of Acquired Immune Deficiency Syndromes 75, no. 3: 338-344.
The impact of HIV infection on the frequency and differentiation capability of CD34+ bone marrow hematopoietic progenitor cells (BM-HPCs) is still debated, having a possible primary role in antiretroviral-induced immunoreconstitution. We investigated the influence of HIV replication or proinflammatory cytokines on lymphopoietic capability of BM-HPCs from seven viremic (VR) and five nonviremic (NVR) HIV-infected patients. We found that BM-HPCs from VR patients were unable to differentiate in vitro toward T cells, and produced proinflammatory cytokines in the absence of viral replication. In contrast, the lymphoid differentiation potential of BM-HPCs was partially restored in successfully antiretroviral therapy-treated patients. We also showed that TLR8 triggering induced BM-HPCs from healthy donors to release proinflammatory cytokines affecting T cell differentiation. These data suggest that in HIV-infected patients, the lymphopoiesis capability of BM-HPCs may be modulated by a virus-driven autocrine mechanism involving proinflammatory cytokines.
Veronica Bordoni; Michele Bibas; Domenico Viola; Alessandra Sacchi; Eleonora Cimini; Nicola Tumino; Rita Casetti; Alessandra Amendola; Adriana Ammassari; Chiara Agrati; Federico Martini. Bone Marrow CD34+ Progenitor Cells from HIV-Infected Patients Show an Impaired T Cell Differentiation Potential Related to Proinflammatory Cytokines. AIDS Research and Human Retroviruses 2017, 33, 590 -596.
AMA StyleVeronica Bordoni, Michele Bibas, Domenico Viola, Alessandra Sacchi, Eleonora Cimini, Nicola Tumino, Rita Casetti, Alessandra Amendola, Adriana Ammassari, Chiara Agrati, Federico Martini. Bone Marrow CD34+ Progenitor Cells from HIV-Infected Patients Show an Impaired T Cell Differentiation Potential Related to Proinflammatory Cytokines. AIDS Research and Human Retroviruses. 2017; 33 (6):590-596.
Chicago/Turabian StyleVeronica Bordoni; Michele Bibas; Domenico Viola; Alessandra Sacchi; Eleonora Cimini; Nicola Tumino; Rita Casetti; Alessandra Amendola; Adriana Ammassari; Chiara Agrati; Federico Martini. 2017. "Bone Marrow CD34+ Progenitor Cells from HIV-Infected Patients Show an Impaired T Cell Differentiation Potential Related to Proinflammatory Cytokines." AIDS Research and Human Retroviruses 33, no. 6: 590-596.
Human Ebola infection is characterized by a paralysis of the immune system. A signature of αβ T cells in fatal Ebola infection has been recently proposed, while the involvement of innate immune cells in the protection/pathogenesis of Ebola infection is unknown. Aim of this study was to analyze γδ T and NK cells in patients from the Ebola outbreak of 2014–2015 occurred in West Africa, and to assess their association with the clinical outcome. Nineteen Ebola-infected patients were enrolled at the time of admission to the Ebola Treatment Centre in Guinea. Patients were divided in two groups on the basis of the clinical outcome. The analysis was performed by using multiparametric flow cytometry established by the European Mobile Laboratory in the field. A low frequency of Vδ2 T-cells was observed during Ebola infection, independently from the clinical outcome. Moreover, Vδ2 T-cells from Ebola patients massively expressed CD95 apoptotic marker, suggesting the involvement of apoptotic mechanisms in Vδ2 T-cell loss. Interestingly, Vδ2 T-cells from survivors expressed an effector phenotype and presented a lower expression of the CTLA-4 exhaustion marker than fatalities, suggesting a role of effector Vδ2 T-cells in the protection. Furthermore, patients with fatal Ebola infection were characterized by a lower NK cell frequency than patients with non fatal infection. In particular, both CD56bright and CD56dim NK frequency were very low both in fatal and non fatal infections, while a higher frequency of CD56neg NK cells was associated to non-fatal infections. Finally, NK activation and expression of NKp46 and CD158a were independent from clinical outcome. Altogether, the data suggest that both effector Vδ2 T-cells and NK cells may play a role in the complex network of protective response to EBOV infection. Further studies are required to characterize the protective effector functions of Vδ2 and NK cells.
