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      A Neglected Animal Model for a Neglected Disease: Guinea Pigs and the Search for an Improved Animal Model for Human Brucellosis

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          Abstract

          Brucellosis is a bacterial disease caused by species of the Brucella genus and affects a wide variety of domestic and wildlife species and is also an important zoonosis. The global burden of disease is difficult to assess but Brucella spp. have a worldwide distribution and are endemic in the Middle East, Africa, South America, and Asia. The clinical signs of fever and malaise are non-specific, and the available serological diagnostic tests lack a high degree specificity in endemic regions compared to other important public health diseases such as malaria. A better understanding of the pathogenesis of brucellosis through discoveries in animal models could lead to improved diagnostics and potentially a vaccine for human use. Mouse models have played an important role in elucidating the pathogenesis but do not replicate key features of the disease such as fever. Guinea pigs were instrumental in exploring the pathogenesis of brucellosis in the early nineteenth century and could offer an improvement on the mouse model as a model for human brucellosis.

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          Most cited references 81

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          Brucellosis: an overview.

           M Corbel (1997)
          Brucellosis remains a major zoonosis worldwide. Although many countries have eradicated Brucella abortus from cattle, in some areas Brucella melitensis has emerged as a cause of infection in this species as well as in sheep and goats. Despite vaccination campaigns with the Rev 1 strain, B. melitensis remains the principal cause of human brucellosis. Brucella suis is also emerging as an agent of infection in cattle, thus extending its opportunities to infect humans. The recent isolation of distinctive strains of Brucella from marine mammals has extended its ecologic range. Molecular genetic studies have demonstrated phylogenetic affiliation to Agrobacterium, Phyllobacterium, Ochrobactrum, and Rhizobium. Polymerase chain reaction and gene probe development may provide more effective typing methods. Pathogenicity is related to production of lipopolysaccharides containing a poly N-formyl perosamine O chain, CuZn superoxide dismutase, erythrlose phosphate dehydrogenase, stress-induced proteins related to intracellular survival, and adenine and guanine monophosphate inhibitors of phagocyte functions. Protective immunity is conferred by antibody to lipopolysaccharide and T-cell-mediated macrophage activation triggered by protein antigens. Diagnosis still centers on isolation of the organism and serologic test results, especially enzyme immunoassay, which is replacing other methods. Polymerase chain reaction is also under evaluation. Therapy is based on tetracyclines with or without rifampicin, aminoglycosides, or quinolones. No satisfactory vaccines against human brucellosis are available, although attenuated purE mutants appear promising.
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            An overview of human brucellosis.

             Susan Young (1995)
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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
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                31 October 2018
                2018
                : 9
                Affiliations
                Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University , College Station, TX, United States
                Author notes

                Edited by: Axel Cloeckaert, Institut National de la Recherche Agronomique (INRA), France

                Reviewed by: Roy Martin Roop II, East Carolina University, United States; Ignacio Moriyón, Universidad de Navarra, Spain

                *Correspondence: Angela M. Arenas-Gamboa, aarenas@ 123456cvm.tamu.edu

                This article was submitted to Infectious Diseases, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2018.02593
                6220108
                Copyright © 2018 Hensel and Arenas-Gamboa.

                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.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 90, Pages: 9, Words: 0
                Categories
                Microbiology
                Review

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