“If you bring an alarm, we will destroy it,” said Brucella to the host cell

Pathogenic brucellae are the agent of brucellosis, a disease that causes abortion and infertility in natural hosts such as sheep, goats, or cattle. Brucella melitensis, Brucella abortus, and Brucella suis are the most pathogenic Brucella species for humans and also the most relevant bacteria involved in economical loses and in animal and human health problems. In addition, these Brucella represent a zoonotic risk in low-income countries. Humans are infected through contacts with infected animals by aerosols or by ingestion of contaminated dairy products. Human brucellosis is a re-emerging febrile illness that may progress into a chronic phase characterized by the appearance of severe complications such as endocarditis, arthralgia, epididymitis, etc. If untreated, chronic brucellosis represents a threat, especially in endemic areas (Central and South America, the Middle East, Mediterranean countries, northern Africa, and countries of the Caucasus and Central Asia). A figure of 500 000 new cases/ year is usually given as an estimate. Because of all these circumstances, brucellosis is classified according WHO among the top seven neglected zoonoses. These diseases in endemic area are considered as a human health problem with a direct link to poverty. Brucella species are facultative gram-negative intracellular bacteria. In both humans and animals, Brucella first targets the respiratory epithelium, the conjunctiva, and sexual organs. Even nowadays, the cells targeted by the pathogen for entry remain uncharacterized and efforts have to be done to decipher where and how Brucella invade the body. However, what we do know is that bacteria internalized by phagocytes at the periphery move to regional lymph nodes, which may play a barrier to subsequent systemic dissemination. Brucella is capable of colonizing macrophages, monocytes, and dendritic cells and can be found in large numbers in the liver, the medulla, and the spleen. Therefore, it is not surprising that Brucella has engineered several devices to make its pathogenic life easier, defeating both innate and adaptive immunity. Brucella, like many other intracellular pathogenic bacteria, secretes effector proteins inside the host cytoplasm of infected cells in order to circumvent essential functions of the host defense, the final goal being the establishment a long-lasting chronic infection beneficial for the invader. The mechanisms involved in Brucella entry into host cells still remain to be characterized. Brucella can colonize macrophages and dendritic cells (DCs) as well as trophoblasts, fibroblasts, endothelial cells, and epithelial cells. In both murine macrophages and human monocytes Brucella enters through lipid rafts. This event, also observed in DCs is dependent on the PI3-kinase and TLR4. Indeed, it has been shown that Brucella mutants lacking LPS O-chain do not use lipid rafts and are killed by the host cell suggesting that the Brucella O-chain plays an important role in early events of the Brucella-containing vacuole (BCV). Brucella entry into host cells also depends on the expression of BvrR/BvrS. This two component regulator system controls the expression of genes controlling the acylation of the Brucella LPS lipid A and the surface expression of several outer membrane proteins. Lipid raft-mediated Brucella internalization has been proposed to be under the control of the class A scavenger receptor and the cellular prion protein PrPc in macrophages. Brucella adhesion to macrophages and epithelial cells seems to be associated to the host surface expression of sialic acids, which bind the Brucella surface protein 41 encoded by the ugpB locus. Other Brucella proteins such as the product of the gene BMEI0216 have been implicated in adhesion and/or internalization into phagocytes. In addition, the B. abortus efp gene and the pathogenicity island Bab1_2009–2012 encoding a Brucella adhesin seem to play a role in Brucella uptake. In this issue of Virulence, Alva-Perez et al. investigated the role of a subfamily of (di)nucleoside oligophosphate molecules linked to other “X” molecules (NUDIX) enzymes. NUDIX have been described in other bacteria as invasins and are present in Brucella spp. The authors called this NUDIX enzyme InvA and generated a deletion mutant of the B. melitensis invA gene to understand its role in virulence. Such a mutant was attenuated during the first steps of invasion in HeLa cells and goat macrophages with a maximum attenuation at 2 h p.i. Interestingly, the mutant strain exhibited a low level of colocalization with cathepsin D, similar to the parental strain colocalization at 24 h p.i. showing that the invA gene is important during invasion but not for intracellular replication. The authors also showed that InvA