Eleonora Cimini; Domenico Viola; Mar Cabeza-Cabrerizo; Antonella Romanelli; Nicola Tumino; Alessandra Sacchi; Veronica Bordoni; Rita Casetti; Federica Turchi; Federico Martini; Joseph A. Bore; Fara Raymond Koundouno; Sophie Duraffour; Janine Michel; Tobias Holm; Elsa Gayle Zekeng; Lauren Cowley; Isabel Garcia Dorival; Juliane Doerrbecker; Nicole Hetzelt; Jonathan H. J. Baum; Jasmine Portmann; Roman Wölfel; Martin Gabriel; Osvaldo Miranda; Graciliano Díaz; José E. Díaz; Yoel A. Fleites; Carlos A. Piñeiro; Carlos M. Castro; Lamine Koivogui; N’Faly Magassouba; Boubacar Diallo; Paula Ruibal; Lisa Oestereich; David Wozniak; Anja Lüdtke; Beate Becker-Ziaja; Maria R. Capobianchi; Giuseppe Ippolito; Miles Carroll; Stephan Günther; Antonino Di Caro; César Muñoz-Fontela; Chiara Agrati. Different features of Vδ2 T and NK cells in fatal and non-fatal human Ebola infections. PLOS Neglected Tropical Diseases 2017, 11, e0005645 .
AMA StyleEleonora Cimini, Domenico Viola, Mar Cabeza-Cabrerizo, Antonella Romanelli, Nicola Tumino, Alessandra Sacchi, Veronica Bordoni, Rita Casetti, Federica Turchi, Federico Martini, Joseph A. Bore, Fara Raymond Koundouno, Sophie Duraffour, Janine Michel, Tobias Holm, Elsa Gayle Zekeng, Lauren Cowley, Isabel Garcia Dorival, Juliane Doerrbecker, Nicole Hetzelt, Jonathan H. J. Baum, Jasmine Portmann, Roman Wölfel, Martin Gabriel, Osvaldo Miranda, Graciliano Díaz, José E. Díaz, Yoel A. Fleites, Carlos A. Piñeiro, Carlos M. Castro, Lamine Koivogui, N’Faly Magassouba, Boubacar Diallo, Paula Ruibal, Lisa Oestereich, David Wozniak, Anja Lüdtke, Beate Becker-Ziaja, Maria R. Capobianchi, Giuseppe Ippolito, Miles Carroll, Stephan Günther, Antonino Di Caro, César Muñoz-Fontela, Chiara Agrati. Different features of Vδ2 T and NK cells in fatal and non-fatal human Ebola infections. PLOS Neglected Tropical Diseases. 2017; 11 (5):e0005645.
Chicago/Turabian StyleEleonora Cimini; Domenico Viola; Mar Cabeza-Cabrerizo; Antonella Romanelli; Nicola Tumino; Alessandra Sacchi; Veronica Bordoni; Rita Casetti; Federica Turchi; Federico Martini; Joseph A. Bore; Fara Raymond Koundouno; Sophie Duraffour; Janine Michel; Tobias Holm; Elsa Gayle Zekeng; Lauren Cowley; Isabel Garcia Dorival; Juliane Doerrbecker; Nicole Hetzelt; Jonathan H. J. Baum; Jasmine Portmann; Roman Wölfel; Martin Gabriel; Osvaldo Miranda; Graciliano Díaz; José E. Díaz; Yoel A. Fleites; Carlos A. Piñeiro; Carlos M. Castro; Lamine Koivogui; N’Faly Magassouba; Boubacar Diallo; Paula Ruibal; Lisa Oestereich; David Wozniak; Anja Lüdtke; Beate Becker-Ziaja; Maria R. Capobianchi; Giuseppe Ippolito; Miles Carroll; Stephan Günther; Antonino Di Caro; César Muñoz-Fontela; Chiara Agrati. 2017. "Different features of Vδ2 T and NK cells in fatal and non-fatal human Ebola infections." PLOS Neglected Tropical Diseases 11, no. 5: e0005645.
