Novel replication profiles of Brucella in human trophoblasts give insights into the pathogenesis of infectious abortion.

Many infectious agents cause abortion in humans and in animals. In this issue of the Journal of Infectious Diseases, an article by Salcedo et al [1] describes the behavior of Brucella strains in human trophoblasts and presents data that change the current paradigm regarding Brucella virulence. Brucellosis is a serious disease caused by bacteria of the genus Brucella. The disease affects all species of farm animals, although it is most important when it affects ruminants. Brucellosis has a worldwide impact in terms of its epidemiology, human health risks, and effects on trade. In most natural animal hosts the predominant symptom is abortion, with consequent loss of offspring and milk yield. In males, orchitis and epididymitis occur with a resulting loss in fertility. Three species, B. melitensis, B. abortus, and B. suis, can be readily transmitted to man, either following professional contact with infected animals or following the ingestion of contaminated dairy products. Despite much effort worldwide, no vaccine is available for human prophylaxis, but infections can be treated with a combination of antibiotics. Brucella is a facultative intracellular pathogen that can survive and replicate in many types of host cells, with macrophages as prime targets. This ability of Brucella to replicate intracellularly is central to its pathogenicity. When Brucella infects pregnant animals, it colonizes the trophoblasts in the placenta where it grows to very high density. In the mid-1980s, seminal studies from the Cheville lab showed that during placentitis of goats, Brucella were first seen in phagosomes in erythrophagocytic trophoblasts and in a compartment resembling rough endoplasmic reticulum in chorioallantoic trophoblasts [2, 3]. Although brucellosis is recognized as a cause of infectious abortion in animals, evidence that it causes abortion in humans is less clear. In the late 1990s, studies expanded on the observations in goat placentas, unraveling the cell biology of Brucella infections using HeLa cells [4, 5]. Unlike certain intracellular pathogens that escape from the phagosome and multiply freely in the cytoplasm, Brucella stays within a membrane bound Brucella-containing vacuole (BCV). The Gorvel group used confocal microscopy to follow the interactions of the BCV with the endocytic pathways in the cell, finding that it transiently interacts with early endosomes, late endosomes and lysosomes. In these early stages, BCVs are positive for the lysosomal membrane-associated protein 1 (LAMP1). Acidification of the BCV is essential to induce expression of genes encoding virulence factors, including the VirB type IV secretion system. Brucella then replicates in a novel compartment built by capturing vesicles derived from the endoplasmic reticulum (ER). This compartment has been seen in both phagocytes and nonprofessional phagocytes in vitro [6, 7] and in trophoblasts of infected animals [21–23]. The placenta has many roles; it allows the passage of nutrients and waste products between the maternal and fetal blood steams, acts as an immunological barrier providing tolerance to the fetal allograft, and acts as a barrier to prevent transmission of infectious agents from the mother to the fetus. The placenta is, in fact, composed of both maternal and fetal cells. Four days after fertilization, the early stage embryo enters the uterus and develops into a blastocyst. The outer layer of the blastocyst (cytotrophoblasts) Received 27 November 2012; accepted 10 December 2012; electronically published 9 January 2013. Correspondence: David O’Callaghan, PhD, Université Montpellier 1, INSERM U1047, UFR Médecine, 186 Chemin de Carreau de Lanes, 30908 Nîmes Cédex 2, France; UFR Médecine, 186 Chemin de Carreau de Lanes, Nîmes Cédex 2 30908, France ([email protected]). The Journal of Infectious Diseases 2013;207:1034–6 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit010