Role of Excessive Inflammatory Response to
            <i>Stenotrophomonas maltophilia</i>
            Lung Infection in DBA/2 Mice and Implications for Cystic Fibrosis

Bonaventura, Giovanni Di; Pompilio, Arianna; Zappacosta, Roberta; Petrucci, Francesca; Fiscarelli, Ersilia; Rossi, Cosmo; Piccolomini, R

doi:10.1128/iai.01391-09

Cited by 49 publications

(57 citation statements)

References 52 publications

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“…Similar results were reported for the MucD serine protease secreted by P. aeruginosa, which degraded IL-8 secreted by a human intestinal epithelial cell line during infection (58). In a murine model of S. maltophilia pneumonia, the IL-8 homologues GRO␣/KC and MIP-2 are also upregulated in the murine lung in a time-dependent manner (14). The murine immune response was characterized by an early and robust increase in these chemokines at 1 day postinfection followed by a decline at three days postinfection (14).…”

Section: Discussionsupporting

confidence: 71%

“…In a murine model of S. maltophilia pneumonia, the IL-8 homologues GRO␣/KC and MIP-2 are also upregulated in the murine lung in a time-dependent manner (14). The murine immune response was characterized by an early and robust increase in these chemokines at 1 day postinfection followed by a decline at three days postinfection (14). It is possible that StmPr1, and potentially to a lesser extent StmPr2, may contribute to the observed decrease in GRO␣/KC and MIP-2 levels in the murine lung.…”

Section: Discussionmentioning

confidence: 99%

“…In order to begin to investigate the effects of Xps, StmPr1, and StmPr2 on the innate immune response, we incubated A549 cells with strain K279a at an initial MOI of 1 for 24 h and then monitored IL-8 levels in the culture supernatant by ELISA. IL-8 is a proinflammatory cytokine and neutrophil chemoattractant, and elevated levels of the murine homologues of IL-8, MIP-2 and GRO␣/KC occur in the lungs of mice infected with S. maltophilia (14). IL-8 was detected in the supernatant of WT-infected cells at 6 and 8 h postinfection; however, by 24 h postinfection, IL-8 was no longer detected (Fig.…”

Section: Activities Of S Maltophilia Stmpr1 and Stmpr2mentioning

confidence: 95%

“…In the murine lung, S. maltophilia induces inflammation and neutrophil recruitment, and it has been shown to grow and persist in certain mouse strains (11,(13)(14)(15). In all infection models, S. maltophilia strains have displayed various degrees of virulence (13,(15)(16)(17)(18), but the molecular mechanisms mediating S. maltophilia pathogenesis have yet to be determined.…”

mentioning

confidence: 99%

“…The multidrug-resistant nature of S. maltophilia makes treatment of infections highly difficult (7), and in recent years, an increased resistance to the preferred antibiotic trimethoprim-sulfamethoxazole has been reported (8-10). These findings emphasize the need to better understand the virulence mechanisms employed by S. maltophilia.The current understanding of S. maltophilia pathogenesis is limited, although studies have begun to investigate S. maltophilia infection in mammalian and nonmammalian animal models (11)(12)(13)(14)(15)(16)(17)(18). In the murine lung, S. maltophilia induces inflammation and neutrophil recruitment, and it has been shown to grow and persist in certain mouse strains (11,(13)(14)(15).…”

mentioning

confidence: 99%

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Type II Secretion-Dependent Degradative and Cytotoxic Activities Mediated by Stenotrophomonas maltophilia Serine Proteases StmPr1 and StmPr2

2015

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Stenotrophomonas maltophilia is an emerging opportunistic pathogen that primarily causes pneumonia and bacteremia in immunocompromised individuals. We recently reported that S. maltophilia strain K279a encodes the Xps type II secretion system and that Xps promotes rounding, actin rearrangement, detachment, and death in the human lung epithelial cell line A549. Here, we show that Xps-dependent cell rounding and detachment occur with multiple human and murine cell lines and that serine protease inhibitors block Xps-mediated rounding and detachment of A549 cells. Using genetic analysis, we determined that the serine proteases StmPr1 and StmPr2, which were confirmed to be Xps substrates, are predominantly responsible for secreted proteolytic activities exhibited by strain K279a, as well as the morphological and cytotoxic effects on A549 cells. Supernatants from strain K279a also promoted the degradation of type I collagen, fibrinogen, and fibronectin in a predominantly Xps-and protease-dependent manner, although some Xps-independent degradation of fibrinogen was observed. Finally, Xps, and predominantly StmPr1, degraded interleukin 8 (IL-8) secreted by A549 cells during coculture with strain K279a. Our findings indicate that while StmPr1 and StmPr2 are predominantly responsible for A549 cell rounding, extracellular matrix protein degradation, and IL-8 degradation, additional Xps substrates also contribute to these activities. Altogether, our data provide new insight into the virulence potential of the S. maltophilia Xps type II secretion system and its StmPr1 and StmPr2 substrates. The Gram-negative bacterium Stenotrophomonas maltophilia, prevalent in the aqueous environment, is now emerging as a prominent opportunistic and nosocomial pathogen (1, 2). S. maltophilia infects an array of host tissues and organs, including the respiratory tract, blood, bone, soft tissue, eye, urinary tract, heart, and brain. However, pneumonia is the most common infection associated with S. maltophilia, followed by bloodstream infection as the second most common (1, 2). S. maltophilia, though relatively nonvirulent for healthy individuals, can cause serious infection in immunocompromised individuals. Therefore, S. maltophilia poses the biggest threat for patients with severe burns, cystic fibrosis, and HIV, as well as those undergoing chemotherapy or immunosuppressive therapy (3). Prolonged hospitalization in intensive care units and long-term antibiotic treatment are also considered risk factors for developing pneumonia and bacteremia, for which mortality rates can range from 23 to 77% and 14 to 69%, respectively (1, 4). Community-acquired S. maltophilia infections, especially in the high-risk populations mentioned, have been reported (5), and recently, a communityacquired skin infection was reported for the first time in an immunocompetent individual (6). The multidrug-resistant nature of S. maltophilia makes treatment of infections highly difficult (7), and in recent years, an increased resistance to the preferred antibiotic trimeth...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Activities Of S Maltophilia Stmpr1 and Stmpr2mentioning

confidence: 95%