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Mitogen-activated protein kinases (MAPKs) regulate IL-6 over-production during concomitant influenza virus and
Carolin Klemm1, Christin Bruchhagen1, Andre van Krüchten1
1Institute of Virology Muenster (IVM), Westfaelische Wilhelms-University Muenster, Von Esmarch-Str. 56, D-48149 Muenster, Germany.
Abstract:
Bacterial super-infections are a major complication of influenza virus (IV) infections and often lead to severe pneumonia. One hallmark of IV-associated Staphylococcus aureus (S. aureus) infection is rapid progression to a serious disease outcome. Changes in immune and inflammatory host responses increase morbidity and complicate efficient therapy. A key player during inflammation is the multifunctional cytokine IL-6. Although increased IL-6 levels have been observed after severe disease upon IV and/or bacterial super-infection, the underlying molecular mechanisms still remain to be elucidated. In the present study, we focused on cellular signalling pathways regulating IL-6 production upon IV/S. aureus super-infection. Additionally, infection with viable bacteria was mimicked by lipoteichoic acid stimulation in this model. Analyses of cellular signalling mechanisms revealed synergistically increased activation of the MAPK p38 as well as enhanced phosphorylation of the MAPKs ERK1/2 and JNK in the presence of super-infecting bacteria. Interestingly, inhibition of MAPK activity indicated a strong dependence of IL-6 expression on p38 and ERK1/2, while the MAPK JNK seems not to be involved. Thus, our results provide new molecular insights into the regulation of IL-6, a marker of severe disease, which might contribute to the lethal synergism of IV and S. aureus.
Insights
Influenza virus and Staphylococcus aureus co-infections elevate interleukin-6 (IL-6) by activating specific MAPK pathways. Understanding these mechanisms is key to treating severe pneumonia caused by these super-infections.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Bacterial super-infections, particularly Staphylococcus aureus, are severe complications of influenza virus (IV) infections, leading to pneumonia.
- Interleukin-6 (IL-6) is a key cytokine in inflammation, with elevated levels observed in severe IV and bacterial co-infections, but its regulation remains unclear.
Purpose of the Study:
- To investigate the cellular signaling pathways governing IL-6 production during IV/S. aureus super-infection.
- To elucidate the role of mitogen-activated protein kinases (MAPKs) in IL-6 regulation in this context.
Main Methods:
- Studied IL-6 production in a model of IV/S. aureus super-infection.
- Used lipoteichoic acid to mimic viable bacterial stimulation.
- Analyzed MAPK pathway activation (p38, ERK1/2, JNK) and IL-6 expression.
- Utilized MAPK inhibitors to assess pathway involvement.
Main Results:
- Super-infection synergistically increased activation of MAPK p38 and phosphorylation of ERK1/2 and JNK.
- IL-6 expression was significantly dependent on p38 and ERK1/2 activity.
- MAPK JNK did not appear to play a significant role in IL-6 regulation.
Conclusions:
- Identified specific MAPK pathways (p38 and ERK1/2) crucial for IL-6 regulation during bacterial super-infection post-influenza.
- These findings offer molecular insights into the synergistic lethality of IV and S. aureus co-infections.
- May inform therapeutic strategies targeting IL-6 in severe pneumonia.
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