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Listeria monocytogenes ( Lm ) is a major human and animal foodborne pathogen. Here we show that hypervirulent Lm clones, particularly CC1, are strongly associated with dairy products, whereas hypovirulent clones, CC9 and CC121, are associated with meat products. Clone adaptation to distinct ecological niches and/or different food products contamination routes may account for this uneven distribution. Indeed, hypervirulent clones colonize better the intestinal lumen and invade more intestinal tissues than hypovirulent ones, reflecting their adaption to host environment. Conversely, hypovirulent clones are adapted to food processing environments, with a higher prevalence of stress resistance and benzalkonium chloride tolerance genes and a higher survival and biofilm formation capacity in presence of sub-lethal benzalkonium chloride concentrations. Lm virulence heterogeneity therefore reflects the diversity of the ecological niches in which it evolves. These results also have important public health implications and may help in reducing food contamination and improving food consumption recommendations to at-risk populations. Here, Maury et al. show that hypervirulent Listeria monocytogenes ( Lm ) clones associated to dairy products exhibit higher adaptation to the mammalian gut environment, while hypovirulent clones persist in food processing environment, suggesting a relationship between Lm pathogenic potential and niche adaptation.

Elevated levels of type I interferon (IFN) during pregnancy are associated with intrauterine growth retardation, preterm birth, and fetal demise through mechanisms that are not well understood. A critical step of placental development is the fusion of trophoblast cells into a multinucleated syncytiotrophoblast (ST) layer. Fusion is mediated by syncytins, proteins deriving from ancestral endogenous retroviral envelopes. Using cultures of human trophoblasts or mouse cells, we show that IFN-induced transmembrane proteins (IFITMs), a family of restriction factors blocking the entry step of many viruses, impair ST formation and inhibit syncytin-mediated fusion. Moreover, the IFN inducer polyinosinic:polycytidylic acid promotes fetal resorption and placental abnormalities in wild-type but not in Ifitm-deleted mice. Thus, excessive levels of IFITMs may mediate the pregnancy complications observed during congenital infections and other IFN-induced pathologies.

A total of 937 cases of listeriosis associated with consumption of the processed meat polony were identified in South Africa. Pregnant girls and women, neonates, and persons infected with HIV-1 were disproportionately affected. Molecular techniques identified cases associated with this event and the source of the contamination.

Infections of the central nervous system are among the most serious infections 1 , 2 , but the mechanisms by which pathogens access the brain remain poorly understood. The model microorganism Listeria monocytogenes ( Lm ) is a major foodborne pathogen that causes neurolisteriosis, one of the deadliest infections of the central nervous system 3 , 4 . Although immunosuppression is a well-established host risk factor for neurolisteriosis 3 , 5 , little is known about the bacterial factors that underlie the neuroinvasion of Lm . Here we develop a clinically relevant experimental model of neurolisteriosis, using hypervirulent neuroinvasive strains 6 inoculated in a humanized mouse model of infection 7 , and we show that the bacterial surface protein InlB protects infected monocytes from Fas-mediated cell death by CD8 + T cells in a manner that depends on c-Met, PI3 kinase and FLIP. This blockade of specific anti- Lm  cellular immune killing lengthens the lifespan of infected monocytes, and thereby favours the transfer of Lm from infected monocytes to the brain. The intracellular niche that is created by InlB-mediated cell-autonomous immune resistance also promotes Lm faecal shedding, which accounts for the selection of InlB as a core virulence gene of Lm . We have uncovered a specific mechanism by which a bacterial pathogen confers an increased lifespan to the cells it infects by rendering them resistant to cell-mediated immunity. This promotes the persistence of Lm within the host, its dissemination to the central nervous system and its transmission. Studies in a mouse model of neurolisteriosis show that the effector protein InlB produced by Listeria monocytogenes protects infected monocytes in the host from T cell-mediated cell death, and thereby increases bacterial neuroinvasion, persistence and transmission.

The intracellular pathogen Listeria monocytogenes is distinguished by its ability to invade and replicate within mammalian cells. Remarkably, of the 15 serovars within the genus, strains belonging to serovar 4b cause the majority of listeriosis clinical cases and outbreaks. The Listeria O-antigens are defined by subtle structural differences amongst the peptidoglycan-associated wall-teichoic acids (WTAs), and their specific glycosylation patterns. Here, we outline the genetic determinants required for WTA decoration in serovar 4b L. monocytogenes, and demonstrate the exact nature of the 4b-specific antigen. We show that challenge by bacteriophages selects for surviving clones that feature mutations in genes involved in teichoic acid glycosylation, leading to a loss of galactose from both wall teichoic acid and lipoteichoic acid molecules, and a switch from serovar 4b to 4d. Surprisingly, loss of this galactose decoration not only prevents phage adsorption, but leads to a complete loss of surface-associated Internalin B (InlB),the inability to form actin tails, and a virulence attenuation in vivo. We show that InlB specifically recognizes and attaches to galactosylated teichoic acid polymers, and is secreted upon loss of this modification, leading to a drastically reduced cellular invasiveness. Consequently, these phage-insensitive bacteria are unable to interact with cMet and gC1q-R host cell receptors, which normally trigger cellular uptake upon interaction with InlB. Collectively, we provide detailed mechanistic insight into the dual role of a surface antigen crucial for both phage adsorption and cellular invasiveness, demonstrating a trade-off between phage resistance and virulence in this opportunistic pathogen.