Background It has been demonstrated that Myeloid Derived Suppressor Cells (MDSC) are expanded in HIV-1 infected individuals and correlated with disease progression. The phase of HIV infection during which MDSC expansion occurs, and the mechanisms that regulate this expansion remain to be established. In this study we evaluated the frequency of MDSC in patients during primary HIV infection, and factors involved in MDSC control.\ud Methods Patients with primary (PHI) and chronic (CHI) HIV infection were enrolled.\ud PHI staging was performed according to Fiebig classification, and circulating MDSC frequency and function were evaluated by flow cytometry. Cytokine levels were evaluated by Luminex technology.\ud Results We found that granulocytic MDSC (Gr-MDSC) frequency was higher in PHI compared to healthy donors, but lower than CHI. Interestingly, Gr-MDSC expansion was observed in the early phases of HIV infection (Fiebig II/III), but it was not associated to HIV viral load and CD4 T cell count.\ud Interestingly, in PHI Gr-MDSC frequency was inversely correlated with plasmatic level of TRAIL, while a direct correlation was observed in CHI. Further, lower level of GMCSF was observed in PHI compared with CHI. In vitro experiments demonstrated that, differently from CHI, recombinant TRAIL induced apoptosis of Gr-MDSC from PHI, can effect that can be abrogated by GM-CSF.\ud Conclusion We found that Gr-MDSC are expanded early during primary HIV infection and may be regulated by TRAIL and GM-CSF levels. These findings shed light on the fine mechanisms regulating the immune system during HIV infection, and open new perspectives for immune-based strategies
Nicola Tumino; Maria T. Bilotta; Carmela Pinnetti; Adriana Ammassari; Andrea Antinori; Federica Turchi; Chiara Agrati; Rita Casetti; Veronica Bordoni; Eleonora Cimini; Isabella Abbate; Maria R. Capobianchi; Federico Martini; Alessandra Sacchi. Granulocytic Myeloid–Derived Suppressor Cells Increased in Early Phases of Primary HIV Infection Depending on TRAIL Plasma Level. Journal of Acquired Immune Deficiency Syndromes 2017, 74, 575 -582.
AMA StyleNicola Tumino, Maria T. Bilotta, Carmela Pinnetti, Adriana Ammassari, Andrea Antinori, Federica Turchi, Chiara Agrati, Rita Casetti, Veronica Bordoni, Eleonora Cimini, Isabella Abbate, Maria R. Capobianchi, Federico Martini, Alessandra Sacchi. Granulocytic Myeloid–Derived Suppressor Cells Increased in Early Phases of Primary HIV Infection Depending on TRAIL Plasma Level. Journal of Acquired Immune Deficiency Syndromes. 2017; 74 (5):575-582.
Chicago/Turabian StyleNicola Tumino; Maria T. Bilotta; Carmela Pinnetti; Adriana Ammassari; Andrea Antinori; Federica Turchi; Chiara Agrati; Rita Casetti; Veronica Bordoni; Eleonora Cimini; Isabella Abbate; Maria R. Capobianchi; Federico Martini; Alessandra Sacchi. 2017. "Granulocytic Myeloid–Derived Suppressor Cells Increased in Early Phases of Primary HIV Infection Depending on TRAIL Plasma Level." Journal of Acquired Immune Deficiency Syndromes 74, no. 5: 575-582.
The advent of directly acting antivirals (DAA) has revolutionized hepatitis C virus (HCV) treatment, also in patients with HIV co-infection.1 DAA are able to quickly clear HCV with a high success rate because of their potent antiviral action, resulting in more than 90% of sustained virological response (SVR). Although this is an extraordinary improvement in virological efficacy, several issues concerning the medium and long-term response remain to be addressed: regression of hepatic fibrosis, reduction of liver cancer incidence, and normalization of immunological functions. In this regard, the very interesting paper by Langhans et al. published in Journal of Hepatology analyzed CD4+ regulatory T cells (Treg) before and after two different anti-HCV treatments (DAA plus interferon [IFN]/ribavirin, n = 12 and DAA, n = 14).2 The authors showed that the frequency and activation of Foxp3+ CD25+ CD4+ T cells remained elevated above those of normal controls with both treatments, even long-term after HCV elimination. This observation supports the hypothesis that HCV clearance by DAA is not sufficient to normalize immunological parameters, skewing immune surveillance in favor of invading microbes and/or cancer development.We obtained similar results in a small cohort of 18 HIV/HCV co-infected patients enrolled in a prospective, observational study at the National Institute for Infectious Diseases (INMI) “Lazzaro Spallanzani” in Rome, Italy. All patients were receiving successful antiretroviral therapy (HIV-RNA <40 copies/ml), 15 individuals had F3-F4 hepatic fibrosis, and three had F2 hepatic fibrosis. Patients were treated with DAA as follows: ledipasvir/sofosbuvir: n = 11, sofosbuvir/daclatasvir: n = 3; ombitasvir/paritaprevir/ritonavir/dasabuvir/ribavirin: n = 4. All patients reached SVR. Samples were collected just before starting DAA treatment (baseline, BL), at the end of treatment (EOT) and 12 weeks after EOT (SVR). Frequency of Treg