Abstract
In patients with influenza, morbidity and mortality are strongly influenced by infections with Staphylococcus aureus producing high amounts of certain toxins. Here we tested the impact of influenza virus on the pro-inflammatory and cytotoxic actions of a panel of S. aureus virulence factors, including Panton-Valentine Leucocidin (PVL), phenol-soluble modulin α1 (PSMα1) and 3 (PSMα3), α-hemolysin (Hla), and cell wall components, i.e., heat-killed S. aureus (HKSA) and protein A. We initially screened for potential synergic interactions using a standardized in vitro model in influenza-infected continuous human monocytic cell lines. Then we tested the identified associations using an ex vivo model in influenza-infected human monocytes freshly isolated from blood. Co-exposure to influenza virus and HKSA, PVL, PSMα1, and PSMα3 increased NF-κB/AP-1 pathway activation in THP1-XBlue cells, and co-exposure to influenza virus and PVL increased cytotoxicity in U937 cells. In monocytes isolated from blood, the synergy between influenza virus and HKSA was confirmed based on cytokine production (TNF-α, IL-1β, IL-6), and co-exposure to influenza virus and Hla-increased cytotoxicity. Our findings suggest that influenza virus potentiates the pro-inflammatory action of HKSA and contributes to the cytotoxicity of Hla on monocytes. Synergic interactions identified in the cell-line model must be cautiously interpreted since few were relevant in the ex vivo model.
Highlights
The World Health Organization estimates that influenza is responsible for 3 to 5 million cases of severe illness and 250,000 to 500,000 deaths per year worldwide [1]
Staphylococcus aureus has recently emerged as a major pathogen in influenza virus superinfection [4,5], seemingly concomitant with the emergence of community-acquired methicillin-resistant S. aureus (CA-MRSA) since the early 2000s [6]
Virulence determinants involved in the pathophysiology of S. aureus lung infection include S. aureus pathogen-associated molecular patterns (PAMPs), such as cell-wall anchored lipoproteins, lipoteichoic acid, peptidoglycan, and protein A; and excreted toxins, such as alpha-toxin (Hla), Panton-Valentine Leukocidin (PVL), and α-type phenol-soluble modulins (PSMα)
Summary
The World Health Organization estimates that influenza is responsible for 3 to 5 million cases of severe illness and 250,000 to 500,000 deaths per year worldwide [1]. Toll-like receptors (TLR) and other pattern recognition receptors, prompting activation of innate immune responses [7]. Virulence determinants involved in the pathophysiology of S. aureus lung infection include S. aureus PAMPs, such as cell-wall anchored lipoproteins, lipoteichoic acid, peptidoglycan, and protein A; and excreted toxins, such as alpha-toxin (Hla), Panton-Valentine Leukocidin (PVL), and α-type phenol-soluble modulins (PSMα). These factors activate the immune system through different receptors, but all trigger the NF-κB pathway and release of pro-inflammatory mediators [8,9,10,11,12,13]. Recognition of influenza virus nucleic acids by TLR3, 7, and 8 leads to NF-κB pathway activation [14,15]
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