Staphylococcus aureus Elicits Marked Alterations in the Airway Proteome during Early Pneumonia

Abstract

Pneumonia caused by Staphylococcus aureus is a growing concern in the health care community. We hypothesized that characterization of the early innate immune response to bacteria in the lungs would provide insight into the mechanisms used by the host to protect itself from infection. An adult mouse model of Staphylococcus aureus pneumonia was utilized to define the early events in the innate immune response and to assess the changes in the airway proteome during the first 6 h of pneumonia. S. aureus actively replicated in the lungs of mice inoculated intranasally under anesthesia to cause significant morbidity and mortality. By 6 h postinoculation, the release of proinflammatory cytokines caused effective recruitment of neutrophils to the airway. Neutrophil influx, loss of alveolar architecture, and consolidated pneumonia were observed histologically 6 h postinoculation. Bronchoalveolar lavage fluids from mice inoculated with phosphate-buffered saline (PBS) or S. aureus were depleted of overabundant proteins and subjected to strong cation exchange fractionation followed by liquid chromatography and tandem mass spectrometry to identify the proteins present in the airway. No significant changes in response to PBS inoculation or 30 min following S. aureus inoculation were observed. However, a dramatic increase in extracellular proteins was observed 6 h postinoculation with S. aureus, with the increase dominated by inflammatory and coagulation proteins. The data presented here provide a comprehensive evaluation of the rapid and vigorous innate immune response mounted in the host airway during the earliest stages of S. aureus pneumonia.Staphylococcus aureus is a leading cause of hospital-acquired and health care-associated pneumonia and may be increasing in importance as a cause of severe community-acquired pneumonia. In the inpatient setting, it is the most common grampositive bacterium implicated in cases of ventilator-associated and hospital-acquired pneumonia (1, 9, 31). In addition, S. aureus is a frequent cause of health care-associated pneumonia occurring in residents of long-term-care facilities, individuals recently discharged from acute-care hospitals, and patients receiving outpatient treatment at hospitals and dialysis centers (1, 27, 30). A steady increase in the isolation of methicillinresistant strains of S. aureus from patients with hospital-acquired pneumonia and, more recently, community-acquired pneumonia underscores the importance of identifying host and bacterial factors that facilitate the progression of staphylococcal pneumonia.Mice have been used extensively to study pneumonia caused by a variety of bacteria (2,6,26,35,36,45,55,63,64). Murine models of airborne infection with S. aureus have been useful in characterizing host responses during the first 4 to 8 h of lung infection but do not mimic the natural route of infection and result in self-limited disease, even in immunocompromised animals (28,53,56). In these studies, proinflammatory cytokines and chemokines were released and neutrophils ...

Surfactant Protein A (SP-A)-mediated Clearance of Staphylococcus aureus Involves Binding of SP-A to the Staphylococcal Adhesin Eap and the Macrophage Receptors SP-A Receptor 210 and Scavenger Receptor Class A

“…SP-A is the principal lung opsonin that associates with S. aureus within 30 min after intranasal infection in mice (67,68). The present and previous studies demonstrate that two members of the collectin family of proteins, SP-A and MBL, are crucial for eradication of acute infections with S. aureus.…”

“…MBL binding to S. aureus cell wall glycoconjugates activates the lectin pathway of complement, enhancing recruitment and clearance of S. aureus through macrophages and neutrophils (69,70). In the lung, however, MBL appears later in inflammatory fluid from the periphery, associating with S. aureus 6 h after infection (67,68). Unlike MBL, SP-A does not bind cell wall glycoconjugates, such as LTA or peptidoglycan, on S. aureus.…”

Transcription of Inflammatory Genes in the Lung after Infection with Community-Associated Methicillin-Resistant Staphylococcus aureus : a Role for Panton-Valentine Leukocidin?

“…The results of several recent studies employing animal models of S. aureus pneumonia demonstrated that there was an early influx of neutrophils into the alveolar air spaces (2,20,21). Ventura et al recently employed a proteomics-based approach to demonstrate increased abundance of many proteins associated with the inflammatory response and the coagulation cascade in the bronchoalveolar lavage fluid from mice infected with a clinical blood isolate of S. aureus (21).…”

Assessment of an Anti-Alpha-Toxin Monoclonal Antibody for Prevention and Treatment of Staphylococcus aureus-Induced Pneumonia

“…with S. aureus exhibit an early increase in proinflammatory mediators (e.g., interleukin-1 beta [IL-1␤], keratinocyte chemoattractant [KC], and macrophage inflammatory protein 2 [MIP-2]), leading to increased lung protein levels, polymorphonuclear leukocyte (PMN) influx, necrosis, and ultimately a consolidating pneumonia similar to that seen in humans (16)(17)(18). A key virulence determinant involved in the pathogenesis of murine S. aureus pneumonia is the pore-forming toxin, alpha-toxin (AT).…”