and myeloid-derived suppressor cells (MDSC) were analyzed by multiparametric flow cytometry. Treg were identified as Foxp3+ CD25+ cells among CD4+ T lymphocytes and MDSC as HLA-DR− CD3− CD56− CD19− CD33+ CD11b+. The study was approved by the Institutional Review Board of “Lazzaro Spallanzani” and written signed informed consent was obtained from all patients.At BL, a higher frequency of Treg and MDSC were observed in HIV/HCV co-infected patients than in healthy donors (controls) (Fig. 1Fig. 1). Moreover, in line with Langhans et al., DAA treatment did not modify the frequency of Treg, that persisted significantly higher than in controls during the entire study period (p <0.01 for all comparisons, Fig. 1Fig. 1B). Accordingly, DAA treatment failed to normalize also MDSC frequency; surprisingly, MDSC increased at SVR (p <0.05, Fig. 1Fig. 1D).Fig. 1Treg and MDSC are higher in DAA-treated HIV/HCV co-infected patients than in healthy donors. Gating strategy used for the identification of Treg (A) and MDSC (C) are shown. Frequency of CD4+ CD25+ FOXP3+ regulatory T cells (B) and Lin-(CD3− CD56− CD19−) HLA-DR− CD33+ CD11b+ MDSC (D) are shown at baseline (BL), at the end of treatment (EOT), and three months after EOT (SVR). Healthy donors (Controls) were used as control group. Results are show as median ± interquartile range. GraphPad Prism version 4.00 was used for statistical analyses. Groups were compared using the non-parametric Mann-Whitney U test and Wilcoxon matched pairs test was used to compare different time points. A p value <0.05 was considered statistically significant.View Large Image | View Hi-Res Image | Download PowerPoint SlideThe persistence of Treg and MDSC may have pleiotropic effects on the immune system. It is known that CD4 Treg cells control many cell types involved in the immune response, are associated to antiviral responses, and contribute to HCV persistence.3MDSC are expanded in HCV-infected patients and correlate with plasma HCV-RNA and liver function tests in blood.4 Data about the effect of IFN/ribavirin treatment on MDSC frequency in HCV mono-infected patients showed an early reduction after 4 weeks of therapy, but a subsequent rebound of these cells was observed later on.4MDSC and Treg cells are both increased during HIV infection, contributing to impaired T cell response and disease progression.[5],[6] Although our patients were receiving successful antiretroviral therapy, a high frequency of both cell populations was observed. Contrasting data are reported on the effect of antiretroviral therapy on Treg[7],[8] and MDSC[6],[9] in HIV mono-infected patients. Moreover, in HIV/HCV co-infected patients antiretrovirals can induce a transient decrease of MDSC.10 Despite these contrasting results, the results reported by Langhans et al. in HCV mono-infected patients and our data derived from HIV/HCV co-infected individuals indicate that, independently from HIV infection, successful DAA was not able to normalize Treg frequency. Further, MDSC remain high during DAA, with a surprising increase after successful DAA. This observation has never been reported before neither in HCV mono-infected nor in HIV/HCV co-infected DAA-treated individuals. The reason for this phenomenon needs to be explored.Overall our and Langhans’ data show that DAA therapy, at least shortly after eradication, may fail to restore regulatory immune cell subsets (Treg and MDSC) in both HCV mono- and HIV/HCV co-infected patients, opening question on the clinical impact of this persistence in HCV-eradicated patients. Further studies are required to evaluate the possible involvement of these regulatory cells in susceptibility to HCV re-infection, risk of liver cirrhosis and/or cancer development. The deeper understanding of these mechanisms in both HCV mono- and HIV/HCV co-infected patients, may allow identifying HCV-eradicated individuals at higher risk of complications after DAA therapy.Financial supportJump to SectionFinancial supportConflict of interestAuthors’ contributionsReferencesThis work was supported by grants from Italian Ministry of Health (Ricerca Corrente) to INMI L. Spallanzani, IRCCS.Conflict of interestJump to SectionFinancial supportConflict of interestAuthors’ contributionsReferencesThe authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.Authors’ contributionsJump to SectionFinancial supportConflict of interestAuthors’ contributionsReferencesGF, AA, AA enrolled the patients; NT, RC, EC, AR, FT, OF performed the experiments; VB, RC, AS performed the analysis; AS, CA design the study and wrote the manuscript. All author revised the manuscript. This work was supported by grants from Italian Ministry of Health (Ricerca Corrente) to INMI L. Spallanzani, IRCCS. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. GF, AA, AA enrolled the patients; NT, RC, EC, AR, FT, OF performed the experiments; VB, RC, AS performed the analysis; AS, CA design the study and wrote the manuscript. All author revised the manuscript.
