The Varied Role of Efflux Pumps of the MFS Family in the Interplay of Bacteria with Animal and Plant Cells

Efflux pumps represent an important and large group of transporter proteins found in all organisms. The importance of efflux pumps resides in their ability to extrude a wide range of antibiotics, resulting in the emergence of multidrug resistance in many bacteria. Besides antibiotics, multidrug efflux pumps can also extrude a large variety of compounds: Bacterial metabolites, plant-produced compounds, quorum-sensing molecules, and virulence factors. This versatility makes efflux pumps relevant players in interactions not only with other bacteria, but also with plant or animal cells. The multidrug efflux pumps belonging to the major facilitator superfamily (MFS) are widely distributed in microbial genomes and exhibit a large spectrum of substrate specificities. Multidrug MFS efflux pumps are present either as single-component transporters or as tripartite complexes. In this review, we will summarize how the multidrug MFS efflux pumps contribute to the interplay between bacteria and targeted host cells, with emphasis on their role in bacterial virulence, in the colonization of plant and animal host cells and in biofilm formation. We will also address the complexity of these interactions in the light of the underlying regulatory networks required for the effective activation of efflux pump genes

Fatty Acids Abolish Shigella Virulence by Inhibiting Its Master Regulator, VirF

The pathogenicity of Shigella, the intracellular pathogen responsible for human bacillary dysentery, depends on a coordinated and tightly regulated expression of its virulence determinants. This is the result of a cascade organization of its positive regulators, with VirF, a transcriptional activator belonging to the AraC-XylS family, in a pivotal position. VirF itself is submitted to several well-known regulations at the transcriptional level. In this work, we present evidence for a novel posttranslational regulatory mechanism of VirF mediated by the inhibitory interaction with specific fatty acids. By homology modeling and molecular docking analyses, we identify a jelly roll motif in the structure of ViF capable of interacting with medium-chain saturated and long-chain unsaturated fatty acids. In vitro and in vivo assays show that capric, lauric, myristoleic, palmitoleic, and sapienic acids interact effectively with the VirF protein, abolishing its transcription-promoting activity. This silences the virulence system of Shigella, leading to a drastic reduction in its ability to invade epithelial cells and proliferate in their cytoplasm. IMPORTANCE In the absence of a valid vaccine, the main therapeutic approach currently used to treat shigellosis is based on the use of antibiotics. The emergence of antibiotic resistance jeopardizes the future effectiveness of this approach. The importance of the present work resides both in the identification of a new level of posttranslational regulation of the Shigella virulence system and in the characterization of a mechanism offering new opportunities for the design of antivirulence compounds, which may change the treatment paradigm of Shigella infections by limiting the emergence of antibiotic-resistant bacteria

Paracoccidioidomycosis 40 years after renal transplantation: a case-report: Paracoccidioidomicose 40 anos após transplante renal: um relato de caso

Paracoccidioidomycosis is a systemic mycotic disease caused by termic-dimorphic fungi from the Paracoccidioides sp complex, which are endemic in Brazil and over 90% of cases are presented in the chronic form. It is a rare and severe infection in patients that underwent organ transplantation, according to few reported cases in literature. Our aim is to report a rare occurence of paracoccidioidomycosis in a renal transplant recipient, diagnosed over 40 years after the procedure and to draw attention to the importance of considering the diagnosis in immunosuppressed patients from endemic areas

Role of the MDR Efflux Pump AcrAB in Epithelial Cell Invasion by Shigella flexneri

The tripartite complex AcrAB-TolC is the major RND pump in Escherichia coli and other Enterobacteriaceae, including Shigella, the etiological agent of bacillary dysentery. In addition to conferring resistance to many classes of antibiotics, AcrAB plays a role in the pathogenesis and virulence of several bacterial pathogens. Here, we report data demonstrating that AcrAB specifically contributes to Shigella flexneri invasion of epithelial cells. We found that deletion of both acrA and acrB genes causes reduced survival of S. flexneri M90T strain within Caco-2 epithelial cells and prevents cell-to-cell spread of the bacteria. Infections with single deletion mutant strains indicate that both AcrA and AcrB favor the viability of the intracellular bacteria. Finally, we were able to further confirm the requirement of the AcrB transporter activity for intraepithelial survival by using a specific EP inhibitor. Overall, the data from the present study expand the role of the AcrAB pump to an important human pathogen, such as Shigella, and add insights into the mechanism governing the Shigella infection process

Scarabaeoidea (Insecta : Coleoptera) in the Brazilian Cerrado : current state of knowledge

Besouros pertencentes à superfamília Scarabaeoidea ocupam habitats variados, possuem hábitos alimentares diversifi cados, desempenham importante papel ecológico e diversas espécies apresentam importância agrícola. No entanto, estudos com esse grupo na região do Cerrado são escassos. Nesta revisão realizou-se um levantamento dos artigos publicados nos últimos 30 anos a respeito dos Scarabaeoidea no Cerrado. Foram recuperados 64 artigos, realizados em nove unidades da federação, que focavam quatro temas principais espécies praga, aspectos bioecológicos, biodiversidade e importância ecológica, e técnicas e metodologias de coleta de Scarabaeoidea. Os resultados desta revisão indicam que poucos estudos foram realizados com os Scarabaeoidea no Cerrado brasileiro nas últimas décadas frente à importância e diversidade desse grupo de insetos.Beetles belonging to the superfamily Scarabaeoidea occupy different habitats, present feeding habits diversifi ed, play an important ecological role and several species have agricultural importance. However, studies with this group in the Brazilian Cerrado are scarce. In this review we carried out a survey of scientifi c articles published in the past 30 years concerning Scarabaeoidea in the Cerrado. Were found 64 studies in nine Brazilian states. The studies focused on four main topics: pest species, bioecology, biodiversity and ecological importance, techniques and methodologies for collecting Scarabaeoidea. The results of this review indicate that few studies have been conducted with Scarabaeoidea in the Cerrado in recent decades compared to the importance and diversity of this group of insects

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements