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      Not Quite the Bully in the Schoolyard: Staphylococcus aureus Can Survive and Coexist with Pseudomonas aeruginosa in the Cystic Fibrosis Lung

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          Abstract

          Microorganisms often dwell and interact in complex environmental communities. These interactions may benefit multiple parties (e.g., protection in biofilms) or just one member (e.g., metabolite exchange). However, interspecies interactions can be antagonistic interactions in which one organism inhibits or kills its neighbor, especially involving nutrient and niche competition. In either case, polymicrobial interactions can alter the behavior, physiology, and persistence of microbes impacting human infections (1). Scientists have gained a greater appreciation for the constituents and causes of human polymicrobial infections, including respiratory tract infections (1). In addition to identifying the microbiota, studies have begun to define the interactions between microbes in these infections. The cystic fibrosis (CF) lung environment represents an ideal location for diverse microbes to interact. Although diverse bacterial species colonize the airways of individuals with CF, Pseudomonas aeruginosa and Staphylococcus aureus are two key pathogens in terms of prevalence, sputum abundance, and associations with lung disease (2–4). P. aeruginosa has long been considered the dominant CF pathogen on the basis of circumstantial evidence. First, the U.S. CF Foundation Patient Registry reports an inverse relationship between the prevalence of both species; specifically, S. aureus declines during late teenage years, whereas P. aeruginosa increases (2) (Figure 1). Given the relatively high S. aureus prevalence in children and young adults (60–80%), P. aeruginosa is often believed to actively supplant S. aureus in secretions (5, 6). Second, P. aeruginosa outcompetes and suppresses S. aureus growth during in vitro coculture by producing antistaphylococcal compounds (7), which are induced by S. aureus (8) and are detected in CF sputum (9, 10). P. aeruginosa benefits from iron released after S. aureus lysis (11), potentially explaining why it targets S. aureus. Figure 1. Data from the U.S. Cystic Fibrosis Foundation Patient Registry showing the prevalence of individuals with cystic fibrosis who had positive culture results for a bacterial species according to age group during 2018. The age cohort is presented on the x-axis, and the percentages of positive culture results are displayed on the y-axis for the following organisms: Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-susceptible), MRSA, Haemophilus influenzae, Achromobacter species, Burkholderia cepacia complex, and Stenotrophomonas maltophilia. Although coinfections are not displayed, individuals may have been colonized with multiple organisms. Reprinted by permission from Reference 2. MRSA = methicillin-resistant S. aureus. Based on this evidence, an assumption is that P. aeruginosa suppresses S. aureus in the CF lung, shifting prevalence with age. However, the Patient Registry figure depicts cross-sectional rather than longitudinal data of individuals and lacks quantitative culture results to measure changes in bacterial abundance (Figure 1). Rather than succumbing to P. aeruginosa antagonism, S. aureus may simply disappear with age, either in response to host physiological changes or with treatment, allowing other pathogens to occupy the space. S. aureus prevalence and coinfection rates with P. aeruginosa have risen over the last decade (2), which also challenges the assumed in vivo dominance of P. aeruginosa over S. aureus. Finally, in vitro coculture models involve cells in a metabolically active state and in physical contact or immediate proximity to each other, both of which may not exist in vivo. In this issue of the Journal, Fischer and colleagues (pp. 328–338) thoughtfully scrutinize the dynamic relationship between P. aeruginosa and S. aureus. The authors examined retrospective, longitudinal, and quantitative culture data from people with CF who regularly expectorated sputum (12). This large collection of culture data provided a unique resource to assess the presence and densities of these pathogens over an extended timeframe. Among patients with CF who provided ≥10 sputum or BAL quantitative cultures over 13 years, a majority of patients had cultures positive for each organism, high rates of simultaneous coinfection, and high bacterial densities of each (median log10 colony-forming units/ml of 6.52 for P. aeruginosa and 6.42 for S. aureus). This permitted longitudinal analyses of changes in culture abundance after acquisition of the competing species or during simultaneous coinfection. Contrary to the longstanding assumptions of P. aeruginosa dominance, the authors found that S. aureus had stable, long-term coexistence with P. aeruginosa in CF samples. Regardless of whether S. aureus preceded the introduction of P. aeruginosa or whether both organisms were cocultured early in the study, S. aureus bacterial densities did not decline with time in the presence of P. aeruginosa. Interestingly, coinfections actually increased rather than decreasing over time, and replacement of S. aureus by P. aeruginosa rarely occurred. In comparison, Haemophilus influenzae, another early CF pathogen, did not compete well against either organism. S. aureus is typically categorized according to methicillin susceptibility (methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]). National surveillance has shown an increase in MRSA culture positivity in U.S. patients with CF from 2000 to 2010 (2). This increase was even more pronounced at the authors’ center, raising doubts whether persistence was related to changes in S. aureus susceptibility rather than resilience to P. aeruginosa antagonism. To address this question, the authors repeated their analyses for MSSA and MRSA individually and found both subtypes had similar durations of infection and maintained high culture abundances when coinfecting with P. aeruginosa, although MRSA sputum densities were generally higher and persisted longer than MSSA. Because these findings are provocative, a number of questions emerge. How generalizable are these single site findings to the broader CF population and other centers? The authors analyzed quantitative culture results from subjects who expectorated. These subjects represented ∼40% of the clinic population, were relatively older, had worse lung disease, and had higher P. aeruginosa culture rates than the other patients with CF in the center. The interactions between P. aeruginosa and S. aureus may differ in younger, healthier patients with newly acquired bacteria. For example, persistent (late) CF P. aeruginosa isolates lose their competitive advantage in vitro over S. aureus compared with recently acquired (early) P. aeruginosa isolates (13, 14). In addition, the relatively high MRSA rates at this center raise doubts about whether treatment and antibiotic susceptibility alter outcomes between P. aeruginosa and S. aureus. A prospective, multicenter study encompassing a larger, younger, and healthier patient population with lower MRSA prevalence and including a longitudinal linkage between microbiology and antibiotic usage would alleviate these limitations. Regardless of limitations, these results suggest that S. aureus is more resilient than previously believed, but how does S. aureus coexist with P. aeruginosa in vivo, given P. aeruginosa’s in vitro dominance? These two species may be compartmentalized within the airways and only mix on expectoration. The concept of microbial compartmentalization in the CF airway has previously been demonstrated (15). Alternatively, S. aureus may adapt to the presence of P. aeruginosa, facilitating its in vivo coexistence. For example, P. aeruginosa and certain antibiotics select for S. aureus small colony variants in vitro that are tolerant to P. aeruginosa antagonism (9). The detection of small colony variants was not evaluated in this report. Importantly, what does this information mean for the health and care of people with CF? Patients with CF coinfected with P. aeruginosa and S. aureus reportedly have worse respiratory outcomes than those with single infections (16). Characteristics associated with persistence, pathogenesis, and response to therapy of each species were affected by interactions between these bacteria in vitro (7). Fischer and colleagues (12) conclude that P. aeruginosa and S. aureus can coinfect for much longer than previously anticipated. These results suggest that concurrent treatments directed at both organisms may improve CF clinical outcomes.

