Pathogenesis of Staphylococcus aureus Necrotizing Pneumonia

The Role of PVL and an Influenza Coinfection

Bettina Löffler; Silke Niemann; Christina Ehrhardt; Dagmar Horn; Christian Lanckohr; Gerard Lina; Stephan Ludwig; Georg Peters


Expert Rev Anti Infect Ther. 2013;11(10):1041-1051. 

In This Article

The Role of a Preceding Virus Infection in Necrotizing Pneumonia

The major epidemiological studies on the causative factors for necrotizing pneumonia revealed that a preceding influenza infection is a very common feature[2,3,8] This association was further supported by individual case reports. From the 43 reviewed cases in 12 patients, an influenza infection could be confirmed and 16 patients featured typical symptoms of influenza (Table 1). As the symptoms of a virus infection are not always clear and obvious and can be also unspecific, this represents a high rate of documented or suspected viral coinfections. It was also remarkable that in 12 clinical cases, as well as in our described case, unspecific symptoms, including nausea, vomiting, diarrhea or bowl inflammation, have been reported (Table 1). These symptoms are rarely described in a 'classical' S. aureus pneumonia, but have been more commonly found in influenza infections, for example, during the swine influenza (H1N1) pandemic that began in 2009 [39]. It remains unclear, if there is a direct effect of viral infections on the gastrointestinal system, or if influenza predisposes to increased frequency of bacterial bowl inflammation, such as appendicitis.

Viral factors that contribute to the outcome of severe pneumonia are particularly changes and dynamics in influenza virus protein expression varying between different strains. Strain-specific sequence variations of virulence factors, such as the non-structural proteins NS-1 and PB1-F2, are responsible for differences in cellular responses. The latter protein is not expressed by each influenza virus strain, but is often connected with pneumonia.[40] In context of the onset of severe secondary pneumonia cellular mechanisms including the induction of apoptosis upon influenza virus infection regulated by NS-1, PB1-F2 and the ion-channel protein M2 are discussed.[41,42] Furthermore, influenza viruses are able to manipulate apoptotic and immunomodulatory cellular mechanisms and to take advantage of apoptosis to support their replication.[40] Especially influenza virus-induced tissue damage is considered as major cause to pave the way for infection with bacterial pathogens.[41,42]

To evaluate the impact of a preceding influenza infection in S. aureus pneumonia, different coinfection models have been performed that propose a number of mechanisms of pathogen–pathogen and host–pathogen interactions. There is some evidence that influenza virus and bacteria promote the infection process of each other, for example, viral infection enhances bacterial binding and invasion of lung cells[43] and some S. aureus strains secrete proteases that cleave and activate virus hemagglutinin and in this way enhance influenza virus replication, infectivity and pathogenicity.[44,45] Regarding host defense, it was demonstrated that pulmonary virus infections can impair the immune system and promote secondary pulmonary infections. An important mechanism is that pulmonary IFN-I produced by T cells during an influenza infection disrupt defense against bacteria, for example, by inhibiting clearance of alveolar macrophages and by impairing the natural killer cell responses.[46,47] The multiple interactions between pathogens and host can be very strain specific and probably differ between epidemics and geographical regions, which needs to be considered particularly for vaccine developments.[41,42]

Another critical pathogenic factor can be the exacerbated pulmonary inflammatory situation in the lung during bacterial superinfection of influenza.[48] It is well known that influenza virus is a strong pro-inflammatory stimulus in the lung. The cytokine release induced by an influenza infection causes influx of immune cells, including neutrophils, monocytes and macrophages, to lung tissue.[49,50] Although cytokine responses are essential during immune responses to influenza pneumonia, an overly aggressive and dysregulated cytokine release, known as a 'cytokine storm', has been associated with influenza-related morbidity and mortality.[51,52] If a lung that is massively infiltrated with immune cells is superinfected by a PVL-producing S. aureus strain, lysis of recruited immune cells by PVL can be expected at a large scale resulting in necrotizing pneumonia (Figure 2).

Figure 2.

The pathogenesis of necrotizing pneumonia. A viral infection activates lung epithelial cells that release chemokines and induce the influx of immune cells. In case of a superinfection with a PVL-producing Staphylococcus aureus strain, PVL rapidly kills the recruited immune cells. Active components such as proteases stored in neutrophils are uncontrolled released in the surrounding lung tissue that can result in massive tissue destruction with the clinical picture of necrotizing pneumonia.