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Article ; Online: Brief Report: In cART-Treated HIV-Infected Patients, Immunologic Failure Is Associated With a High Myeloid-Derived Suppressor Cell Frequency.

Grassi, Germana / Notari, Stefania / Cicalini, Stefania / Casetti, Rita / Cimini, Eleonora / Bordoni, Veronica / Gagliardini, Roberta / Mazzotta, Valentina / Antinori, Andrea / Agrati, Chiara / Sacchi, Alessandra

Journal of acquired immune deficiency syndromes (1999)

2024 Volume 95, Issue 2, Page(s) 185–189

Abstract: Background: During HIV infection, effective combined antiretroviral therapy suppresses viral replication and restores the number of circulating CD4+ T cells. However, 15%-30% of treated patients show a discordant response to combined antiretroviral ... ...

Abstract	Background: During HIV infection, effective combined antiretroviral therapy suppresses viral replication and restores the number of circulating CD4+ T cells. However, 15%-30% of treated patients show a discordant response to combined antiretroviral therapy. Myeloid-derived suppressor cells (MDSC) are expanded in HIV+ patients; to better understand the role of MDSC on CD4 T-cell recovery, we evaluated the frequency of MDSC in HIV+ patients under combined antiretroviral therapy and its association with immunologic response. Methods: We enrolled 60 HIV+ patients, including complete responders (R, n = 44), virologic nonresponders (VNR, n = 5), and immunologic nonresponders (INR, n = 11). The frequency of circulating MDSC and the percentage of activated and naïve CD4 T cells were evaluated by flow cytometry. Plasmatic cytokine levels were analyzed by automated ELISA. Results: As previously observed, polymorphonuclear MDSC (PMN-MDSC) frequency was higher in HIV+ patients compared with healthy donors. Furthermore, PMN-MDSC percentage was higher in INR than R patients, and a significant association between MDSC frequency and immunologic failure was confirmed by a receiver operator characteristic analysis. Accordingly, an inverse correlation was found between the percentages of PMN-MDSC and naïve CD4 T cells. A positive correlation was observed between PMN-MDSC frequency and the percentage of human leucocyte antigen locus DR + CD4 T cells and the plasmatic level of IL-1β and IL-8. Conclusion: Our results show that a high frequency of PMN-MDSC persists in INR, possibly because of immune activation, contributing to CD4 T-cell recovery failure. These findings further highlight the detrimental role of MDSC during HIV infection, suggesting these cells as a possible new therapeutic target.
MeSH term(s)	Humans ; Myeloid-Derived Suppressor Cells ; HIV Infections ; CD4-Positive T-Lymphocytes ; Cytokines ; Enzyme-Linked Immunosorbent Assay
Chemical Substances	Cytokines
Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	645053-2
ISSN	1944-7884 ; 1077-9450 ; 0897-5965 ; 0894-9255 ; 1525-4135
ISSN (online)	1944-7884 ; 1077-9450
ISSN	0897-5965 ; 0894-9255 ; 1525-4135
DOI	10.1097/QAI.0000000000003335
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Article: In Acute Dengue Infection, High TIM-3 Expression May Contribute to the Impairment of IFNγ Production by Circulating Vδ2 T Cells

Cimini, Eleonora / Grassi, Germana / Beccacece, Alessia / Casetti, Rita / Castilletti, Concetta / Capobianchi, Maria Rosaria / Nicastri, Emanuele / Agrati, Chiara

Viruses. 2022 Jan. 12, v. 14, no. 1

2022

Abstract: γδ T cells are innate cells able to quickly eliminate pathogens or infected/tumoral cells by their antiviral and adjuvancy activities. The role of γδ T cells during Dengue Viral Infection (DENV) infection is not fully elucidated. Nevertheless, human ... ...