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          Regional Isolation Drives Bacterial Diversification within Cystic Fibrosis Lungs.

          Bacterial lineages that chronically infect cystic fibrosis (CF) patients genetically diversify during infection. However, the mechanisms driving diversification are unknown. By dissecting ten CF lung pairs and studying ∼12,000 regional isolates, we were able to investigate whether clonally related Pseudomonas aeruginosa inhabiting different lung regions evolve independently and differ functionally. Phylogenetic analysis of genome sequences showed that regional isolation of P. aeruginosa drives divergent evolution. We investigated the consequences of regional evolution by studying isolates from mildly and severely diseased lung regions and found evolved differences in bacterial nutritional requirements, host defense and antibiotic resistance, and virulence due to hyperactivity of the type 3 secretion system. These findings suggest that bacterial intermixing is limited in CF lungs and that regional selective pressures may markedly differ. The findings also may explain how specialized bacterial variants arise during infection and raise the possibility that pathogen diversification occurs in other chronic infections characterized by spatially heterogeneous conditions.
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            Selection for Staphylococcus aureus small-colony variants due to growth in the presence of Pseudomonas aeruginosa.

            Opportunistic infections are often polymicrobial. Two of the most important bacterial opportunistic pathogens of humans, Pseudomonas aeruginosa and Staphylococcus aureus, frequently are coisolated from infections of catheters, endotracheal tubes, skin, eyes, and the respiratory tract, including the airways of people with cystic fibrosis (CF). Here, we show that suppression of S. aureus respiration by a P. aeruginosa exoproduct, 4-hydroxy-2-heptylquinoline-N-oxide (HQNO), protects S. aureus during coculture from killing by commonly used aminoglycoside antibiotics such as tobramycin. Furthermore, prolonged growth of S. aureus with either P. aeruginosa or with physiological concentrations of pure HQNO selects for typical S. aureus small-colony variants (SCVs), well known for stable aminoglycoside resistance and persistence in chronic infections, including those found in CF. We detected HQNO in the sputum of CF patients infected with P. aeruginosa, but not in uninfected patients, suggesting that this HQNO-mediated interspecies interaction occurs in CF airways. Thus, in all coinfections with P. aeruginosa, S. aureus may be underappreciated as a pathogen because of the formation of antibiotic-resistant and difficult to detect small-colony variants. Interspecies microbial interactions, analogous to those mediated by HQNO, commonly may alter not only the course of disease and the response to therapy, but also the population structure of bacterial communities that promote the health of host animals, plants, and ecosystems.
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              Polymicrobial interactions: impact on pathogenesis and human disease.

              Microorganisms coexist in a complex milieu of bacteria, fungi, archaea, and viruses on or within the human body, often as multifaceted polymicrobial biofilm communities at mucosal sites and on abiotic surfaces. Only recently have we begun to appreciate the complicated biofilm phenotype during infection; moreover, even less is known about the interactions that occur between microorganisms during polymicrobial growth and their implications in human disease. Therefore, this review focuses on polymicrobial biofilm-mediated infections and examines the contribution of bacterial-bacterial, bacterial-fungal, and bacterial-viral interactions during human infection and potential strategies for protection against such diseases.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am J Respir Crit Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                1 February 2021
                1 February 2021
                1 February 2021
                1 February 2021
                : 203
                : 3
                : 279-281
                Affiliations
                [ 1 ]Department of Pediatrics

                University of Washington

                Seattle, Washington
                [ 2 ]Division of Pediatric Pulmonology

                Seattle Children’s Hospital

                Seattle, Washington

                and
                [ 3 ]Center for Clinical and Translational Research

                Seattle Children’s Research Institute

                Seattle, Washington
                Author notes
                [* ]B.W.R. is Associate Editor of AJRCCM. Her participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.
                Article
                202008-3077ED
                10.1164/rccm.202008-3077ED
                7874311
                32846098
                257b65d1-ab57-42c4-865d-a654a87dde2f
                Copyright © 2021 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

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