Participation of CD11c ⁺ Leukocytes in Methicillin-Resistant Staphylococcus aureus Clearance from the Lung

Abstract

Staphylococcus aureus causes especially severe pulmonary infection, associated with high morbidity and mortality. In addition to the effects of specific virulence factors, it appears that the intensity of the host proinflammatory response, particularly in the initial stages of infection, contributes substantially to pulmonary damage. We tested the hypothesis that the CD11c ؉ leukocytes are important in the host response to pulmonary infection with methicillin-resistant S. aureus (MRSA) USA300. Clodronate-induced depletion of the alveolar macrophage population resulted in increased numbers of dendritic cells (DCs) and CD4؉ cells in bronchoalveolar lavage (BAL) fluid and was associated with significantly increased mortality by 18 h following S. aureus inoculation but had no effect on bacterial load or polymorphonuclear leukocyte (PMN) numbers in the lung. These clodronate-treated mice also had increased expression of interleukin-17A/F (IL-17A/F) and Staphylococcus aureus bacteria, particularly the epidemic methicillin-resistant USA300 strains, have recently been associated with severe invasive pneumonias in previously well individuals, as well as being a complication of influenza (15). These pneumonias are characterized by a predominant polymorphonuclear leukocyte (PMN) response with significant areas of necrosis and hemorrhage (6). Numerous studies have addressed which of the several virulence factors expressed by the USA300 strains are most important in the pathogenesis of pulmonary infection. In the C57BL/6J mouse model of acute pneumonia, the contributions of ␣-hemolysin (Hla) (3) and protein A (SpA) (8) have been well documented. The importance of Panton-Valentine leukocidin (PVL) has also been confirmed in a rabbit model of infection; rabbits, like humans, have highly PVL-susceptible leukocytes (6). Besides the direct toxicity of staphylococcal toxins, some of the pathological consequences of staphylococcal virulence factors are due to the intensity of the host immune response. Both Tnfr1 Ϫ/Ϫ (8) and Ifnar Ϫ/Ϫ (17) mice are highly resistant to S. aureus pneumonia and even to the USA300 strains expressing these virulence factors, suggesting that the intensity of the host immune response to infection is critical in the pathogenesis of severe pneumonia.Exactly which components of the innate immune response contribute to lethality in these models of acute S. aureus pneumonia has not been clearly delineated. PMNs have long been thought to be critical for efficient staphylococcal clearance (19,22), and the increased incidence of severe staphylococcal infection in humans with disorders of PMN function or activation, such as chronic granulomatous disease (10, 12), confirm this observation. PMNs themselves can also contribute to the pathology associated with staphylococcal infection. A substantial component of the lung pathology associated with S. aureus USA300 pneumonia has been attributed to the PVL-associated release of cytotoxic components from PMN granules (5). In models of soft tissue infection, the importance ...

Humanized Mice Exhibit Increased Susceptibility toStaphylococcus aureusPneumonia

“…Macrophages can play both proinflammatory and antiinflammatory roles and thus have many functions within the host [40]. Their loss can prevent proper bacterial clearance [19,20], while their signaling cascades can contribute to inflammation and inefficient clearance [19]. Our results from the humanized mice suggest that human macrophages are especially susceptible to PVL-mediated lysis in vivo.…”

“…Exactly which immune cell types are involved and what their functions are in pulmonary defenses are difficult to establish, especially if certain leukocyte populations are targeted by human-specific S. aureus toxins. Recent studies suggest that the resident alveolar macrophage populations are especially important in orchestrating staphylococcal clearance [19], whereas dendritic cells [20] and even CD4 + T cells have not been found to be essential in murine models of pneumonia [21]. The human-specific bicomponent toxins PVL and LukAB have been associated with activation of the NLRP3 inflammasome [22][23][24].…”

Activation of inflammasome signaling mediates pathology of acute P. aeruginosa pneumonia

“…Control mice were treated with DMSO and rat IgG for caspase inhibitor and cytokine antibody experiments, respectively. Clodronate depletion of AM was done as described previously (44,45,61). BAL fluid was harvested 18 hours after infection and used to quantify immune cell populations, cytokine expression, and bacteria CFU.…”

Ablation of Pericyte-Like Cells in Lungs by Oropharyngeal Aspiration of Diphtheria Toxin

“…T dendritic cells (14)(15)(16). Several features delineate our model from these previous methodologies.…”