Abstract
BackgroundThe brucellae are facultative intracellular bacteria that cause brucellosis, one of the major neglected zoonoses. In endemic areas, vaccination is the only effective way to control this disease. Brucella melitensis Rev 1 is a vaccine effective against the brucellosis of sheep and goat caused by B. melitensis, the commonest source of human infection. However, Rev 1 carries a smooth lipopolysaccharide with an O-polysaccharide that elicits antibodies interfering in serodiagnosis, a major problem in eradication campaigns. Because of this, rough Brucella mutants lacking the O-polysaccharide have been proposed as vaccines.Methodology/Principal FindingsTo examine the possibilities of rough vaccines, we screened B. melitensis for lipopolysaccharide genes and obtained mutants representing all main rough phenotypes with regard to core oligosaccharide and O-polysaccharide synthesis and export. Using the mouse model, mutants were classified into four attenuation patterns according to their multiplication and persistence in spleens at different doses. In macrophages, mutants belonging to three of these attenuation patterns reached the Brucella characteristic intracellular niche and multiplied intracellularly, suggesting that they could be suitable vaccine candidates. Virulence patterns, intracellular behavior and lipopolysaccharide defects roughly correlated with the degree of protection afforded by the mutants upon intraperitoneal vaccination of mice. However, when vaccination was applied by the subcutaneous route, only two mutants matched the protection obtained with Rev 1 albeit at doses one thousand fold higher than this reference vaccine. These mutants, which were blocked in O-polysaccharide export and accumulated internal O-polysaccharides, stimulated weak anti-smooth lipopolysaccharide antibodies.Conclusions/SignificanceThe results demonstrate that no rough mutant is equal to Rev 1 in laboratory models and question the notion that rough vaccines are suitable for the control of brucellosis in endemic areas.
Highlights
Brucellosis is a group of closely related zoonotic bacterial diseases caused by the members of the genus Brucella, a group of gram-negative bacteria that behave as facultative intracellular parasites
Conclusions/Significance: The results demonstrate that no rough mutant is equal to Rev 1 in laboratory models and question the notion that rough vaccines are suitable for the control of brucellosis in endemic areas
Vaccines B. abortus S19 and B. melitensis Rev 1 have been successfully used in some developed countries, but both induce abortions when applied during pregnancy, are virulent for humans and elicit antibodies to the smooth (S) lipopolysaccharide (LPS) of the Brucella surface that interfere in serodiagnosis
Summary
Brucellosis is a group of closely related zoonotic bacterial diseases caused by the members of the genus Brucella, a group of gram-negative bacteria that behave as facultative intracellular parasites. There is no human vaccine, vaccination of animals against brucellosis is one of the most cost-effective measures to improve human health in endemic areas [4] as well as an essential tool to achieve eradication [5,6]. For these purposes, vaccines B. abortus S19 and B. melitensis Rev 1 have been successfully used in some developed countries, but both induce abortions when applied during pregnancy, are virulent for humans and elicit antibodies to the smooth (S) lipopolysaccharide (LPS) of the Brucella surface that interfere in serodiagnosis. Rough Brucella mutants lacking the O-polysaccharide have been proposed as vaccines
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