Abstract	γδ T cells are innate cells able to quickly eliminate pathogens or infected/tumoral cells by their antiviral and adjuvancy activities. The role of γδ T cells during Dengue Viral Infection (DENV) infection is not fully elucidated. Nevertheless, human primary γδ T cells have been shown to kill in vitro DENV-infected cells, thus highlighting their possible antiviral function. The aim of this work was to characterize the phenotype and function of Vδ2 T cells in DENV patients. Fifteen DENV patients were enrolled for this study and peripheral blood mononuclear cells (PBMC) were used to analyze Vδ2-T-cell frequency, differentiation profile, activation/exhaustion status, and functionality by multiparametric flow cytometry. Our data demonstrated that DENV infection was able to significantly reduce Vδ2-T-cell frequency and to increase their activation (CD38 and HLA-DR) and exhaustion markers (PD-1 and TIM-3). Furthermore, Vδ2 T cells showed a reduced capability to produce IFN-γ after phosphoantigenic stimulation that can be associated to TIM-3 expression. Several studies are needed to depict the possible clinical impact of γδ-T-cell impairment on disease severity and to define the antiviral and immunoregulatory activities of γδ T cells in the first phases of infection.
Keywords	dengue ; disease severity ; flow cytometry ; humans ; immunomodulation ; phenotype
Language	English
Dates of publication	2022-0112
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v14010130
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Myeloid-Derived Suppressor Cells in COVID-19: The Paradox of Good.

Grassi, Germana / Notari, Stefania / Gili, Simona / Bordoni, Veronica / Casetti, Rita / Cimini, Eleonora / Tartaglia, Eleonora / Mariotti, Davide / Agrati, Chiara / Sacchi, Alessandra

Frontiers in immunology

2022 Volume 13, Page(s) 842949

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Viral replication in the respiratory tract induces the death of infected cells and the release of pathogen- ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Viral replication in the respiratory tract induces the death of infected cells and the release of pathogen- associated molecular patterns (PAMPs). PAMPs give rise to local inflammation, increasing the secretion of pro- inflammatory cytokines and chemokines, which attract immune cells from the blood into the infected lung. In most individuals, lung-recruited cells clear the infection, and the immune response retreats. However, in some cases, a dysfunctional immune response occurs, which triggers a cytokine storm in the lung, leading to acute respiratory distress syndrome (ARDS). Severe COVID-19 is characterized by an impaired innate and adaptive immune response and by a massive expansion of myeloid-derived suppressor cells (MDSCs). MDSCs function as protective regulators of the immune response, protecting the host from over-immunoreactivity and hyper-inflammation. However, under certain conditions, such as chronic inflammation and cancer, MDSCs could exert a detrimental role. Accordingly, the early expansion of MDSCs in COVID-19 is able to predict the fatal outcome of the infection. Here, we review recent data on MDSCs during COVID-19, discussing how they can influence the course of the disease and whether they could be considered as biomarker and possible targets for new therapeutic approaches.
MeSH term(s)	COVID-19 ; Humans ; Inflammation ; Myeloid-Derived Suppressor Cells ; Pathogen-Associated Molecular Pattern Molecules ; SARS-CoV-2
Chemical Substances	Pathogen-Associated Molecular Pattern Molecules
Language	English
Publishing date	2022-04-27
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.842949
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Article ; Online: In Acute Dengue Infection, High TIM-3 Expression May Contribute to the Impairment of IFNγ Production by Circulating Vδ2 T Cells.

Cimini, Eleonora / Grassi, Germana / Beccacece, Alessia / Casetti, Rita / Castilletti, Concetta / Capobianchi, Maria Rosaria / Nicastri, Emanuele / Agrati, Chiara

