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      Coxiella burnetii Whole Cell Vaccine Produces a Th1 Delayed-Type Hypersensitivity Response in a Novel Sensitized Mouse Model

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          Abstract

          Q-VAX®, a whole cell, formalin-inactivated vaccine, is the only vaccine licensed for human use to protect against Coxiella burnetii, the cause of Q fever. Although this vaccine provides long-term protection, local and systemic reactogenic responses are common in previously sensitized individuals which prevents its use outside of Australia. Despite the importance of preventing these adverse reactions to develop widely accepted, novel vaccines against C. burnetii, little is understood about the underlying cellular mechanisms. This is mostly attributed to the use of a guinea pig reactogenicity model where complex cellular analysis is limited. To address this, we compared three different mouse strains develop a model of C. burnetii whole cell vaccine reactogenic responses. SKH1 and C57Bl/6, but not BALBc mice, develop local granulomatous reactions after either infection- or vaccine-induced sensitization. We evaluated local and systemic responses by measuring T cell populations from the vaccination site and spleen during elicitation using flow cytometry. Local reaction sites showed influx of IFNγ+ and IL17a+ CD4 T cells in sensitized mice compared with controls and a reduction in IL4+ CD4 T cells. Additionally, sensitized mice showed a systemic response to elicitation by an increase in IFNγ+ and IL17a+ CD4 T cells in the spleen. These results indicate that local and systemic C. burnetii reactogenic responses are consistent with a Th1 delayed-type hypersensitivity. Our experiments provide insights into the pathophysiology of C. burnetii whole cell vaccine reactogenicity and demonstrate that C57Bl/6 and SKH1 mice can provide a valuable model for evaluating the reactogenicity of novel C. burnetii vaccine candidates.

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          Most cited references51

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          QuPath: Open source software for digital pathology image analysis

          QuPath is new bioimage analysis software designed to meet the growing need for a user-friendly, extensible, open-source solution for digital pathology and whole slide image analysis. In addition to offering a comprehensive panel of tumor identification and high-throughput biomarker evaluation tools, QuPath provides researchers with powerful batch-processing and scripting functionality, and an extensible platform with which to develop and share new algorithms to analyze complex tissue images. Furthermore, QuPath’s flexible design makes it suitable for a wide range of additional image analysis applications across biomedical research.
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            M-1/M-2 Macrophages and the Th1/Th2 Paradigm

            Evidence is provided that macrophages can make M-1 or M-2 responses. The concept of M-1/M-2 fomented from observations that macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more easily activated to produce NO with either IFN-gamma or LPS than macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS stimulates Th2, but not Th1, macrophages to increase arginine metabolism to ornithine. Thus, M-1/M-2 does not simply describe activated or unactivated macrophages, but cells expressing distinct metabolic programs. Because NO inhibits cell division, while ornithine can stimulate cell division (via polyamines), these results also indicate that M-1 and M-2 responses can influence inflammatory reactions in opposite ways. Macrophage TGF-beta1, which inhibits inducible NO synthase and stimulates arginase, appears to play an important role in regulating the balance between M-1 and M-2. M-1/M-2 phenotypes are independent of T or B lymphocytes because C57BL/6 and BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2 proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID macrophages cause CB6F1 lymphocytes to increase IFN-gamma production, while BALB/c SCID macrophages increase TGF-beta production. Together, the results indicate that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur.
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              From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation

              Studies on monocyte and macrophage biology and differentiation have revealed the pleiotropic activities of these cells. Macrophages are tissue sentinels that maintain tissue integrity by eliminating/repairing damaged cells and matrices. In this M2-like mode, they can also promote tumor growth. Conversely, M1-like macrophages are key effector cells for the elimination of pathogens, virally infected, and cancer cells. Macrophage differentiation from monocytes occurs in the tissue in concomitance with the acquisition of a functional phenotype that depends on microenvironmental signals, thereby accounting for the many and apparently opposed macrophage functions. Many questions arise. When monocytes differentiate into macrophages in a tissue (concomitantly adopting a specific functional program, M1 or M2), do they all die during the inflammatory reaction, or do some of them survive? Do those that survive become quiescent tissue macrophages, able to react as naïve cells to a new challenge? Or, do monocyte-derived tissue macrophages conserve a “memory” of their past inflammatory activation? This review will address some of these important questions under the general framework of the role of monocytes and macrophages in the initiation, development, resolution, and chronicization of inflammation.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                20 September 2021
                2021
                : 12
                : 754712
                Affiliations
                [1] 1Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University , College Station, TX, United States
                [2] 2Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University , Bryan, TX, United States
                [3] 3Department of Physiology & Biophysics, School of Medicine, University of California Irvine , Irvine, CA, United States
                Author notes

                Edited by: Arun Kumar, Coalition for Epidemic Preparedness Innovations (CEPI), Norway

                Reviewed by: Anders Omsland, Washington State University, United States; Gilbert Kersh, Centers for Disease Control and Prevention (CDC), United States

                *Correspondence: James E. Samuel, jsamuel@ 123456tamu.edu

                This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2021.754712
                8488435
                34616410
                1f16848e-5a8e-4296-82fb-eac613aebc0c
                Copyright © 2021 Fratzke, Gregory, van Schaik and Samuel

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 August 2021
                : 06 September 2021
                Page count
                Figures: 9, Tables: 0, Equations: 0, References: 52, Pages: 15, Words: 7651
                Funding
                Funded by: Defense Threat Reduction Agency , doi 10.13039/100000774;
                Award ID: HDTRA1-14-C-0113
                Funded by: National Institutes of Health , doi 10.13039/100000002;
                Award ID: 2T32OD011083-11
                Categories
                Immunology
                Original Research

                Immunology
                coxiella burnetii,delayed-type hypersensitivity,mouse model,q fever,vaccine,th1
                Immunology
                coxiella burnetii, delayed-type hypersensitivity, mouse model, q fever, vaccine, th1

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