<i>Listeria monocytogenes</i>
            multidrug resistance transporters activate a cytosolic surveillance pathway of innate immunity

Crimmins, Gregory T.; Herskovits, Anat A.; Rehder, Kai; Sivick, Kelsey E.; Lauer, Peter; Dubensky, Thomas W.; Portnoy, Daniel A.

doi:10.1073/pnas.0804170105

Cited by 106 publications

(143 citation statements)

References 33 publications

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“…Bacterial microarrays. Bacterial RNA was harvested from infected mouse bone marrow-derived macrophages at 4 h postinfection, as previously described (11). Briefly, infected macrophages were washed with PBS and then lysed in ice-cold water with 1% saponin.…”

Section: Methodsmentioning

confidence: 99%

“…Bacterial strain-specific infection inoculums were as listed in Table S1 in the supplemental material, with the multiplicity of infection (MOI) defined as the number of gentamicin-resistant (intracellular) bacteria per macrophage. Bacterial intracellular growth curves were performed as previously described (11).…”

Section: Methodsmentioning

confidence: 99%

“…Genetic and biochemical studies have identified two L. monocytogenes major facilitator superfamily multidrug resistance (MDR) efflux pumps, MdrM and MdrT, as necessary and sufficient for both the bacterial secretion of c-di-AMP and the resulting induction of host IFN-␤ (11,41). While MDR efflux pumps can often secrete multiple different substrates, these pumps usually transport exogenous rather than endogenous molecules (37), suggesting that MdrM and MdrT may have physiologically relevant substrates in addition to c-di-AMP.…”

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confidence: 99%

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Hyperinduction of Host Beta Interferon by a Listeria monocytogenes Strain Naturally Overexpressing the Multidrug Efflux Pump MdrT

et al. 2012

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ABSTRACTMany pathogens regulate or modify their immune-stimulating ligands to avoid detection by their infected hosts.Listeria monocytogenes, a facultative intracellular bacterial pathogen, interacts with multiple components of mammalian innate immunity during its infection cycle. During replication within the cytosol of infected cells,L. monocytogenesutilizes two multidrug efflux pumps, MdrM and MdrT, to secrete the small nucleic acid second messenger cyclic-di-AMP (c-di-AMP). Host recognition of c-di-AMP triggers the production of type I interferons, including beta interferon (IFN-β), which, surprisingly, promoteL. monocytogenesvirulence. In this study, we have examined the capacity of multiple laboratory and clinical isolates ofL. monocytogenesto stimulate host production of IFN-β. We have identified theL. monocytogenesstrain LO28 as able to hyperinduce IFN-β production in infected cells ∼30-fold more than the common laboratory cloneL. monocytogenesstrain 10403S. Genomic analyses determined that LO28 contains a naturally occurring loss-of-function allele of the transcriptional regulator BrtA and correspondingly derepresses expression of MdrT. Surprisingly, while derepression of MdrT resulted in hyperstimulation of IFN-β, it results in significant attenuation in multiple mouse models of infection. While type I interferons may promoteL. monocytogenesvirulence, this study demonstrates that unregulated expression of the c-di-AMP-secreting efflux pump MdrT significantly restricts virulencein vivoby an unknown mechanism.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Hyperinduction of Host Beta Interferon by a Listeria monocytogenes Strain Naturally Overexpressing the Multidrug Efflux Pump MdrT

et al. 2012

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“…This gene codes for a multiple-drug resistance transporter that contributes to the activation of type I interferon in infected cells (31). This innate immune response to a cytosolic infection by L. monocytogenes decreases the ability of the host to control the infection (32,33).…”

Section: Methodsmentioning

confidence: 99%

A Listeria monocytogenes-Based Vaccine That Secretes Sand Fly Salivary Protein LJM11 Confers Long-Term Protection against Vector-Transmitted Leishmania major

et al. 2014

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c Cutaneous leishmaniasis is a sand fly-transmitted disease characterized by skin ulcers that carry significant scarring and social stigmatization. Over the past years, there has been cumulative evidence that immunity to specific sand fly salivary proteins confers a significant level of protection against leishmaniasis. In this study, we used an attenuated strain of Listeria monocytogenes as a vaccine expression system for LJM11, a sand fly salivary protein identified as a good vaccine candidate. We observed that mice were best protected against an intradermal needle challenge with Leishmania major and sand fly saliva when vaccinated intravenously. However, this protection was short-lived. Importantly, groups of vaccinated mice were protected long term when challenged with infected sand flies. Protection correlated with smaller lesion size, fewer scars, and better parasite control be-