Nicola Tumino; Rita Casetti; Gabriele Fabbri; Eleonora Cimini; Antonella Romanelli; Federica Turchi; Olindo Forini; Veronica Bordoni; Andrea Antinori; Adriana Ammassari; Alessandra Sacchi; Chiara Agrati. In HIV/HCV co-infected patients T regulatory and myeloid-derived suppressor cells persist after successful treatment with directly acting antivirals. Journal of Hepatology 2017, 67, 422 -424.
AMA StyleNicola Tumino, Rita Casetti, Gabriele Fabbri, Eleonora Cimini, Antonella Romanelli, Federica Turchi, Olindo Forini, Veronica Bordoni, Andrea Antinori, Adriana Ammassari, Alessandra Sacchi, Chiara Agrati. In HIV/HCV co-infected patients T regulatory and myeloid-derived suppressor cells persist after successful treatment with directly acting antivirals. Journal of Hepatology. 2017; 67 (2):422-424.
Chicago/Turabian StyleNicola Tumino; Rita Casetti; Gabriele Fabbri; Eleonora Cimini; Antonella Romanelli; Federica Turchi; Olindo Forini; Veronica Bordoni; Andrea Antinori; Adriana Ammassari; Alessandra Sacchi; Chiara Agrati. 2017. "In HIV/HCV co-infected patients T regulatory and myeloid-derived suppressor cells persist after successful treatment with directly acting antivirals." Journal of Hepatology 67, no. 2: 422-424.
We have shown that Cholera Toxin (CT) and other cyclic AMP (cAMP) elevating agents induce up-regulation of the inhibitory molecule CTLA-4 in human resting CD4+ T lymphocytes, which following the treatment acquired suppressive functions. In this study, we evaluated the effect of cAMP elevating agents on human CD4+CD25+ T cells, which include the T regulatory (Treg) cells that play a pivotal role in the maintenance of immunological tolerance. We found that cAMP elevating agents induce up-regulation of CTLA-4 in CD4+CD25- and further enhance its expression in CD4+CD25+ T cells. We observed an increase of two isoforms of mRNA coding for the membrane and the soluble CTLA-4 molecules, suggesting that the regulation of CTLA-4 expression by cAMP is at the transcriptional level. In addition, we found that the increase of cAMP in CD4+CD25+ T cells converts the CD4+CD25+Foxp3- T cells in CD4+CD25+Foxp3+ T cells, whereas the increase of cAMP in CD4+CD25- T cells did not up-regulate Foxp3 in the absence of activation stimuli. To investigate the function of these cells, we performed an in vitro suppression assay by culturing CD4+CD25+ T cells untreated or pre-treated with CT with anti-CD3 mAbs-stimulated autologous PBMC. We found that CT enhances the inhibitory function of CD4+CD25+ T cells, CD4+ and CD8+ T cell proliferation and IFNγ production are strongly inhibited by CD4+CD25+ T cells pre-treated with cAMP elevating agents. Furthermore, we found that CD4+CD25+ T lymphocytes pre-treated with cAMP elevating agents induce the up-regulation of CD80 and CD86 co-stimulatory molecules on immature dendritic cells (DCs) in the absence of antigenic stimulation, however without leading to full DC maturation. These data show that the increase of intracellular cAMP modulates the phenotype and function of human CD4+CD25+ T cells.
