Biology subjects

Azeredo, J.

Publications and source records attributed to Azeredo, J..

3 recordsLinked to original sources

bioRxiv2019

Effect of progesterone on Candida albicans biofilm formation under acidic conditions: a transcriptomic analysis

Vulvovaginal candidiasis (VVC) caused by Candida albicans is a common disease worldwide. A very important C. albicans virulence factor is its ability to form biofilms on epithelium and/or on intrauterine devices promoting VVC. It has been shown that VVC has a hormonal dependency and that progesterone affects virulence traits of C. albicans cells. To understand how the acidic environment (pH 4) and progesterone (either alone and in combination) modulate C. albicans response during formation of biofilm, a transcriptomic analysis was performed together with characterization of the biofilm properties. Compared to planktonic cells, acidic biofilm-cells exhibited major changes in their transcriptome, including modifications in the expression of 286 genes that were not previously associated with biofilm formation in C. albicans. The vast majority of the genes up-regulated in the acidic biofilm cells (including those uniquely identified here) are known targets of Sfl1, and the expression of this regulator impaired formation of the acidic biofilm. Under the acidic conditions used, progesterone treatment reduced C. albicans biofilm biomass, structural cohesion, matrix quantity and susceptibility to fluconazole. Transcriptomic analysis of progesterone-exposed biofilms led to the identification of 65 down-regulated genes including, among others, the regulator Tec1 and several of its target genes suggesting that the function of this transcription factor is inhibited by the presence of the hormone. Overall, the results of this study show that progesterone modulates C. albicans biofilm formation and genomic expression under acidic conditions, which may have implications for C. albicans pathogenicity in the vaginal environment.\n\nAuthor summaryVulvovaginal candidiasis (VVC) is an infection of the vaginal tract that affects millions of women every year. It is caused by fungi of the genus Candida, mainly Candida albicans. Several C. albicans virulence factors contribute to the establishment of this infection, including the ability to form biofilms on vaginal walls and intrauterine devices. Candida species belong to vaginal microflora, however under certain conditions they can cause infection. It has been shown that conditions that prompt VVC include those leading to high progesterone levels, as pregnancy. Here we show that progesterone impairs the ability of C. albicans cells to form biofilms but causes a potential protective stress response. Indeed, we reveal an increased fluconazole resistance of biofilm cells grown in the presence of the hormone. Additionally, our results suggest that biofilm cells have a specific response to acidic conditions, as those established in the vaginal environment. Deepening the knowledge on the modulation of C. albicans virulence by vaginal conditions is essential for a full understanding of the pathogenesis of this species in the vaginal tract and contribute to the disclosure of new targets to treat VVC.

microbiology↗

bioRxiv2018

Antimicrobial activity of Mycobacteriophage D29 Lysin B during Mycobacterium ulcerans infection

Buruli Ulcer (BU) is a cutaneous disease caused by Mycobacterium ulcerans. The pathogenesis of this disease is closely related to the secretion of the toxin mycolactone that induces extensive destruction of the skin and soft tissues. Although the World Health Organization recommends a combination of rifampicin and streptomycin for the treatment of BU, clinical management of advanced stages often requires extensive surgical resection of the infected tissue. Therefore, it is important to develop alternative strategies for the treatment of BU.\n\nEndolysins (lysins) are phage encoded enzymes that degrade peptidoglycan of bacterial cell walls. Over the past years, lysins have been emerging as alternative antimicrobial agents against Gram-positive bacteria. Amongst Gram-positive bacteria, mycobacteria have an unusual outer membrane that is covalently attached to the mycolylarabinogalactan-peptidoglycan complex. To overcome this additional barrier to phage-mediated lysis, some mycobacteriophages encode a lipolytic enzyme, Lysin B (Lys B).\n\nIn this study, we demonstrated for the first time that recombinant Lys B displays lytic activity against M. ulcerans isolates. Moreover, using a mouse model of M. ulcerans footpad infection, we show that subcutaneous treatment with Lys B leads to a reduction in bacterial burdens, associated with IFN-{gamma} and TNF production in the draining lymph node. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease.\n\nAUTHOR SUMMARYBuruli Ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans. Standard treatment for BU lesions consists of a combination of rifampicin and streptomycin for 8 weeks. However, clinical management of advanced stages of the disease often requires extensive surgical resection of the infected tissue. Therefore, it is important to develop alternative strategies for the treatment of BU. In that sense, we tested the efficacy of Lysin B (Lys B), a phage encoded lipolytic enzyme that degrades the mycolylarabinogalactan-peptidoglycan complex present in the mycobacterial cell wall. In this study, we show that Lys B not only displays lytic activity against M. ulcerans isolates in vitro, but also leads to a reduction in bacterial burdens in M. ulcerans-infected mouse footpads. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease.

microbiology↗

bioRxiv2018

Genomic analysis of Acinetobacter baumannii prophages reveals remarkable diversity and suggests profound impact on bacterial virulence and fitness

The recent nomination by the World Health Organization of Acinetobacter baumannii as the number one priority pathogen for the development of new antibiotics is a direct consequence of its fast evolution of pathogenicity, and in particular of multidrug resistance. While the development of new antibiotics is critical, understanding the mechanisms behind the crescent bacterial pathogenicity is equally relevant. Often, resistance and other bacterial virulence elements are contained on highly mobile pieces of DNA that can easily spread to other bacteria. Prophages are one of the mediators of this form of gene transfer, and have been frequently found in bacterial genomes, often offering advantageous features to the host. Here we question the contribution of prophages for the evolution of A. baumannii pathogenicity. We found prophages to be notably diverse and widely disseminated in A. baumannii genomes. Also remarkably, A. baumannii prophages encode for multiple putative virulence factors that may be implicated in the bacteriums capacity to colonize host niches, evade the host immune system, subsist in unfavorable environments, and tolerate antibiotics. Overall our results point towards a significant contribution of prophages for the dissemination and evolution of pathogenicity in A. baumannii, and highlight their clinical relevance.

microbiology↗