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      Characterization of an intratracheal aerosol challenge model of Brucella melitensis in guinea pigs

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          Abstract

          B. melitensis is considered the most virulent of the Brucella species, and a need exists for an improved laboratory animal model of infection that mimics natural transmission and disease. Guinea pigs are highly susceptible to infection with Brucella spp. and develop a disease syndrome that mimics natural disease after aerosol inoculation. Intratracheal inoculation is a targeted means of generating aerosols that offer advantages over aerosol chamber delivery. To establish this delivery method, female, Hartley guinea pigs were infected via intratracheal inoculation with PBS or 16M B. melitensis at low dose (10 1 to 10 3) or high dose (10 6 to 10 8) and monitored for 30 days for signs of disease. Guinea pigs in the high dose groups developed fever between 12–17 days post-inoculation. Bacteria were recovered from the spleen, liver, lymph nodes, lung, and uterus at 30-days post-inoculation and demonstrated dose dependent mean increases in colonization and pathologic changes consistent with human brucellosis. To study the kinetics of extrapulmonary dissemination, guinea pigs were inoculated with 10 7 CFU and euthanized at 2-hours post inoculation and at weekly intervals for 3 weeks. 5.8x10 5 to 4.2x10 6 CFU were recovered from the lung 2 hours post-inoculation indicating intratracheal inoculation is an efficient means of infecting guinea pigs. Starting at 1-week post inoculation bacteria were recovered from the aforementioned organs with time dependent mean increases in colonization. This data demonstrates that guinea pigs develop a disease syndrome that models the human manifestation of brucellosis, which makes the guinea pig a valuable model for pathogenesis studies.

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          Most cited references 33

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          An overview of human brucellosis.

           Susan Young (1995)
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            Non-invasive pulmonary aerosol delivery in mice by the endotracheal route.

            In this report we present in detail a non-invasive pulmonary application method that can be a useful tool in studying drug and vaccine delivery to the lower airways. In this method the formulation is sprayed directly into the lungs of mice via the endotracheal route using a MicroSprayer aerolizer. Mean droplet size produced was 8 microm, appropriate for deposition in the large airways. Endotracheal application of suspension of fluorescent nanospheres, 200 nm in size, by this method resulted in nanoparticle deposition in the smaller airways (bronchi and bronchioles). Mice showed full recovery one day after administration of 50 microl of formulation. Furthermore, no mortality was observed as a result of the technique. We conclude that this endotracheal application is a useful tool for studying pulmonary drug delivery in mice. The technique is especially useful for the pulmonary application of vaccines, since it enables multiple administrations without a need for analgesics.
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              What have we learned from brucellosis in the mouse model?

              Brucellosis is a zoonosis caused by Brucella species. Brucellosis research in natural hosts is often precluded by practical, economical and ethical reasons and mice are widely used. However, mice are not natural Brucella hosts and the course of murine brucellosis depends on bacterial strain virulence, dose and inoculation route as well as breed, genetic background, age, sex and physiological statu of mice. Therefore, meaningful experiments require a definition of these variables. Brucella spleen replication profiles are highly reproducible and course in four phases: i), onset or spleen colonization (first 48 h); ii), acute phase, from the third day to the time when bacteria reach maximal numbers; iii), chronic steady phase, where bacterial numbers plateaus; and iv), chronic declining phase, during which brucellae are eliminated. This pattern displays clear physiopathological signs and is sensitive to small virulence variations, making possible to assess attenuation when fully virulent bacteria are used as controls. Similarly, immunity studies using mice with known defects are possible. Mutations affecting INF-γ, TLR9, Myd88, Tγδ and TNF-β favor Brucella replication; whereas IL-1β, IL-18, TLR4, TLR5, TLR2, NOD1, NOD2, GM-CSF, IL/17r, Rip2, TRIF, NK or Nramp1 deficiencies have no noticeable effects. Splenomegaly development is also useful: it correlates with IFN-γ and IL-12 levels and with Brucella strain virulence. The genetic background is also important: Brucella-resistant mice (C57BL) yield lower splenic bacterial replication and less splenomegaly than susceptible breeds. When inoculum is increased, a saturating dose above which bacterial numbers per organ do not augment, is reached. Unlike many gram-negative bacteria, lethal doses are large (≥ 108 bacteria/mouse) and normally higher than the saturating dose. Persistence is a useful virulence/attenuation index and is used in vaccine (Residual Virulence) quality control. Vaccine candidates are also often tested in mice by determining splenic Brucella numbers after challenging with appropriate virulent brucellae doses at precise post-vaccination times. Since most live or killed Brucella vaccines provide some protection in mice, controls immunized with reference vaccines (S19 or Rev1) are critical. Finally, mice have been successfully used to evaluate brucellosis therapies. It is concluded that, when used properly, the mouse is a valuable brucellosis model.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Project administration
                Role: InvestigationRole: MethodologyRole: Visualization
                Role: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 March 2019
                2019
                : 14
                : 3
                Affiliations
                [1 ] Texas A&M University, College of Veterinary Medicine and Biomedical Sciences, Department of Veterinary Pathobiology, College Station, Texas, United States of America
                [2 ] Texas A&M University, Health Science Center and College of Medicine, Department of Microbial Pathogenesis and Immunology, College Station, Texas, United States of America
                Consejo Nacional de Investigaciones Cientificas y Tecnicas, ARGENTINA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-18-32292
                10.1371/journal.pone.0212457
                6400394
                30835758
                © 2019 Hensel et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 8, Tables: 1, Pages: 20
                Product
                Funding
                Funded by: T32
                Award ID: 11083-7
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: K01 TW009981-01
                Award Recipient :
                Student stipend support is provided by the National Institute of Health Institutional Training Grant T32 fellowship 5 OD 11083-7 (MEH). Research support provided by the National Institute of Health International Research Scientist Development Award (IRSDA/K01) K01 TW009981-01 (AA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Animal Models
                Guinea Pigs
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Rodents
                Guinea Pigs
                Biology and Life Sciences
                Organisms
                Bacteria
                Brucella
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Brucella
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Bacterial Pathogens
                Brucella
                Physical Sciences
                Materials Science
                Materials
                Mixtures
                Aerosols
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Spleen
                Medicine and Health Sciences
                Physiology
                Immune Physiology
                Spleen
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Fevers
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Fevers
                Biology and Life Sciences
                Anatomy
                Reproductive System
                Uterus
                Medicine and Health Sciences
                Anatomy
                Reproductive System
                Uterus
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Inflammation
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
                Biology and Life Sciences
                Anatomy
                Lymphatic System
                Lymph Nodes
                Medicine and Health Sciences
                Anatomy
                Lymphatic System
                Lymph Nodes
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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