Antonella Riccomi; Valentina Gesa; Alessandra Sacchi; Maria Teresa De Magistris; Silvia Vendetti. Modulation of Phenotype and Function of Human CD4+CD25+ T Regulatory Lymphocytes Mediated by cAMP-Elevating Agents. Frontiers in Immunology 2016, 7, 1 .
AMA StyleAntonella Riccomi, Valentina Gesa, Alessandra Sacchi, Maria Teresa De Magistris, Silvia Vendetti. Modulation of Phenotype and Function of Human CD4+CD25+ T Regulatory Lymphocytes Mediated by cAMP-Elevating Agents. Frontiers in Immunology. 2016; 7 ():1.
Chicago/Turabian StyleAntonella Riccomi; Valentina Gesa; Alessandra Sacchi; Maria Teresa De Magistris; Silvia Vendetti. 2016. "Modulation of Phenotype and Function of Human CD4+CD25+ T Regulatory Lymphocytes Mediated by cAMP-Elevating Agents." Frontiers in Immunology 7, no. : 1.
Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells.
Chiara Agrati; C Castilletti; Rita Casetti; Alessandra Sacchi; L Falasca; F Turchi; Nicola Tumino; Veronica Bordoni; Eleonora Cimini; D Viola; Eleonora Lalle; Licia Bordi; S Lanini; F Martini; Emanuele Nicastri; Nicola Petrosillo; V Puro; M Piacentini; A Di Caro; G P Kobinger; Professor Sir Alimuddin Zumla; G Ippolito; M R Capobianchi. Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection. Cell Death & Disease 2016, 7, e2164 -e2164.
AMA StyleChiara Agrati, C Castilletti, Rita Casetti, Alessandra Sacchi, L Falasca, F Turchi, Nicola Tumino, Veronica Bordoni, Eleonora Cimini, D Viola, Eleonora Lalle, Licia Bordi, S Lanini, F Martini, Emanuele Nicastri, Nicola Petrosillo, V Puro, M Piacentini, A Di Caro, G P Kobinger, Professor Sir Alimuddin Zumla, G Ippolito, M R Capobianchi. Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection. Cell Death & Disease. 2016; 7 (3):e2164-e2164.
Chicago/Turabian StyleChiara Agrati; C Castilletti; Rita Casetti; Alessandra Sacchi; L Falasca; F Turchi; Nicola Tumino; Veronica Bordoni; Eleonora Cimini; D Viola; Eleonora Lalle; Licia Bordi; S Lanini; F Martini; Emanuele Nicastri; Nicola Petrosillo; V Puro; M Piacentini; A Di Caro; G P Kobinger; Professor Sir Alimuddin Zumla; G Ippolito; M R Capobianchi. 2016. "Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection." Cell Death & Disease 7, no. 3: e2164-e2164.
Objective: During HIV infection, a down-modulation of CD3ζ was found on T cells, contributing to T-cell anergy. In this work, we studied the correlation between myeloid-derived suppressor cells (MDSC) frequency and T-cell CD3ζ expression. Moreover, we investigated the mechanisms of CD3ζ decrease exploited by MDSC. Design and method: CD3ζ expression and MDSC frequency were evaluated by flow cytometry on peripheral blood mononuclear cells from 105 HIV-positive (HIV+) patients. The role of MDSC in the modulation of the HIV-specific T-cell response was evaluated. The level of CD3ζ mRNA and ELF-1 protein were analysed by real-time–PCR and western blot, respectively. Results: We found that granulocytic-MDSC (Gr-MDSC) were expanded in HIV+ patients compared with healthy donors; in particular, in cART-treated individuals a higher Gr-MDSC frequency was observed in patients with a CD4+ T-cell count below 400 cells/μl. We found an inverse correlation between the percentage of Gr-MDSC and CD3ζ level. Moreover, in-vitro MDSC depletion induced the up-regulation of CD3ζ in T cells, restoring the functionality of αβ, but not γδ T cells. The in-vitro effect of isolated MDSC on CD3ζ expression was found cell contact-dependent, and was not mediated by previously described molecules. CD3ζ down-modulation corresponds to the decrease of its mRNA induced by silencing the transcription factor ELF-1. Conclusion: Our data provide new knowledge on mechanisms used by Gr-MDSC in immune-modulation and on their role in the immune reconstitution during antiviral treatments.
