The Role of PVL in Necrotizing Pneumonia
Despite the epidemiological data, some authors doubt the pathogenic role of PVL and suggest the presence of PVL genes to be only a marker of other more virulent determinants.[9,10] The underlying reasons are contradictory results from various infection models on necrotizing diseases. Using different species for their models, some groups could demonstrate a pathogenic function of PVL,[25,26] whereas other groups failed to detect an effect of PVL, but proposed other factors, such as α-hemolysin, phenol-soluble modulins, enterotoxins like toxin X and protein A, as responsible agents.[9,11,27–29]
These discrepancies can be partly explained by the strong cell- and species-specificity of PVL. PVL exerts pro-inflammatory and cytotoxic effects on neutrophils, monocytes and macrophages. Incubation of the cells with only low doses of PVL (0.04–0.4 μg/ml; 1–10 nM) results in inflammasome activation and induces a huge IL-1β release within minutes.[30,31] Cell activation is followed by rapid cell death induction (within 20 min) that is mainly caused by pore-formation and largely lacks apoptotic features. These inflammatory and cytotoxic effects are not only strongly cell-specific and restricted to cells derived from the granulocyte precursor line, but also very species-specific.[32,33] Cells originating from humans and rabbits are highly sensitive toward PVL, whereas cells isolated from various mice strains or monkeys are largely resistant toward PVL, even when PVL is applied at 1000-fold higher doses. This strong target cell- and species-specificity can be explained by the binding mechanism of LukS-PV to the C5a complement receptors that has been identified only recently.[34] Other staphylococcal virulence factors, for example, the phenol-soluble modulins, do not exhibit this species-specificity, but act on cells from different species equally.[32] Consequently, murine or even simian models are not always adequate to investigate S. aureus virulence for humans. Particularly to study the role of PVL, more complex models based on cells from human origin or from sensitive organisms, like rabbits, are required.[25,35]
The detrimental effect of PVL on lung tissue cannot be directly explained, as the strong pro-inflammatory and cytotoxic actions of PVL are apparently restricted to granulocytes, monocytes and macrophages, whereas PVL has no effect on lung cells, such as epithelial and endothelial cells.[32,35] These findings point to an indirect impact of PVL on tissue integrity via rapid destruction of granulocytes. Neutrophil granulocytes are the first cells recruited to inflammatory sites and form the earliest line of defense against invading microorganisms such as influenza and S. aureus. They contain serine proteases and other aggressive compounds stored in large quantities in granules that are intended to help degrade engulfed microorganisms inside phagolysosomes.[36,37] In case of an infection with a PVL-producing S. aureus strain, PVL-induced cell death is rapid and largely lacks apoptotic features.[32] As necrosis is an uncontrolled way of cell death, the potent antimicrobial molecules spill within the host tissue and cause tissue damage. The involvement of granulocytes in tissue damage was already shown in a rabbit model of necrotizing pneumonia, as neutropenic rabbits did not develop severe lung damage upon installation of PVL in the lungs.[25] Only recently, this mechanism could be reproduced in a murine model, where PVL-treated human neutrophils induced severe tissue damage when infiltrated in the lungs of mice.[35] Consequently, a massive and uncontrolled death of neutrophils with release of aggressive enzymes is a very unfavorable situation for the organism that needs to be confined. The serum contains various compounds, for example, α1-antitrypsin, that rapidly inactivate neutrophil proteases. Although the surfactant in the lung contains some protease inhibitors,[38] the protective activity is apparently not sufficient in the alveolar spaces. Therefore, proteases released by uncontrolled dying neutrophils can cause disruption of the sensitive alveolar tissue structures resulting in necrotizing pneumonia.
Expert Rev Anti Infect Ther. 2013;11(10):1041-1051. © 2013 Expert Reviews Ltd.
