The interface of biofilm and immune system for Gram-negative ESKAPE pathogens

The ESKAPE group of pathogens comprises Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp., which are capable of developing profound biofilms while infecting host tissues and medical devices. In addition to acting as a barrier to antimicrobial treatments and as a niche for the transmission of antibiotic resistance genes, biofilm-associated extracellular polymeric substances and metabolites modulate innate and adaptive immune responses. With the rise of emerging resistance against last-resort antibiotics, divulging the cross-talk between ESKAPE biofilms and the host immune system is essential for designing therapies aimed at immunoactivation. Compared with their Gram-positive ESKAPE counterparts, limited therapeutics coupled with higher mortality-associated phenotypes make Gram-negative ESKAPE pathogens an urgent priority for immediate action. The ultimate goals for strategizing such interventions are to disrupt biofilm integrity, restore immune efficacy, and improve clinical outcomes against multi- or pan-drug-resistant pathogens. Against this backdrop, this review highlights the alteration of the host immune system and the modifications in innate and adaptive immune responses caused by Gram-negative ESKAPE pathogens. In addition, the possibility of success of immunomodulation-based strategies in combating bacterial biofilms and accentuating the activity of known antimicrobials is discussed objectively.