What have we learned from brucellosis in the mouse model?

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.

INFECTION OF C57BL/6 MICE BYTRYPANOSOMA MUSCULIMODULATES HOST IMMUNE RESPONSES DURINGBRUCELLA ABORTUSCOCOLONIZATION

“…The S19 also displayed early suppressive effects at 7 dpi before returning to concentrations consistent with naïve animals. The S19 IgG suppression is consistent with previous reports in this mouse strain (Grillo et al 2012).…”

“…The murine model for B. abortus is well established and allows for efficient evaluation of the effect trypanosomes have on the host immune system (Montaraz and Winter 1986;Grillo et al 2012). Trypanosoma musculi was also evaluated in C57BL/6 mice and found to induce profound T-cell depression and anergy at 7 days postinfection (dpi) (Magluilo et al 1983).…”

Assessment of Hematological Bio Markers during Vaccination and Challenge of Brucella melitensis in Goats

“…In this regard, based on a substantial data dedicated to standardize the mouse model for vaccine testing, a standardized protocol for controlling the quality of B. melitensis Rev.1 vaccines has been accepted by the World Organization for Animal Health [9]. The vaccine efficacy is generally analyzed 2 weeks after challenge, when the differences between the reference-vaccinated and unvaccinated controls have reached at maximum [7]. Considering these facts, goats were challenged 28 th day post vaccination and sacrificed 90 th day post challenge.…”

“…The higher values of granulocyte in challenged animals indicated more virulence of organisms. The lymphocyte/granulocyte proportions in blood vary according to animal species and breed and may range in between 80/15 % to 90/9 % on Brucella infection [7]. It has been suggested that a phenotype may be related to Brucella clearance due to the regulatory action which neutrophils can display over macrophages [17].…”

“…Moreover, protective ability against locally prevalent virulent strain and its ability to induce adaptive immune response in native breed are always under question as protective efficacy of Rev.1 vaccine greatly depends on the Brucella virulence and challenge dose presented to host species. The genetic makeup of host also affects the effectiveness and protective ability of vaccine [6,7]. All these interactions involve cellular interactions depending upon pathophysiological changes and induction of immune response.…”