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“…Inactivation of mdrL in L. monocytogenes LO28 resulted in increased susceptibility to macrolides, cefotaxime and certain metals (zinc, cobalt and chromium) (144 (83,156), some of which may contribute to the phenotype of mutants described here. Two new transporters of the major facilitator superfamily, mdrT and mdrM, were identified during a screen for genes impacting the elicitation of the innate immune response in macrophages infected with L. monocytogenes 10403S, and transcript levels of mdrM were markedly enhanced in the presence of rhodamine 6G and TPP (46). However, we failed to obtain evidence or increased expression of either mdrT or mdrM in the ciprofloxacin-or BCselected mutants, suggesting that these transporters are likely not involved in the phenotype of the mutants.…”

Section: Assessment Of Othermentioning

confidence: 99%

Identification of the mechanisms of resistance and potential cross resistance of Listeria monocytogenes upon adaptation to different antimicrobials

Rakić-Martinez¹

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ACKNOWLEDGMENTSI would like to thank Dr. Vera Katić for being my mentor, not only through PhD studies, but in my undergraduate years as well. Her objectivity, articulate thinking and dedication to work inspired me to keep moving forward even after long, tiresome days in the lab. I will forever appreciate Dr. Katic's encouragement to pursue personal happiness and her support in important life decisions.I am forever grateful to Dr. Sophia Kathariou for accepting me in her lab and making me feel at home while far from it. Her incredible ability to find the best solutions when things were not looking promising and open completely new horizons along with her creativity and knowledge made science so attractive. Looking at all the great, bright and skilful young people pursuing their dreams under Dr. Kathariou's guidance makes me very proud for being a part of it.My appreciation also goes to Dr. Lepšanović and Dr. Mišić for accepting to be members of the committee. I am thankful to all my lab mates and to Ms. Robin Siletzky for her solid support throughout my work. A special thanks to Dr. Vikrant Dutta for his patience, willingness to help and his much admired teaching skills.Lastly and foremost I would like to thank my family. To my dear parents Ljubo and Zora whose unconditional love, support and presence whenever I needed them have been and will always be my motive to be better. To my big brother Zoran, who has been, and is my role model, but still owes me German lessons. Finally, I want to thank my boys, my beloved husband Sergio and my precious son Gregory, who have been an endless source of energy, support and love. Thanks for being my wingmen guys! ABSTRACTAbility to contaminate ready-to-eat, highly processed, cold-stored food products, relatively high fatality rate and environmental adaptations define .Listeria monocytogenes as a challenging foodborne pathogen of high public health significance. Listeria's adaptations and prolonged persistence in food processing facilities are a key link to contamination of foods.In recent years, bacterial multidrug resistance has been recognized as an emerging health challenge. Exposure to antimicrobials (antibiotics, disinfectants or environmentally ubiquitous heavy metals), may provide selective pressures for resistance with accompanying cross-resistance and increase in environmental fitness.In this work I addressed some of the possible mechanisms of adaptations that may contribute to persistence of L. monocytogenes in the environment as well as to survival and growth in different foods. This includes adaptations to heavy metals such as cadmium, disinfectants such as benzalkonium chloride (BC), selected antibiotics (e.g. the fluoroquinolone ciprofloxacin) and other toxic compounds (e.g. tetraphenyl-phosponium, often used as an anti-carcinogenic and efflux pump substrate). In order to characterize the impact of multidrug resistance on survival and growth of L. monocytogenes in different foods, we tested mutants adapted to higher concentrations of antibiotic ciprofloxacin and ...

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Listeria monocytogenes multidrug resistance transporters activate a cytosolic surveillance pathway of innate immunity

Cited by 106 publications

References 33 publications

Hyperinduction of Host Beta Interferon by a Listeria monocytogenes Strain Naturally Overexpressing the Multidrug Efflux Pump MdrT

Hyperinduction of Host Beta Interferon by a Listeria monocytogenes Strain Naturally Overexpressing the Multidrug Efflux Pump MdrT

A Listeria monocytogenes-Based Vaccine That Secretes Sand Fly Salivary Protein LJM11 Confers Long-Term Protection against Vector-Transmitted Leishmania major

Identification of the mechanisms of resistance and potential cross resistance of Listeria monocytogenes upon adaptation to different antimicrobials

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