The social life of microbes in chronic infection

Abstract

Chronic infections place a significant burden on healthcare systems, requiring over $25 billion in treatment annually in the United States alone [1,2]. Notably, the majority of chronic infections, which include cystic fibrosis (CF), chronic wounds, otitis media, periodontitis, urinary tract infections, and osteomyelitis, are considered polymicrobial and are often recalcitrant to antibiotic treatment [1-9]. Although we know that diverse communities of microbes comprise these infections, how microbes interact and the impacts of these interactions on human disease are less understood. Here, we discuss recent advances in our understanding of how bacteria communicate in chronic infection, with a focus on Staphylococcus aureus and Pseudomonas aeruginosa, and we highlight outstanding questions and controversies in the field.

Figure 1.. Summary of known inter- and intra-species interactions in the model organisms S. aureus and P. aeruginosa in in vitro and in animal infection models.

S. aureus is depicted in in yellow and P. aeruginosa in green. Positive (cooperative) interactions are shown with an arrow (→) while negative (competitive) interactions are shown with an inhibitory arrow (⊣). Depicted interactions (clockwise from right): 1) Inhibition of S. aureus quorum sensing (QS) by non-cognate auto-inducing peptide (AIP) quorum sensing molecules produced by distantly related S. aureus strains or other staphylococcal species (blue) [32, 51]; 2) Peptidoglycan produced by S. aureus increases P. aeruginosa virulence and production of pyocyanin [60]; 3) Secreted Protein A produced by S. aureus coats P. aeruginosa cells leading to increased persistence and reduced phagocytosis by neutrophils [11]; 4) S. aureus has increased expression of the secreted virulence factors alpha-toxin and Panton-Valentine leucocidin and reduced expression of protein A in a murine model of infection through an unknown mechanism [61]; 5) Expression of the quorum sensing system (Agr-system) in S. aureus increases virulence through higher production of virulence factors including toxins (alpha-toxin, gamma-toxin), proteases (SplA-F, SspA, SspB, ScpA), and leukocidins (LukAB, LukGH) [19, 20, 28, 32, 43]; 6) Quinolones (e.g. 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO)) secreted by P. aeruginosa induce cell lysis and block the electron transport chain in S. aureus, resulting in a switch from a respiratory to a fermentative metabolism [15, 63]; 7) Expression of the quorum sensing systems in P. aeruginosa (LasI-LasR; RhlI-RhlR) increases virulence through higher production of secreted molecules including elastase, pyocyanin, and quinolones [25, 26, 30, 31, 33].