Influenza A Virus Pre-Infection Exacerbates Pseudomonas aeruginosa-Mediated Lung Damage Through Increased MMP-9 Expression, Decreased Elafin Production and Tissue Resilience

Abstract

Individuals with impaired immune responses, such as ventilated and cystic fibrosis patients are often infected with Pseudomonas aeruginosa (P.a) bacteria, and a co-infection with the Influenza virus (IAV) is often present. It has been known for many years that infection with IAV predisposes the host to secondary bacterial infections (such as Streptococcus pneumoniae or Staphylococcus aureus), and there is an abundance of mechanistic studies, including those studying the role of desensitization of TLR signaling, type I IFN-mediated impairment of neutrophil chemokines and antimicrobial production, attenuation of IL1β production etc., showing this. However, little is known about the mechanistic events underlying the potential deleterious synergy between Influenza and P.a co-infections. We demonstrate here in vitro in epithelial cells and in vivo in three independent models (two involving mice given IAV +/-P.a, and one involving mice given IAV +/-IL-1β) that IAV promotes secondary P.a-mediated lung disease or augmented IL-1β-mediated inflammation. We show that IAV-P.a-mediated deleterious responses includes increased matrix metalloprotease (MMP) activity, and MMP-9 in particular, and that the use of the MMP inhibitor improves lung resilience. Furthermore, we show that IAV post-transcriptionally inhibits the antimicrobial/anti-protease molecule elafin/trappin-2, which we have shown previously to be anti-inflammatory and to protect the host against maladaptive neutrophilic inflammation in P.a infections. Our work highlights the capacity of IAV to promote further P.a-mediated lung damage, not necessarily through its interference with host resistance to the bacterium, but by down-regulating tissue resilience to lung inflammation instead. Our study therefore suggests that restoring tissue resilience in clinical settings where IAV/P.a co-exists could prove a fruitful strategy.

Secondary bacterial infection in COVID-19 patients is a stronger predictor for death compared to influenza patients

“…Its dissemination to the lungs is attributed to a combination of environmental changes and immune responses that create suitable conditions for Staphylococcus aureus infection 9 . Pseudomonas aeruginosa is also associated with chronic predisposing respiratory conditions, including upper respiratory tract infections such as influenza 10 , 11 . While Pseudomonas aeruginosa is a common respiratory opportunistic pathogen, it is also known as the most common gram-negative bacterial species associated with severe hospital-acquired infections in some hospitals 12 .…”

Neutrophils in respiratory viral infections

“…220 In addition, increased MMP production during IAV infection was suggested to increase lung damage during P. aeruginosa co-infection. 221 Furthermore, blood neutrophils exposed to aspirate fluid from children with viral/ bacterial co-infections showed decreased respiratory burst and killing activity against Haemophilus influenzae and Staphylococcus aureus compared to those transmigrated into the aspirate fluid from children without bacterial co-infection. 222 Suppressive neutrophils (CD16 hi CD62L lo ) were also found in blood and BAL from RSV-infected infants with a bacterial co-infection.…”

Early oseltamivir reduces risk for influenza-associated aspergillosis in a double-hit murine model

“…These pathological processes are the key to success for secondary pathogenic microorganisms to enter the lung parenchyma and colonize patients [12]. Bacterial superinfections with Staphylococcus aureus and Streptococcus pneumoniae are well-defined complications of a severe influenza infection and different mouse models of influenzabacterial-co-infection have been developed [13][14][15][16]. However, until today, influenza-associated fungal coinfection models are not yet widely experimentally addressed.…”