Byproducts of inflammatory radical metabolism provide transient nutrient niches for microbes in the inflamed gut.

Louis Pasteur's experiments on tartaric acid laid the foundation for our understanding of molecular chirality, but major questions remain. By comparing the optical activity of naturally-occurring tartaric acid with chemically-synthesized paratartaric acid, Pasteur realized that naturally-occurring tartaric acid contained only L-tartaric acid while paratartaric acid consisted of a racemic mixture of D- and L-tartaric acid. Curiously, D-tartaric acid has no known natural source, yet several gut bacteria specifically degrade D-tartaric acid. Here, we investigated the oxidation of monosaccharides by inflammatory reactive oxygen and nitrogen species. We found that this reaction yields an array of alpha hydroxy carboxylic acids, including tartaric acid isomers. Utilization of inflammation- derived D- and L-tartaric acid enhanced colonization by Salmonella Typhimurium and E. coli in murine models of gut inflammation. Our findings suggest that byproducts of inflammatory radical metabolism, such as tartrate and other alpha hydroxy carboxylic acids, create transient nutrient niches for enteric pathogens and other potentially harmful bacteria. Furthermore, this work illustrates that inflammatory radicals generate a zoo of molecules, some of which may erroneously presumed to be xenobiotics.

Meta-analysis of brucellosis vaccinology in natural hosts / Meta-análise da vacinologia de brucelose em hospedeiros naturais

Brucellosis is a relevant zoonotic disease for which the most important tool for control is vaccination of susceptible animals. Assessment of vaccine efficacy in natural hosts is based on prevention of abortion and Brucella infection in organs of immunized animals. A meta-analysis of experimental vaccination of Brucella spp. natural hosts was performed, including 45 PubMed and/or Scopus-indexed publications, representing 116 individual experiments. Difference of risk was calculated as an indicator of protection, and a temporal analysis (1980-2016) demonstrated that experimental vaccines tested on natural hosts provided levels of protection that were stable over the past decades. The meta-regression model developed in this study included different vaccine categories (attenuated, inactivated, mutant, subunit, and vectored) considering the difference of risk as the dependent variable. The subcutaneous route of vaccination provided better protection when compared to the intramuscular and oral routes of vaccination. Surprisingly, inactivated vaccines provided better protection than live naturally attenuated vaccine strains (spontaneous mutations) that were considered the reference, whereas subunit vaccines provided lower levels of protection. This is the first meta-analysis of Brucella vaccinology in the natural hosts. These results are useful for the development of new vaccination protocols for controlling animal brucellosis.(AU)

Brucelose é uma doença zoonótica relevante, para a qual a vacinação de animais susceptíveis é a ferramenta mais importante de controle. Avaliação da eficácia vacinal em hospedeiros naturais é baseada na prevenção de aborto e da colonização de órgãos pela Brucella spp. em animais imunizados. Foi realizada meta-análise de estudos de vacinação experimental de Brucella spp. em hospedeiros naturais, incluindo 45 publicações indexadas pela PubMed e/ou Scopus, representando 116 experimentos individuais. Diferença de risco foi calculada como indicador de proteção e uma análise temporal (1980-2016) demonstrou que vacinas experimentais testadas em hospedeiros naturais promoveram níveis de proteção que foram estáveis ao longo das últimas décadas. O modelo de meta-regressão desenvolvido neste estudo incluiu diferentes categorias de vacinas (atenuada, inativada, mutante, subunidade e vetorial) considerando a diferença de risco como variável dependente. A via de vacinação subcutânea promoveu melhor proteção quando comparada às vias intramuscular e oral. Surpreendentemente, vacinas inativadas promoveram melhor proteção que vacinas vivas atenuadas (com mutações espontâneas) que foram consideradas como referência, enquanto vacinas de subunidades promoveram menor proteção. Este é o primeiro estudo de meta-análise da vacinologia de Brucella em hospedeiros naturais. Estes resultados são úteis para o desenvolvimento de novos protocolos vacinais para controle de brucelose animal.(AU)

Brucella ovis mutant in ABC transporter protects against Brucella canis infection in mice and it is safe for dogs.

BACKGROUND/OBJECTIVES: Vaccination is the most important tool for controlling brucellosis, but currently there is no vaccine available for canine brucellosis, which is a zoonotic disease of worldwide distribution caused by Brucella canis. This study aimed to evaluate protection and immune response induced by Brucella ovis ΔabcBA (BoΔabcBA) encapsulated with alginate against the challenge with Brucella canis in mice and to assess the safety of this strain for dogs. METHODS: Intracellular growth of the vaccine strain BoΔabcBA was assessed in canine and ovine macrophages. Protection induced by BoΔabcBA against virulent Brucella canis was evaluated in the mouse model. Safety of the vaccine strain BoΔabcBA was assessed in experimentally inoculated dogs. RESULTS: Wild type B. ovis and B. canis had similar internalization and intracellular multiplication profiles in both canine and ovine macrophages. The BoΔabcBA strain had an attenuated phenotype in both canine and ovine macrophages. Immunization of BALB/c mice with alginate-encapsulated BoΔabcBA (108 CFU) induced lymphocyte proliferation, production of IL-10 and IFN-γ, and protected against experimental challenge with B. canis. Dogs immunized with alginate-encapsulated BoΔabcBA (109 CFU) seroconverted, and had no hematologic, biochemical or clinical changes. Furthermore, BoΔabcBA was not detected by isolation or PCR performed using blood, semen, urine samples or vaginal swabs at any time point over the course of this study. BoΔabcBA was isolated from lymph nodes near to the site of inoculation in two dogs at 22 weeks post immunization. CONCLUSION: Encapsulated BoΔabcBA protected mice against experimental B. canis infection, and it is safe for dogs. Therefore, B. ovis ΔabcBA has potential as a vaccine candidate for canine brucellosis prevention.

Meta-Analysis and Advancement of Brucellosis Vaccinology.

BACKGROUND/OBJECTIVES: In spite of all the research effort for developing new vaccines against brucellosis, it remains unclear whether these new vaccine technologies will in fact become widely used. The goal of this study was to perform a meta-analysis to identify parameters that influence vaccine efficacy as well as a descriptive analysis on how the field of Brucella vaccinology is advancing concerning type of vaccine, improvement of protection on animal models over time, and factors that may affect protection in the mouse model. METHODS: A total of 117 publications that met the criteria were selected for inclusion in this study, with a total of 782 individual experiments analyzed. RESULTS: Attenuated (n = 221), inactivated (n = 66) and mutant (n = 102) vaccines provided median protection index above 2, whereas subunit (n = 287), DNA (n = 68), and vectored (n = 38) vaccines provided protection indexes lower than 2. When all categories of experimental vaccines are analyzed together, the trend line clearly demonstrates that there was no improvement of the protection indexes over the past 30 years, with a low negative and non significant linear coefficient. A meta-regression model was developed including all vaccine categories (attenuated, DNA, inactivated, mutant, subunit, and vectored) considering the protection index as a dependent variable and the other parameters (mouse strain, route of vaccination, number of vaccinations, use of adjuvant, challenge Brucella species) as independent variables. Some of these variables influenced the expected protection index of experimental vaccines against Brucella spp. in the mouse model. CONCLUSION: In spite of the large number of publication over the past 30 years, our results indicate that there is not clear trend to improve the protective potential of these experimental vaccines.

Apoptose e maturação placentária bovina: um estudo imunohistoquímico e morfométrico / Apoptosis and maturation of the bovine placenta: an immunohistochemical and morphometric study

A liberação da placenta após o parto envolve a perda da adesão materno-fetal e ocorre somente após a maturação completa do placentoma, que está relacionada com a diminuição da celularidade dos tecidos fetal e materno. A apoptose é requerida tanto para a maturação quanto para a liberação normal da placenta após o parto. O objetivo do presente estudo foi avaliar a ocorrência de apoptose em amostras de placenta de vacas em diferentes fases de gestação. Amostras de placentomas de 15 vacas saudáveis com 4 (n=5), 6 (n=5) e 9 (n=5) meses de gestação foram colhidas e processadas rotineiramente para a histologia, imunoistoquímica e histoquímica. As lâminas obtidas foram coradas em HE, Picrosirius Red e submetidas à análise imunoistoquímica das proteínas Caspase 3, Caspase 8, Bax e Bid. O aumento no número de vasos não necessariamente se associou ao aumento do calibre destes durante a evolução da gestação. Os resultados de histomorfometria revelaram aumento da marcação para Bax e Caspases 3 e 8 em células trofoblásticas binucleadas no final da gestação, enquanto o Bid se manteve sem alteração significativa. A histomorfometria das células trofoblásticas mononucleadas revelou expressão alta para Bax no início de gestação, com diminuição aos 6 meses de gestação e aumento das imunomarcações para Caspases 3 e 8, e Bid com o avanço gestacional. Os colágenos tipo I e III não aumentaram do terço médio ao final da gestação, o que é importante para a diminuição da adesão materno-fetal. Esses resultados confirmam que as Caspases 3 e 8, e o Bax estão envolvidos nos mecanismos de ativação da apoptose pela via intrínseca mitocondrial e/ou extrínseca ao longo da gestação em células trofoblásticas binucleadas, e que nas células trofoblásticas mononucleadas o Bax deixa de ser importante, enquanto o Bid e as Caspases 3 e 8 se tornam os mais significativos.

Placental release after birth involves loss of maternal-fetal adhesion and occurs only after complete maturation of the placentoma related to the decrease in cellularity of fetal and maternal tissues. Apoptosis is required for both the normal maturation and release of the placenta after birth. The aim of this study was to evaluate the occurrence of apoptosis in samples of the placenta of cows in different stages of gestation. Samples of 15 healthy cow placentomas at 4 (n=5), 6 (n=5) and 9 (n=5) months of gestation were harvested and processed for routine histology, immunohistochemistry and histochemistry. The slides were stained with HE, PicroSirius Red and subjected to immunohistochemical analysis of proteins Caspase 3, Caspase 8, Bax and Bid. Increase in number of vessels was not associated with increase in vascular area during progression of gestation. The results of histomorphometry revealed increased labeling for Bax and Caspases 3 and 8 in trophoblastic binucleated cells in late pregnancy, where the Bid remained without significant change. Histomorphometry analyzing the mononuclear trophoblast cells showed a high expression for Bax in early pregnancy, but decreased at 6 months of gestation. Immunolabeling revealed increased Caspases 3/8 and Bid with advancing of gestation. Further evaluation of type I and III collagen showed a decrease of both types of collagens at the end of gestation, what is very important for the reduction of maternal-fetal adhesion. These results confirm that Caspases 3 and 8 and Bax are involved in the mechanisms of activation of apoptosis through mitochondrial intrinsic and/or extrinsic pathway during pregnancy in trophoblastic binucleated cells. In mononuclear trophoblast cells Bax looses importance in the apoptosis process, awhile Bid and caspases 3 and 8 become the most significant.