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Toward implementation of quorum sensing autoinducers as biomarkers for infectious disease states.

ABSTRACT: The opportunistic bacterial pathogen Pseudomonas aeruginosa causes chronic lung infections in cystic fibrosis (CF) patients. Importantly, virulence factor expression and biofilm formation in P. aeruginosa is coordinated by quorum sensing (QS) and one of the key QS signaling molecules is 3-oxo-C12-HSL. Remarkably, a tetramic acid, (C12-TA), with antibacterial properties is formed spontaneously from 3-oxo-C12-HSL under physiological conditions. Seeking to better understand this relationship, we sought to investigate whether 3-oxo-C12-HSL and C12-TA may be contributing factors to the overall pathogenicity of P. aeruginosa in CF individuals and if their detection and quantitation in sputum samples might be used as an indicator to assess disease states and monitor therapy success in CF patients. To this end, 3-oxo-C12-HSL and C12-TA concentrations were initially analyzed in P. aeruginosa flow cell biofilms using liquid chromatography coupled with mass spectrometry (LC-MS). A liquid chromatography tandem mass spectrometry (LC-MS/MS)-based method was then developed and validated for their detection and quantification in the sputa of CF patients. To the best of our knowledge, this is the first report to show the presence of both the quorum sensing molecule (3-oxo-C12-HSL) and its rearranged product (C12-TA) in human clinical samples such as sputum. A total of 47 sputum samples from 20 CF and 2 non-CF individuals were analyzed. 3-Oxo-C12-HSL was detected and quantified in 45 samples with concentrations ranging from 20 to >1000 nM; C12-TA was found in 14 samples (13-900 nM). On the basis of our findings, quorum sensing autoinducers merit further investigation as biomarkers for infectious disease states.

SUBMITTER: Struss AK

PROVIDER: S-EPMC3604138 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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Toward implementation of quorum sensing autoinducers as biomarkers for infectious disease states.

Struss Anjali K AK Nunes Ashlee A Waalen Jill J Lowery Colin A CA Pullanikat Prasanna P Denery Judith R JR Conrad Douglas J DJ Kaufmann Gunnar F GF Janda Kim D KD

Analytical chemistry 20130226 6

The opportunistic bacterial pathogen Pseudomonas aeruginosa causes chronic lung infections in cystic fibrosis (CF) patients. Importantly, virulence factor expression and biofilm formation in P. aeruginosa is coordinated by quorum sensing (QS) and one of the key QS signaling molecules is 3-oxo-C12-HSL. Remarkably, a tetramic acid, (C12-TA), with antibacterial properties is formed spontaneously from 3-oxo-C12-HSL under physiological conditions. Seeking to better understand this relationship, we so ...[more]

PMID: 23391272

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Project description:Many studies have been devoted to understand the mechanisms used by pathogenic bacteria to exploit human hosts. These mechanisms are very diverse in the detail, but share commonalities whose quantification should enlighten the evolution of virulence from both a molecular and an ecological perspective. We mined the literature for experimental data on infectious dose of bacterial pathogens in humans (ID50) and also for traits with which ID50 might be associated. These compilations were checked and complemented with genome analyses. We observed that ID50 varies in a continuous way by over 10 orders of magnitude. Low ID50 values are very strongly associated with the capacity of the bacteria to kill professional phagocytes or to survive in the intracellular milieu of these cells. Inversely, high ID50 values are associated with motile and fast-growing bacteria that use quorum-sensing based regulation of virulence factors expression. Infectious dose is not associated with genome size and shows insignificant phylogenetic inertia, in line with frequent virulence shifts associated with the horizontal gene transfer of a small number of virulence factors. Contrary to previous proposals, infectious dose shows little dependence on contact-dependent secretion systems and on the natural route of exposure. When all variables are combined, immune subversion and quorum-sensing are sufficient to explain two thirds of the variance in infectious dose. Our results show the key role of immune subversion in effective human infection by small bacterial populations. They also suggest that cooperative processes might be important for successful infection by bacteria with high ID50. Our results suggest that trade-offs between selection for population growth-related traits and selection for the ability to subvert the immune system shape bacterial infectiousness. Understanding these trade-offs provides guidelines to study the evolution of virulence and in particular the micro-evolutionary paths of emerging pathogens.

Project description:BackgroundInfectious disease epidemiology has changed over time, reflecting improved clinical interventions and emergence of threats such as antimicrobial resistance. This study investigated infectious disease hospitalizations in the United States from 2001 to 2014.MethodsEstimated rates of infectious disease hospitalizations were calculated by using the National (Nationwide) Inpatient Sample. Infectious disease hospitalizations were defined as hospitalizations with a principal discharge diagnosis of an infectious disease. Diagnoses according to site of infection and sepsis were examined, as was occurrence of in-hospital death. The leading nonsepsis infectious disease secondary diagnoses for hospitalizations with a principal diagnosis of sepsis were identified.ResultsThe mean annual age-adjusted infectious disease hospitalization rate was 1,468.2 (95% CI, 1,459.9-1,476.4) per 100,000 population; in-hospital death occurred in 4.22% (95% CI, 4.18-4.25) of infectious disease hospitalizations. The mean annual age-adjusted infectious disease hospitalization rate increased from 2001-2003 to 2012-2014 (rate ratio, 1.05; 95% CI, 1.01-1.09), as did the percentage of in-hospital death (4.21% [95% CI, 4.13-4.29] to 4.30% [95% CI, 4.26-4.35]; P = .049). The diagnoses with the highest hospitalization rates among all sites of infection and sepsis diagnoses were the lower respiratory tract followed by sepsis. The most common nonsepsis infectious disease secondary diagnoses among sepsis hospitalizations were "urinary tract infection," "pneumonia, organism unspecified," and "intestinal infection due to Clostridium [Clostridioides] difficile."ConclusionsAlthough hospital discharge data are subject to limitations, particularly for tracking sepsis, lower respiratory tract infections and sepsis seem to be important contributors to infectious disease hospitalizations. Prevention of infections that lead to sepsis and improvements in sepsis management would decrease the burden of infectious disease hospitalizations and improve outcomes, respectively.

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Toward implementation of quorum sensing autoinducers as biomarkers for infectious disease states.

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Toward implementation of quorum sensing autoinducers as biomarkers for infectious disease states.

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