Brucella Melitensis: a Nasty Bug with Hidden Credentials for Virulence
Total Page：16
File Type：pdf, Size：1020Kb
Commentary Brucella melitensis: A nasty bug with hidden credentials for virulence Edgardo Moreno*† and Ignacio Moriyo´ n‡ *Tropical Disease Research Program, Veterinary School, National University, Apartado 304-3000, Heredia, Costa Rica; and ‡Department of Microbiology, University of Navarra, Apartado 177, 3208, Pamplona, Spain n September 23, 1905, a cargo carrying supporting information on the PNAS web secretion systems. On the other hand, O60 goats from Malta arrived in New site, www.pnas.org) and do not survive for some potential sequences for virulence York. The herd was kept in quarantine protracted periods of time outside the were discovered. For instance, Brucella because of several deaths that occurred dur- host. Their textbook description, ‘‘facul- recruits actin and activates small GTP- ing the journey. Crewmen, an agent from tative intracellular parasites,’’ does not ases during its internalization to cells (6), the U.S. Bureau of Animal Industry, which give credit to their true behavior, which is but the molecules involved in these was responsible for the shipment, and a better described as that of a facultatively events remain unknown. The revelation woman who drank milk that ‘‘escaped’’ from extracellular intracellular parasite. There- of putative genes coding for adhesins, the quarantine station displayed the char- fore, understanding the pathogenicity of invasins, and virG-like genes for attach- acteristic symptoms of ‘‘Mediterranean fe- brucellae is relevant not only because this ment and actin recruitment calls for the ver.’’ Lieutenant Colonel David Bruce, a pathogenicity represents a major infec- generation of null mutants in these se- physician of the Royal Army, who discov- tious disease but also because it will shed quences. Whether some of the presumed ered ‘‘Micrococcus melitensis ’’ in 1887 in light on basic aspects of intracellular par- hemolysins and proteases could be pro- infected British soldiers residing in Malta, asites and of cellular immunity. One of the duced during intracellular parasitism and had forewarned the U.S. sanitary authori- striking features that distinguishes Bru- transferred by alternative secretion sys- ties about the risk of ‘‘Mediterranean fever’’ cella organisms is that they do not display tems such as type IV or V, incomplete by importing goats from Malta. In Novem- obvious virulence factors such as capsules, type III, or flagellar type secretion sys- ber 1906, after isolation of ‘‘M. melitensis,’’ fimbriae, flagella, exotoxins, exopro- tems, remains speculative. Among these, the goats were destroyed. Almost 100 years teases, or other exoenzymes, cytolysins, the type IV secretion system plays a after this episode, the genome sequence of resistance forms, antigenic variation, plas- relevant role during Brucella intracellu- COMMENTARY Brucella melitensis (renamed after David mids, or lysogenic phages. Thus identifi- lar trafficking (7) (see Table 2, which is Bruce) has been resolved by DelVecchio et cation of classical virulence factors has published as supporting information on al. (1), bringing new light to the understand- been elusive. It is in this context that the PNAS web site), presuming by this ing of the biology of this pathogen. The genomics and comparative phylogenetic the translocation of bacterial factors in- disease, known as analyses are yielding side cells. Other proteins such as the brucellosis, is found data that improve putative outer membrane TolC, which is in all continents, af- our understanding of required for hemolysin secretion in en- fecting mainly low- The genome analyses of three Brucella pathobiol- teric bacteria, may also serve for para- income countries; Brucella species have confirmed the ogy (1, 3–5) and are sitism (8). Legionella hemolysins form in addition, it con- leading us to a re- absence of functional sequences pores in the vacuolar and cellular mem- stitutes a contempo- finement of classical branes soon after bacterial replication rary concern be- for most of the ‘‘classical’’ concepts about ceases (9), suggesting that a similar phe- cause Brucella virulence. virulence factors. nomenon could take place with other strains are potential The brucellae are intravacuolar parasites, including Bru- ␣ agents of biological -Proteobacteria, phy- cella. Concomitantly to this, Brucella warfare. logenetically related inhibits apoptosis (10) and replicates The six recognized Brucella species, to other cell-associated parasites of plants within cells without interfering with mi- named according to their host preference, and animals as well as to free living bacteria tosis (Fig. 1). affect economically important livestock, (3). Their closest relatives (Ochrobactrum Most features