Viruses

2022 Volume 14, Issue 1

Abstract	γδ T cells are innate cells able to quickly eliminate pathogens or infected/tumoral cells by their antiviral and adjuvancy activities. The role of γδ T cells during Dengue Viral Infection (DENV) infection is not fully elucidated. Nevertheless, human primary γδ T cells have been shown to kill in vitro DENV-infected cells, thus highlighting their possible antiviral function. The aim of this work was to characterize the phenotype and function of Vδ2 T cells in DENV patients. Fifteen DENV patients were enrolled for this study and peripheral blood mononuclear cells (PBMC) were used to analyze Vδ2-T-cell frequency, differentiation profile, activation/exhaustion status, and functionality by multiparametric flow cytometry. Our data demonstrated that DENV infection was able to significantly reduce Vδ2-T-cell frequency and to increase their activation (CD38 and HLA-DR) and exhaustion markers (PD-1 and TIM-3). Furthermore, Vδ2 T cells showed a reduced capability to produce IFN-γ after phosphoantigenic stimulation that can be associated to TIM-3 expression. Several studies are needed to depict the possible clinical impact of γδ-T-cell impairment on disease severity and to define the antiviral and immunoregulatory activities of γδ T cells in the first phases of infection.
MeSH term(s)	Adaptation, Physiological ; Adult ; Dengue/immunology ; Flow Cytometry ; Hepatitis A Virus Cellular Receptor 2/genetics ; Hepatitis A Virus Cellular Receptor 2/metabolism ; Humans ; Immunity, Innate ; Interferon-gamma/metabolism ; Intraepithelial Lymphocytes/immunology ; Leukocytes, Mononuclear/immunology ; Lymphocyte Activation/immunology ; Male ; Middle Aged ; T-Lymphocyte Subsets/immunology
Chemical Substances	HAVCR2 protein, human ; Hepatitis A Virus Cellular Receptor 2 ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2022-01-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v14010130
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Article: Torquetenovirus Loads in Peripheral Blood Predict Both the Humoral and Cell-Mediated Responses to SARS-CoV-2 Elicited by the mRNA Vaccine in Liver Transplant Recipients.

Minosse, Claudia / Matusali, Giulia / Meschi, Silvia / Grassi, Germana / Francalancia, Massimo / D'Offizi, Gianpiero / Spezia, Pietro Giorgio / Garbuglia, Anna Rosa / Montalbano, Marzia / Focosi, Daniele / Girardi, Enrico / Vaia, Francesco / Ettorre, Giuseppe Maria / Maggi, Fabrizio

Vaccines

2023 Volume 11, Issue 11

Abstract: Three years into the COVID-19 pandemic, mass vaccination campaigns have largely controlled the disease burden but have not prevented virus circulation. Unfortunately, many immunocompromised patients have failed to mount protective immune responses after ... ...

Abstract	Three years into the COVID-19 pandemic, mass vaccination campaigns have largely controlled the disease burden but have not prevented virus circulation. Unfortunately, many immunocompromised patients have failed to mount protective immune responses after repeated vaccinations, and liver transplant recipients are no exception. Across different solid organ transplant populations, the plasma levels of Torquetenovirus (TTV), an orphan and ubiquitous human virus under control of the immune system, have been shown to predict the antibody response after COVID-19 vaccinations. We show here a single-institution experience with TTV viremia in 134 liver transplant recipients at their first or third dose. We found that TTV viremia before the first and third vaccine doses predicts serum anti-SARS-CoV-2 Spike receptor-binding domain (RBD) IgG levels measured 2-4 weeks after the second or third dose. Pre-vaccine TTV loads were also associated with peripheral blood anti-SARS-CoV-2 cell-mediated immunity but not with serum SARS-CoV-2 neutralizing antibody titers.
Language	English
Publishing date	2023-10-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines11111656
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Article: In Vitro and In Vivo Crosstalk between Type I IFN and IL-8 Responses in SARS-CoV-2 Infection.

Biava, Mirella / Notari, Stefania / Grassi, Germana / Bordi, Licia / Tartaglia, Eleonora / Agrati, Chiara / Cimini, Eleonora / Sberna, Giuseppe / Nicastri, Emanuele / Antinori, Andrea / Girardi, Enrico / Vaia, Francesco / Maggi, Fabrizio / Lalle, Eleonora

Microorganisms

2023 Volume 11, Issue 11

Abstract: COVID-19 patients show characteristic over-expression of different cytokines that may interfere with the interferon (IFN) response, delaying its production. Within the overexpressed cytokines, IL-8 plays a key role, and it may impede IFN-I activation. ... ...