Nicola Tumino; Federica Turchi; Silvia Meschi; Eleonora Lalle; Veronica Bordoni; Rita Casetti; Chiara Agrati; Eleonora Cimini; Carla Montesano; Vittorio Colizzi; Federico Martini; Alessandra Sacchi. In HIV-positive patients, myeloid-derived suppressor cells induce T-cell anergy by suppressing CD3ζ expression through ELF-1 inhibition. AIDS 2015, 29, 2397 -2407.
AMA StyleNicola Tumino, Federica Turchi, Silvia Meschi, Eleonora Lalle, Veronica Bordoni, Rita Casetti, Chiara Agrati, Eleonora Cimini, Carla Montesano, Vittorio Colizzi, Federico Martini, Alessandra Sacchi. In HIV-positive patients, myeloid-derived suppressor cells induce T-cell anergy by suppressing CD3ζ expression through ELF-1 inhibition. AIDS. 2015; 29 (18):2397-2407.
Chicago/Turabian StyleNicola Tumino; Federica Turchi; Silvia Meschi; Eleonora Lalle; Veronica Bordoni; Rita Casetti; Chiara Agrati; Eleonora Cimini; Carla Montesano; Vittorio Colizzi; Federico Martini; Alessandra Sacchi. 2015. "In HIV-positive patients, myeloid-derived suppressor cells induce T-cell anergy by suppressing CD3ζ expression through ELF-1 inhibition." AIDS 29, no. 18: 2397-2407.
Alteration of γδ T-cell distribution and function in peripheral blood is among the earliest defects during HIV-infection. We asked whether the polyfunctional response could also be affected, and how this impairment could be associated to CD4 T-cell count. To this aim, we performed a cross-sectional study on HIV-infected individuals. In order to evaluate the polyfunctional-Vγ9Vδ2 T-cell response after phosphoantigen-stimulation, we assessed the cytokine/chemokine production and cytotoxicity by flow-cytometry in HAART-treated-HIV+ persons and healthy-donors. During HIV-infection Vγ9Vδ2-polyfunctional response quality is affected, since several Vγ9Vδ2 T-cell subsets resulted significantly lower in HIV+ patients in respect to healthy donors. Interestingly, we found a weak positive correlation between Vγ9Vδ2 T-cell-response and CD4 T-cell counts. By dividing the HIV+ patients according to CD4 T-cell count, we found that Low-CD4 patients expressed a lower number of two Vγ9Vδ2 T-cell subsets expressing MIP-1β in different combinations with other molecules (CD107a/IFNγ) in respect to High-CD4 individuals. Our results show that the Vγ9Vδ2 T-cell-response quality in Low-CD4 patients is specifically affected, suggesting a direct link between innate Vγ9Vδ2 T-cells and CD4 T-cell count. These findings suggest that Vγ9Vδ2 T-cell quality may be indirectly influenced by HAART therapy and could be included in a new therapeutical strategy which would perform an important role in fighting HIV infection.
Rita Casetti; Gabriele De Simone; Alessandra Sacchi; Alessandra Rinaldi; Domenico Viola; Chiara Agrati; Veronica Bordoni; Eleonora Cimini; Nicola Tumino; Francesca Besi; Federico Martini. Vγ9Vδ2 T-Cell Polyfunctionality Is Differently Modulated in HAART-Treated HIV Patients according to CD4 T-Cell Count. PLOS ONE 2015, 10, e0132291 .
AMA StyleRita Casetti, Gabriele De Simone, Alessandra Sacchi, Alessandra Rinaldi, Domenico Viola, Chiara Agrati, Veronica Bordoni, Eleonora Cimini, Nicola Tumino, Francesca Besi, Federico Martini. Vγ9Vδ2 T-Cell Polyfunctionality Is Differently Modulated in HAART-Treated HIV Patients according to CD4 T-Cell Count. PLOS ONE. 2015; 10 (7):e0132291.
Chicago/Turabian StyleRita Casetti; Gabriele De Simone; Alessandra Sacchi; Alessandra Rinaldi; Domenico Viola; Chiara Agrati; Veronica Bordoni; Eleonora Cimini; Nicola Tumino; Francesca Besi; Federico Martini. 2015. "Vγ9Vδ2 T-Cell Polyfunctionality Is Differently Modulated in HAART-Treated HIV Patients according to CD4 T-Cell Count." PLOS ONE 10, no. 7: e0132291.