Denitrification by cystic fibrosis pathogens – Stenotrophomonas maltophilia is dormant in sputum

Kolpen, Mette; Kragh, Kasper Nørskov; Bjarnsholt, Thomas; Line, Laura; Hansen, C.R.; Dalbøge, C.S.; Hansen, Nana Wesley; Kühl, Michael; Høiby, Niels; Jensen, Peter Østrup

doi:10.1016/j.ijmm.2014.07.002

Cited by 35 publications

(38 citation statements)

References 70 publications

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“…No patients from this series received MABSC inhaled antibiotic therapy at the time of transplantation and it should be noted that the conditions in the end-stage lungs of patients with cystic fibrosis in continuous anti-MABSC treatment might not be representative of all disease stages. The reason why very limited MABSC biofilm formation was seen in sputum in the conductive zones of the examined lungs may be that mycobacteria are dormant in sputum, which is predominantly anaerobic due to the activity of polymorphonuclear leukocytes, as previously demonstrated for the aerobic S. maltophilia [14]. Our finding that the in vivo MABSC biofilms appeared to be of the smooth colony morphology type concurs with reports that this morphology is associated with persistent infection [15].…”

Section: To the Editorsupporting

confidence: 90%

Chronic pulmonary disease withMycobacterium abscessuscomplex is a biofilm infection

et al. 2015

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Section: To the Editorsupporting

confidence: 90%

Chronic pulmonary disease withMycobacterium abscessuscomplex is a biofilm infection

et al. 2015

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“…Several studies have investigated the growth pattern of bacteria in the lungs of patients with CF. It is interesting that these studies have shown that species frequently classified as obligate aerobes, such as Staphylococcus aureus, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans, exhibit virtually zero growth, which is in line with depletion of O 2 in infected parts of the CFs lungs, whereas the facultative anaerobe P. aeruginosa exhibits slow growth under these conditions (6,(55)(56)(57)(58). We conclude that PMNs apparently play a major role in modifying the chemical microenvironment thereby imposing growth restriction upon pathogens in biofilm aggregates associated with chronic lung infections of CF patients.…”

Section: Growth and Biofilm Structurementioning

confidence: 98%

“…The CF pathogens, P. aeruginosa , A. xylosoxidans , B. multivorans , and S. maltophilia , all exhibit biofilm growth associated with chronic lung infections . During anoxia, clinical isolates of these four pathogens responded to supplemental NO 3 − by increased growth and were apparently capable of NO 3 − depletion, while only P. aeruginosa and A. xylosoxidans displayed the formation of N 2 O . The genetic set‐up for complete denitrification from NO 3 − to N 2 is found in P. aeruginosa as well as in A. xylosoxidans .…”

Section: The Host Immune Response Changes the Chemical Microenvironmementioning

confidence: 99%

Microenvironmental characteristics and physiology of biofilms in chronic infections of CF patients are strongly affected by the host immune response

Jensen

Kolpen

Kragh

et al. 2017

APMIS

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Jensen PØ, Kolpen M, Kragh KN, K€ uhl M. Microenvironmental characteristics and physiology of biofilms in chronic infections of CF patients are strongly affected by the host immune response. APMIS 2017; 125: 276-288.In vitro studies of Pseudomonas aeruginosa and other pathogenic bacteria in biofilm aggregates have yielded detailed insight into their potential growth modes and metabolic flexibility under exposure to gradients of substrate and electron acceptor. However, the growth pattern of P. aeruginosa in chronic lung infections of cystic fibrosis (CF) patients is very different from what is observed in vitro, for example, in biofilms grown in flow chambers. Dense in vitro biofilms of P. aeruginosa exhibit rapid O 2 depletion within <50-100 lm due to their own aerobic metabolism. In contrast, in vivo investigations show that P. aeruginosa persists in the chronically infected CF lung as relatively small cell aggregates that are surrounded by numerous PMNs, where the activity of PMNs is the major cause of O 2 depletion rendering the P. aeruginosa aggregates anoxic. High levels of nitrate and nitrite enable P. aeruginosa to persist fueled by denitrification in the PMN-surrounded biofilm aggregates. This configuration creates a potentially long-term stable ecological niche for P. aeruginosa in the CF lung, which is largely governed by slow growth and anaerobic metabolism and enables persistence and resilience of this pathogen even under the recurring aggressive antimicrobial treatments of CF patients. As similar slow growth of other CF pathogens has recently been observed in endobronchial secretions, there is now a clear need for better in vitro models that simulate such in vivo growth patterns and anoxic microenvironments in order to help unravel the efficiency of existing or new antimicrobials targeting anaerobic metabolism in P. aeruginosa and other CF pathogens. We also advocate that host immune responses such as PMN-driven O 2 depletion play a central role in the formation of anoxic microniches governing bacterial persistence in other chronic infections such as chronic wounds.

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“…CF patients expectorate infected mucus daily, making the in vivo environment directly accessible to experimental investigation. Few prior estimates of microbial growth rates exist for CF sputum (5)(6)(7). These estimates are based on detecting the ribosomal RNA (rRNA) content of bacterial cells using fluorescence in situ hybridization (FISH).…”

mentioning

confidence: 99%

Trace incorporation of heavy water reveals slow and heterogeneous pathogen growth rates in cystic fibrosis sputum

Kopf

Sessions

Cowley

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

150

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Effective treatment for chronic infections is undermined by a significant gap in understanding of the physiological state of pathogens at the site of infection. Chronic pulmonary infections are responsible for the morbidity and mortality of millions of immunocompromised individuals worldwide, yet drugs that are successful in laboratory culture are far less effective against pathogen populations persisting in vivo. Laboratory models, upon which preclinical development of new drugs is based, can only replicate host conditions when we understand the metabolic state of the pathogens and the degree of heterogeneity within the population. In this study, we measured the anabolic activity of the pathogen Staphylococcus aureus directly in the sputum of pediatric patients with cystic fibrosis (CF), by combining the high sensitivity of isotope ratio mass spectrometry with a heavy water labeling approach to capture the full range of in situ growth rates. Our results reveal S. aureus generation times with a median of 2.1 d, with extensive growth rate heterogeneity at the single-cell level. These growth rates are far below the detection limit of previous estimates of CF pathogen growth rates, and the rates are slowest in acutely sick patients undergoing pulmonary exacerbations; nevertheless, they are accessible to experimental replication within laboratory models. Treatment regimens that include specific antibiotics (vancomycin, piperacillin/tazobactam, tobramycin) further appear to correlate with slow growth of S. aureus on average, but follow-up longitudinal studies must be performed to determine whether this effect holds for individual patients.slow growth | infectious disease | metabolic heterogeneity | cystic fibrosis | hydrogen isotope labeling

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Denitrification by cystic fibrosis pathogens – Stenotrophomonas maltophilia is dormant in sputum

Cited by 35 publications

References 70 publications

Chronic pulmonary disease withMycobacterium abscessuscomplex is a biofilm infection

Chronic pulmonary disease withMycobacterium abscessuscomplex is a biofilm infection

Microenvironmental characteristics and physiology of biofilms in chronic infections of CF patients are strongly affected by the host immune response

Trace incorporation of heavy water reveals slow and heterogeneous pathogen growth rates in cystic fibrosis sputum

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