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.