Abstract	COVID-19 patients show characteristic over-expression of different cytokines that may interfere with the interferon (IFN) response, delaying its production. Within the overexpressed cytokines, IL-8 plays a key role, and it may impede IFN-I activation. PBMC from eight healthy donors were exposed to 2019-nCoV/Italy-INMI1 isolate and supernatants/cells were collected at different time points; the production of either IFN-alpha or IL-8 was assessed. The same analysis was performed on plasma samples obtained from 87 COVID-19 patients. Antagonism between IFN-alpha and IL-8 was observed, since in those PBMC with medium or high IL-8 levels, IFN-α levels were low. The same scenario was observed in SARS-CoV-2-infected patients that were divided into three groups based on IL-8 low, medium and high levels; the correlation between low levels of IFN-α and high levels of IL-8 was statistically significant in both the IL-8 medium and IL-8 high group. Overall, our results showed a crosstalk/antagonism between IL-8 and IFN-alpha in PBMC from healthy donors challenged with SARS-CoV-2 and inversely proportional IFN-alpha levels to IL-8 concentrations detected in plasma samples from COVID-19 patients, suggesting that the impairment of the innate immune response in COVID-19 patients may be linked to a dysregulated cytokine response, namely through IL-8 production.
Language	English
Publishing date	2023-11-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms11112787
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Article ; Online: Third dose of SARS-CoV2 mRNA vaccination produces robust persistent cellular and humoral immune responses in liver transplant recipients.

Montalbano, Marzia / Piccolo, Paola / Lionetti, Raffaella / Visco-Comandini, Ubaldo / Agrati, Chiara / Grassi, Germana / Meschi, Silvia / Matusali, Giulia / Conte, Federica / Angelone, Federica / Ettorre, Giuseppe Maria / Guglielmo, Nicola / Maggi, Fabrizio / Francalancia, Massimo / Mereu, Tiziana / Puro, Vincenzo / Girardi, Enrico / D'Offizi, Gianpiero

Liver international : official journal of the International Association for the Study of the Liver

2023 Volume 43, Issue 5, Page(s) 1120–1125

Abstract: Weaker responses have been described after two doses of anti-SARS-CoV2 vaccination in liver transplant recipients (LTRs). At the Italian National Institute for Infectious Diseases, 122 LTRs (84% males, median age 64 years) were tested for humoral and ... ...

Abstract	Weaker responses have been described after two doses of anti-SARS-CoV2 vaccination in liver transplant recipients (LTRs). At the Italian National Institute for Infectious Diseases, 122 LTRs (84% males, median age 64 years) were tested for humoral and cell-mediated immune response after a third doses of anti-SARS-CoV2 mRNA vaccines. Humoral response was measured by quantifying anti-receptor binding domain and neutralizing antibodies; cell-mediated response was measured by quantifying IFN-γ after stimulation of T cells with SARS-CoV-2-specific peptides. Humoral and cellular responses improved significantly compared to the second vaccine dose; 86.4% of previous non-responders to the first 2 vaccine doses (N = 22) became responders. Mycophenolate mofetil-containing regimens were not associated with lower response rates to a third vaccine; shorter time since transplantation (<6 years) was associated with lower humoral and cellular responses to third vaccine. Protective antibodies against Omicron variant were detected in 60% of patients 12 weeks after third vaccine dose.
MeSH term(s)	Male ; Humans ; Middle Aged ; Female ; Immunity, Humoral ; Liver Transplantation ; COVID-19/prevention & control ; SARS-CoV-2 ; Vaccination ; RNA, Messenger ; Antibodies, Viral ; Transplant Recipients
Chemical Substances	RNA, Messenger ; Antibodies, Viral
Language	English
Publishing date	2023-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2102783-3
ISSN	1478-3231 ; 1478-3223
ISSN (online)	1478-3231
ISSN	1478-3223
DOI	10.1111/liv.15557
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Article ; Online: The interplay between SARS-CoV-2 infected airway epithelium and immune cells modulates regulatory/inflammatory signals.

Bordoni, Veronica / Matusali, Giulia / Mariotti, Davide / Antonioli, Manuela / Cimini, Eleonora / Sacchi, Alessandra / Tartaglia, Eleonora / Casetti, Rita / Grassi, Germana / Notari, Stefania / Castilletti, Concetta / Fimia, Gian Maria / Capobianchi, Maria Rosaria / Ippolito, Giuseppe / Agrati, Chiara

iScience

2022 Volume 25, Issue 2, Page(s) 103854

Abstract: To assess the cross-talk between immune cells and respiratory tract during SARS-CoV-2 infection, we analyzed the relationships between the inflammatory response induced by SARS-CoV-2 replication and immune cells phenotype in a reconstituted organotypic ... ...

Abstract	To assess the cross-talk between immune cells and respiratory tract during SARS-CoV-2 infection, we analyzed the relationships between the inflammatory response induced by SARS-CoV-2 replication and immune cells phenotype in a reconstituted organotypic human airway epithelium (HAE). The results indicated that immune cells failed to inhibit SARS-CoV-2 replication in the HAE model. In contrast, immune cells strongly affected the inflammatory profile induced by SARS-CoV-2 infection, dampening the production of several immunoregulatory/inflammatory signals (e.g., IL-35, IL-27, and IL-34). Moreover, these mediators were found inversely correlated with innate immune cell frequency (NK and γδ T cells) and directly with CD8 T cells. The enriched signals associated with NK and CD8 T cells highlighted the modulation of pathways induced by SARS-CoV-2 infected HAE. These findings are useful to depict the cell-cell communication mechanisms necessary to develop novel therapeutic strategies aimed to promote an effective immune response.
Language	English
Publishing date	2022-01-31
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.103854
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Article ; Online: Per2 Upregulation in Circulating Hematopoietic Progenitor Cells During Chronic HIV Infection.

Bordoni, Veronica / Tartaglia, Eleonora / Refolo, Giulia / Sacchi, Alessandra / Grassi, Germana / Antinori, Andrea / Fimia, Gian Maria / Agrati, Chiara

Frontiers in cellular and infection microbiology

2020 Volume 10, Page(s) 362

Abstract: Chronic HIV infection accelerates immune aging and is associated with abnormal hemato-lymphopoiesis, but the relationship between HIV-induced aging and Hematopoietic Progenitor Cells (HPC) function is not well-defined. In the context of aging, it has ... ...

Abstract	Chronic HIV infection accelerates immune aging and is associated with abnormal hemato-lymphopoiesis, but the relationship between HIV-induced aging and Hematopoietic Progenitor Cells (HPC) function is not well-defined. In the context of aging, it has been demonstrated using a murine model that Per2 (Period circadian clock 2) is a negative regulator of HPC survival and lineage potential. A possible involvement of Per2 modulation on hematopoietic failure during HIV infection has not yet been investigated. The aim of this study was to analyze whether Per2 is differently expressed and regulated on HPC during HIV infection, possibly providing a therapeutic target to restore lymphoid potential in the HPC compartment. To this purpose, Per2 expression in circulating HPC was compared in 69 chronic HIV infected patients under successful ART and in matched 30 uninfected healthy donors (HD). HPC aging was assessed by measuring relative telomere length (RTL), and HPC functionality was evaluated by Colony Forming Cell (CFC) assay from both
MeSH term(s)	Aged ; Aging ; Animals ; Cell Differentiation ; HIV Infections ; Hematopoietic Stem Cells ; Humans ; Mice ; Period Circadian Proteins/genetics ; Period Circadian Proteins/metabolism ; Up-Regulation
Chemical Substances	PER2 protein, human ; Per2 protein, mouse ; Period Circadian Proteins
Language	English
Publishing date	2020-07-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2020.00362
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Article ; Online: Expansion of Myeloid Derived Suppressor Cells Contributes to Platelet Activation by L-Arginine Deprivation during SARS-CoV-2 Infection.

Sacchi, Alessandra / Grassi, Germana / Notari, Stefania / Gili, Simona / Bordoni, Veronica / Tartaglia, Eleonora / Casetti, Rita / Cimini, Eleonora / Mariotti, Davide / Garotto, Gabriele / Beccacece, Alessia / Marchioni, Luisa / Bibas, Michele / Nicastri, Emanuele / Ippolito, Giuseppe / Agrati, Chiara

Cells

2021 Volume 10, Issue 8

Abstract: 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- ... ...

Abstract	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.
Language	English
Publishing date	2021-08-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10082111
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