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CyTOF Profiling of Zika and Dengue Virus-Infected Human Peripheral Blood Mononuclear Cells Identifies Phenotypic Signatures of Monotype Subsets and Upregulation of the Interferon-Inducible Protein CD169.

ABSTRACT: Zika and dengue virus (ZIKV and DENV) are two flaviviruses responsible for important vector-borne emerging infectious diseases. While there have been multiple DENV epidemics in the last decades, there have been fewer documented epidemics caused by ZIKV until recent years. Thus, our current knowledge about the biology of ZIKV, the disease, and the immune responses in humans is limited. Here, we used mass cytometry (CyTOF) to perform a detailed characterization of the innate immune responses elicited by ZIKV and DENV in human peripheral blood mononuclear cells (PBMCs) from healthy donors infected ex vivo. We found that ZIKV and DENV exposure of human PBMCs induces global phenotypic changes in myeloid cells, characterized mainly by upregulation of costimulatory molecules (CD86 and CD40), CD38, and the type I interferon-inducible protein CD169, a marker for phagocytic function and cross-priming potential in myeloid cells. We also found that ZIKV induces expansion of nonclassical monocytes in cell culture. The analysis of the phenotype of the three monocyte subtypes (classical, intermediate, and nonclassical) at the single-cell level identified differences in their expression of CD86, CD38, CXCL8, and CXCL10 during ZIKV and DENV infection. Overall, using CyTOF, we found that ex vivo infections of PBMCs with ZIKV and DENV reproduced many aspects of the profile found in blood from patients in previously described cohort studies, which highlights the suitability of this system for the study of the human host responses to these viruses. IMPORTANCE Zika and dengue viruses are emergent arboviruses of great public health impact. Both viruses are responsible for important diseases, yet there is currently no vaccine or specific treatment available. Immune cells play critical roles in the virus cycle as well as in the innate and adaptive immune response elicited in the host; therefore, it is critical to understand the changes induced by virus infection in peripheral blood mononuclear cells (PBMCs). In this study, we used a model of ex vivo infection of PBMCs and CyTOF technology to profile the early innate immune changes induced by Zika virus and dengue virus in blood.

SUBMITTER: Fenutria R

PROVIDER: S-EPMC8265667 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The mechanisms underlying the therapeutic activity of interferon-? in multiple sclerosis are still not completely understood. In the present study, we evaluated the short and long-term effects of interferon-? treatment on different subsets of regulatory T cells in relapsing-remitting multiple sclerosis patients biologically responsive to treatment because of mixovirus resistance protein A inducibility. METHODS:In this prospective longitudinal study, subsets of natural regulatory T cells (naïve, central memory and effector memory) and inducible regulatory T cells (Tr1), as well as in vitro-induced regulatory T cells (Tr1-like cells), were simultaneously quantified by flow cytometry in samples prepared from 148 therapy-naïve multiple sclerosis patients obtained before and after 6, 12, 18, and 24 months of interferon-?-1a treatment. mRNA for interleukin-10 and Tr1-related genes (CD18, CD49b, and CD46, together with Cyt-1 and Cyt-2 CD46-associated isoforms) were quantified in Tr1-like cells. RESULTS:Despite profound inter-individual variations in the modulation of all regulatory T-cell subsets, the percentage of natural regulatory T cells increased after 6, 12, and 24 months of interferon-? treatment. This increase was characterized by the expansion of central and effector memory regulatory T-cell subsets. The percentage of Tr1 significantly enhanced at 12 months of therapy and continued to be high at the subsequent evaluation points. Patients experiencing relapses displayed a higher percentage of naïve regulatory T cells and a lower percentage of central memory regulatory T cells and of Tr1 before starting interferon-? therapy. In addition, an increase over time of central memory and of Tr1 was observed only in patients with stable disease. However, in vitro-induced Tr1-like cells, prepared from patients treated for 24 months, produced less amount of interleukin-10 mRNA compared with pre-treatment Tr1-like cells. CONCLUSION:Interferon-? induces the expansion of T regulatory subsets endowed with a high suppressive activity, especially in clinically stable patients. The overall concurrent modulation of natural and inducible regulatory T-cell subsets might explain the therapeutic effects of interferon-? in multiple sclerosis patients.

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CyTOF Profiling of Zika and Dengue Virus-Infected Human Peripheral Blood Mononuclear Cells Identifies Phenotypic Signatures of Monotype Subsets and Upregulation of the Interferon-Inducible Protein CD169.

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