Abstract
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.
Highlights
Infection modelsThe Brucella stains: replication patterns and related effects Route of the infection Infective dose The mouseResistant and susceptible mouse strains Mutant and knockout mice Age and sex Transmission Physiopathology Onset of the infection Acute phase Acute phase in pregnant mice Chronic steady phase Chronic declining phase Vaccination Superinfection and antigen therapy Passive transfer and immunomodulation Antibiotic treatment Concluding remarks Endnotes Competing interests Authors’ contributions Acknowledgments References
In the understanding that infection with virulent Brucella is a continuous process and that delimitations are not clear cut, this replication profile can be divided into four different phases (Figure 1A): i) the onset of the infection, marked by colonization during the first 48 h pi; ii) the acute phase, extending from the 3rd day to the time when CFU reach their maximum, generally between weeks 2 and 3; iii) the chronic steady phase, that corresponds to the CFU plateau, commonly lasting 8–11 weeks; and iv) the chronic declining phase, at which there is a slow elimination of the bacteria that may last beyond 36 weeks
Mice are quite resistant to Brucella infection but, in contrast to natural hosts, do not seem to shed Brucella significantly and the infection seems to be contained
Summary
The genus Brucella comprises at least eight species named according to their preferred mammal hosts. In the understanding that infection with virulent Brucella (at standard doses, see below) is a continuous process and that delimitations are not clear cut, this replication profile can be divided into four different phases (Figure 1A): i) the onset of the infection, marked by colonization during the first 48 h pi; ii) the acute phase, extending from the 3rd day to the time when CFU reach their maximum, generally between weeks 2 and 3; iii) the chronic steady phase, that corresponds to the CFU plateau, commonly lasting 8–11 weeks; and iv) the chronic declining phase, at which there is a slow elimination of the bacteria that may last beyond 36 weeks The span of these phases may vary depending upon the bacterial dose, route, mouse strain and age [30]. Brucella spleen CFU increase and persistence relative to mouse reference straina
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