[et_pb_section fullwidth=”on” specialty=”off”][et_pb_fullwidth_slider admin_label=”Fullwidth Slider” show_arrows=”on” show_pagination=”on” auto=”off” parallax=”off” parallax_method=”off” module_id=”interior”][et_pb_slide background_image=”https:\/\/depts.washington.edu\/cfrtc\/wp-content\/uploads\/2014\/12\/microscope.jpg” background_color=”#ffffff” alignment=”center” background_layout=”dark” \/][\/et_pb_fullwidth_slider][\/et_pb_section][et_pb_section][et_pb_row][et_pb_column type=”1_4″][et_pb_sidebar admin_label=”Fellowships Sidebar” orientation=”left” area=”et_pb_widget_area_11″ background_layout=”light” \/][\/et_pb_column][et_pb_column type=”3_4″][et_pb_text admin_label=”Past Fellow Kostylev” background_layout=”light” text_orientation=”left”]<\/p>\n
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Fellow: Maxim Kostylev, PhD Mentor: \u00a0Peter Greenberg, PhD<\/a> Chronic lung infection with Pseudomonas aeruginosa<\/em> is the main cause of morbidity and mortality in cystic fibrosis (CF) patients. Many species of bacteria, including P. aeruginosa, have the ability to sense their own population density using specific signal molecules and protein receptors. This phenomenon is termed quorum sensing (QS). In laboratory strains of P. aeruginosa<\/em> there are two sets of signals and receptors and in both cases each receptor corresponds only to its respective signal. When a receptor protein binds its signal, it activates hundreds of genes, which include virulence factors that are believed to be important for the ability of P. aeruginosa<\/em> to infect the lungs of CF patients. The two signal-receptor sets \u2013 termed LasI-R and RhlI-R \u2013 are hierarchically arranged in the laboratory strain of P. aeruginosa<\/em> such that signal-bound LasR protein leads to the activation of the RhlI-R system.<\/p>\n Over the course of chronic infections, P. aerugionsa <\/em>acquires adaptive mutations and in many cases LasI-R system becomes dysfunctional. In laboratory strains the loss of a functional LasI-R system leads to the general loss of QS. However, a recent study suggests that this is not the case in at least some strains of P. aeruginosa <\/em>obtained from CF patients. Specifically, some strains appear to have decoupled the RhlI-R system from LasI-R. They retain the ability to mediate expression of some genes via RhlI-R system even though they do not have a functional LasR receptor. We aim to understand which genes are QS-controlled in these strains. We will do this by comparing gene expression in the absence and presence of an enzyme that degrades QS signals. Our experiments will reveal whether QS is important for the persistence of P. aeruginosa <\/em>in the CF lungs and if it is, which specific QS-controlled genes are involved. In turn, these genes can be targeted in future treatments of P. aeruginosa <\/em>infections in CF patients.<\/p>\n It is also possible that the QS system itself is the optimal target for treatments of P. aeruginosa<\/em> infections. If QS regulates expression of virulence factors in P. aeruginosa<\/em> strains infecting CF patients, then disruption of QS could allow the patient\u2019s immune system to function more effectively to suppress the infection. Because in this approach the bacteria would be disarmed, but not killed by the treatment, its key advantage might be a lower possibility of the evolution of resistance in comparison to conventional antibiotics. Under certain conditions, QS is required for the growth of P. aeruginosa<\/em> because it leads to the expression of genes that enable the cells to utilize an abundant energy and nutrient source present in their environment. Specifically, QS leads to the secretion of enzymes that hydrolyze a bulk substrate to smaller products that can be directly taken up by the cells. Under such conditions, using laboratory strain of P. aeruginosa<\/em>, it has been shown that individual cells that no longer respond to QS signals have an advantage over QS-proficient cells because they utilize the available products, but do not produce the secreted enzymes. If and when such cells reach threshold abundance, the whole population can collapse because not enough secreted enzymes are produced to sustain it. This is referred to as the tragedy of the commons. If QS is required for the persistence of P. aeruginosa<\/em> within the lungs of CF patients, then a QS-targeting treatment would create conditions that lead to the tragedy of the commons even if certain cells develop resistance. We will carry out experiments that compare the social characteristics of clinical P. aeruginosa<\/em> isolates from CF patients to the previously studied laboratory strain. We will also set up evolution experiments to monitor the ability of the clinical isolates to evolve resistance to a QS inhibitor. While the idealized experimental conditions do not necessarily accurately reflect the conditions within infected CF lungs, these experiments will provide a baseline perspective on how P. aeruginosa<\/em> might behave and evolve over the course of infection. This information can prove useful for the development of effective treatment options for CF patients in the future.<\/p>\n [\/et_pb_text][\/et_pb_column][\/et_pb_row][\/et_pb_section]<\/p>\n","protected":false},"excerpt":{"rendered":" Fellow: Maxim Kostylev, PhD Mentor: \u00a0Peter Greenberg, PhD P.I.: Ian de boer, MD<\/a>
\n<\/a>Microbiology<\/p>\n
\nProfessor,\u00a0Microbiology<\/p>\n
\nMicrobiology<\/p>\n
\nProfessor
\nMicrobiology<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"on","_et_pb_old_content":"
Associate Professor of Medicine
Nephrology<\/p>