INSTITUTO DE INVESTIGACIONES EN MICROBIOLOGIA Y PARASITOLOGIA MEDICA
Unidad Ejecutora - UE
capítulos de libros
THE IMPORTANCE OF HAEM VS NON-HAEM IRON IN THE SURVIVAL AND PATHOGENESIS OF BRUCELLA ABORTUS
ALMIRÓN, M.; LUCERO, NE; SANJUAN, N
INSIGHT AND CONTROL OF INFECTIOUS DISEASE IN GLOBAL SCENARIO
Año: 2012; p. 427 - 442
Several members of the genus Brucella are responsible for one of the most important zoonotic diseases named brucellosis, causing abortion in animals and a debilitating febrile disease in humans that can progress into a chronic infection with severe complications. Brucella species are highly related to the genetic level and each one has a particular host, although they can infect other animals. Animal brucellosis is usually endemic in developing countries, entailing a severe economic impact. Human brucellosis is difficult to diagnose because symptoms are extremely variable. Few live vaccines are available for cattle but not for humans. The main problems with this pathogen are the lack of virulence factors commonly identified in other bacteria and the ability to establish a niche inside eukaryotic cells, where they replicate and survive, evading the immune response and the action of other antibacterial molecules. In general, the pathogenic mechanisms used by bacteria have been related to the availability of iron, since this essential nutrient is scarce and not easily accessible for bacteria, either in body fluids or inside eukaryotic cells. Thus, the iron deficient environment that bacteria find during infection leads to the induction of genes which products are required to support an effective survival, thus becoming part of virulence factors. Most of them are related to the acquisition of ionic iron or iron-containing molecules. In the case of Brucella, much effort has been made to study this microbe under iron limitation. The first reports about the nutritional preferences showed that iron is absolutely necessary for Brucella growth. Further studies, mainly on Brucella abortus (the causative agent of brucellosis in cattle) have shown that it produces two catecholic compounds, namely 2,3-dihydroxybenzoic acid and brucebactin, -both of them siderophores- under iron limitation. However, experimental evidence obtained from mutants, unable to synthesize those molecules, failed to demonstrate that their production is critical for bacterial replication inside macrophages. In addition, a mutant in the main iron-response regulator gene, with deficient synthesis of siderophores and increased intracellular haem content showed a better replication pattern inside professional phagocytes than wild-type. On the other hand, a B. abortus mutant that cannot ensemble iron into protoporphyrin IX to produce its own haem was unable to survive inside professional phagocytes. Another B. abortus mutant that cannot internalize haem from the medium showed significant attenuation in cultured murine macrophages. None of these mutants could establish a wild-type pattern of infection in the mice model. Thus, taking together all these results it seems that under iron limitation, as one of the stress conditions that probably Brucella face during infection, the acquisition or biosynthesis of haem renders more benefits to survive than the acquisition of iron. In agreement with this, we found that a mutation in the main iron-reservoir protein of B. abortus did not affect the replication inside professional phagocytes. For a long time, a link between the preference of Brucella to use erythritol as a carbon and energy source and the pathogenesis of this organism has been curiously established, since this molecule is present in high concentration in placental trophoblast, the preferred niche for Brucella. Other authors have suggested that one possible explanation to this phenomenon is the bacterial necessity for iron to catabolize erythritol. We think that another possible justification is that placenta provides a high quantity of haem, since it is a highly vascularized organ that receives nutrients from the mothers blood. Additionally, haem is known to be the main iron source inside eukaryotic cells. In conclusion, we propose to consider the mechanisms involved in haem biosynthesis and haem acquisition as important virulence factors in Brucella.