related to virulence seem and several undesignated strains infect sp.) are bacteria of the rhizosphera that to be concentrated or to act at the Brucella marine mammals. Abortion is the main behave as opportunistic pathogens of hu- surface (Table 2). The Brucella LPS gath- outcome of the infection in pregnant an- mans. Chromosomal sequences of a number ers a remarkable set of properties. Some imals, resulting from complex, not well of ␣-Proteobacteria have been released, fa- are ancestral, such as its very low biolog- understood interactions between the pla- cilitating phylogenetic, biochemical, and bi- ical activity, a favorable attribute for not cental tissues, the intracellular brucellae, ological comparisons (see Table 1, which is activating intracellular killing mechanisms and the fetus. Brucella invades profes- published as supporting information on the through cytokine networks (3). Others are sional and nonprofessional phagocytes PNAS web site). The genome analyses of idiosyncratic (the resistance to bacteri- and replicates within compartments re- three Brucella species have confirmed the cidal peptides). A few may have been sembling the endoplasmic reticulum after absence of functional sequences for most of evading fusion with lysosomes (2). The the ‘‘classical’’ virulence factors, pathogenic See companion article on page 443. brucellae are exceedingly well adapted to islands, as well as the lack of a complete set †To whom reprint requests should be addressed. E-mail: this niche (see Fig. 1, which is published as of genes to mount, types I, II, and III [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.022622699 PNAS ͉ January 8, 2002 ͉ vol. 99 ͉ no. 1 ͉ 1–3 Downloaded by guest on September 28, 2021 acquired horizontally (the O-chain). Most behavior would be reflected at all levels of in various Brucella phylogenetic relatives, other factors depict ancestral systems its biology. It may come as a surprise that and some of them control virulence fac- present in plant and animal cell-associated a bacterium generally described as nutri- tors. Also, these pumps may serve to relatives, with departures reflecting adap- tionally fastidious is endowed, with excep- export moderately hydrophobic metabo- tation to the new environment (Table 2, tions, with all major biosynthetic path- lites, such as the autoinducers of quorum- www.pnas.org). Comparison with the var- ways. However, it has been known for a sensing systems (18). Similar intriguing ious ␣-Proteobacteria chromosomes re- long time that the growth requirements of questions are raised by the conservation of veals that most genes known to be critical smooth Brucella are not excessive because, genes predicted to code for heavy-metal for cycle progression, translation machin- in chemically defined media containing pumps, as these are characteristic of soil ery, stress responses, membrane lipids, mineral salts and glutamate or glucose, microorganisms or microorganisms that basic heterotrophic metabolism, and en- many strains require only niacin and thi- cycle between animal hosts and the envi- ergy conversion have been retained in amin (14). This property is largely consis- ronment. Phagocytes control the level of Brucella organisms. Some of these genes tent with the genome analysis of B. iron within phagosomes and endosomes. seem to be in the interface with virulence melitensis (1). Niacin dependence is the Keeping iron under control is necessary (Table 2), stressing the fine adjustments phenotype of nadA-C mutants of pro- for intracellular parasites, not only be- between essential functions and parasit- totrophic bacteria and, therefore, the ab- cause it is an essential nutrient and a ism. In contrast, genetic cassettes for au- sence of quinolinate synthetase (nadA), component of critical detoxifying en- tothrophy, antibiotic resistance, or for and nicotinate-nucleotide pyrophospho- zymes, but also because free iron catalyzes mounting the required structures for liv- rylase (nadC) genes was not unexpected. production of harmful hydroxyl free rad- ing outside host cells (e.g., flagella) are On the other hand, the presence of the ical. In this regard, the report that B. absent, cryptical, or truncated. Similarly, genes predicted to be necessary for thia- melitensis 16 M carries enterobactin (an the absence of plasmids and lysogenic min synthesis contrasts with the require- iron chelator derived from 2,3-dihydroxy- phages in the intracellular ␣-Proteobacte- ment of this vitamin, a point that needs benzoyl-serine) synthetase gene is also ria of animals corresponds to their con- reexamination. The conflict may lie in the striking. B. melitensis has been shown to fined environment, as these bacteria do fact that some steps en route to the thia- release 2,3-dihydroxybenzoate but no not require additional genetic