Immune Response Modulation by Pseudomonas aeruginosa Persister Cells

Abstract

ABSTRACT Bacterial persister cells—a metabolically dormant subpopulation tolerant to antimicrobials—contribute to chronic infections and are thought to evade host immunity. In this work, we studied the ability of Pseudomonas aeruginosa persister cells to withstand host innate immunity. We found that persister cells resist MAC-mediated killing by the complement system despite being bound by complement protein C3b at levels similar to regular vegetative cells, in part due to reduced bound C5b, and are engulfed at a lower rate (10- to 100-fold), even following opsonization. Once engulfed, persister cells resist killing and, contrary to regular vegetative cells which induce a M1 favored (CD80+/CD86+/CD206−, high levels of CXCL-8, IL-6, and TNF-α) macrophage polarization, they initially induce a M2 favored macrophage polarization (CD80+/CD86+/CD206+, high levels of IL-10, and intermediate levels of CXCL-8, IL-6, and TNF-α), which is skewed toward M1 favored polarization (high levels of CXCL-8 and IL-6, lower levels of IL-10) by 24 h of infection, once persister cells awaken. Overall, our findings further establish the ability of persister cells to evade the innate host response and to contribute chronic infections. IMPORTANCE Bacterial cells have a subpopulation—persister cells—that have a low metabolism. Persister cells survive antimicrobial treatment and can regrow to cause chronic and recurrent infections. Currently little is known as to whether the human immune system recognizes and responds to the presence of persister cells. In this work, we studied the ability of persister cells from Pseudomonas aeruginosa to resist the host defense system (innate immunity). We found that this subpopulation is recognized by the defense system, but it is not killed. The lack of killing likely stems from hindering the immune response regulation, resulting in a failure to distinguish whether a pathogen is present. Findings from this work increase the overall knowledge as to how chronic infections are resilient.

Keywords

• bacterial persister cells
• chronic infections
• immune evasion
• complement
• Pseudomonas aeruginosa