Listeria monocytogenes (Lm) is a ubiquitous bacterium able to survive and thrive within the environment and readily colonizes a wide range of substrates, often as a biofilm. It is also a facultative intracellular pathogen, which actively invades diverse hosts and induces listeriosis. So far, these two complementary facets of Lm biology have been studied independently. Here we demonstrate that the major Lm virulence determinant ActA, a PrfA-regulated gene product enabling actin polymerization and thereby promoting its intracellular motility and cell-to-cell spread, is critical for bacterial aggregation and biofilm formation. We show that ActA mediates Lm aggregation via direct ActA-ActA interactions and that the ActA C-terminal region, which is not involved in actin polymerization, is essential for aggregation in vitro. In mice permissive to orally-acquired listeriosis, ActA-mediated Lm aggregation is not observed in infected tissues but occurs in the gut lumen. Strikingly, ActA-dependent aggregating bacteria exhibit an increased ability to persist within the cecum and colon lumen of mice, and are shed in the feces three order of magnitude more efficiently and for twice as long than bacteria unable to aggregate. In conclusion, this study identifies a novel function for ActA and illustrates that in addition to contributing to its dissemination within the host, ActA plays a key role in Lm persistence within the host and in transmission from the host back to the environment.

Crossing the placental barrier Listeriosis and other microbial infections in pregnancy can affect the fetus as well as the mother, but little is known about how pathogens cross the placental barrier. Disson et al . investigated the process using two complementary animal models infected by Listeria monocytogenes . They show that two virulence factors or invasion proteins, InlA and InlB, are required for the transfer of pathogen to the placenta. Thus by blocking one or both of these pathways it may be possible to stop microbes passing into the fetus. Conversely, it may be possible to exploit these pathways to target therapeutic molecules across the same barrier. Listeria monocytogenes can cross the placental barrier and may result in fetal or neonatal mortality. Using two complementary animal models, it is now shown that virulence factors InlA and InlB are both required for this process in vivo . The ability to cross host barriers is an essential virulence determinant of invasive microbial pathogens. Listeria monocytogenes is a model microorganism that crosses human intestinal and placental barriers, and causes severe maternofetal infections by an unknown mechanism 1 . Several studies have helped to characterize the bacterial invasion proteins InlA and InlB 2 . However, their respective species specificity has complicated investigations on their in vivo role 3 , 4 . Here we describe two novel and complementary animal models for human listeriosis: the gerbil, a natural host for L. monocytogenes , and a knock-in mouse line ubiquitously expressing humanized E-cadherin. Using these two models, we uncover the essential and interdependent roles of InlA and InlB in fetoplacental listeriosis, and thereby decipher the molecular mechanism underlying the ability of a microbe to target and cross the placental barrier.

Listeria monocytogenes (Lm) is an invasive foodborne pathogen that leads to severe central nervous system and maternal-fetal infections. Lm ability to actively cross the intestinal barrier is one of its key pathogenic properties. Lm crosses the intestinal epithelium upon the interaction of its surface protein internalin (InlA) with its host receptor E-cadherin (Ecad). InlA-Ecad interaction is species-specific, does not occur in wild-type mice, but does in transgenic mice expressing human Ecad and knock-in mice expressing humanized mouse Ecad. To study listeriosis in wild-type mice, InlA has been \"murinized\" to interact with mouse Ecad. Here, we demonstrate that, unexpectedly, murinized InlA (InlA(m)) mediates not only Ecad-dependent internalization, but also N-cadherin-dependent internalization. Consequently, InlA(m)-expressing Lm targets not only goblet cells expressing luminally-accessible Ecad, as does Lm in humanized mice, but also targets villous M cells, which express luminally-accessible N-cadherin. This aberrant Lm portal of entry results in enhanced innate immune responses and intestinal barrier damage, both of which are not observed in wild-type Lm-infected humanized mice. Murinization of InlA therefore not only extends the host range of Lm, but also broadens its receptor repertoire, providing Lm with artifactual pathogenic properties. These results challenge the relevance of using InlA(m)-expressing Lm to study human listeriosis and in vivo host responses to this human pathogen.

Listeria monocytogenes causes listeriosis, a human foodborne infection leading to gastroenteritis, meningoencephalitis and maternofetal infections. InlA and InlB, two L. monocytogenes surface proteins, interact with their respective receptors E-cadherin and Met and mediate bacterial entry into human cultured cells. Here, we present protocols for studying listeriosis in three complementary animal models: (i) the human E-cadherin (hEcad) transgenic mouse line; (ii) the knock-in E16P mouse line; and (iii) the gerbil, in which both InlA–E-cadherin and InlB–Met species-specific interactions occur as in humans. Two routes of infection are described: oral inoculation, the natural route for infection; and intravenous inoculation that bypasses the intestinal barrier. We describe how to monitor L. monocytogenes infection, both qualitatively by imaging techniques and quantitatively by bacterial enumeration. The advantage of these methods over the classical intravenous inoculation of L. monocytogenes in wild-type mice (in which the InlA–E-cadherin interaction does not occur) is that it allows the pathophysiology of listeriosis to be studied in animal models relevant to humans, as they are permissive to the interactions that are thought to mediate L. monocytogenes crossing of human host barriers. The whole procedure (inoculation, in vivo imaging, bacterial enumeration, histopathology) takes one full week to complete, including 3 d of actual experiments.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.