Inside the phagosome: A bacterial perspective

Abstract

Summary The neutrophil phagosome is one of the most hostile environments that bacteria must face and overcome if they are to succeed as pathogens. Targeting bacterial defense mechanisms should lead to new therapies that assist neutrophils to kill pathogens, but this has not yet come to fruition. One of the limiting factors in this effort has been our incomplete knowledge of the complex biochemistry that occurs within the rapidly changing environment of the phagosome. The same compartmentalization that protects host tissue also limits our ability to measure events within the phagosome. In this review, we highlight the limitations in our knowledge, and how the contribution of bacteria to the phagosomal environment is often ignored. There appears to be significant heterogeneity among phagosomes, and it is important to determine whether survivors have more efficient defenses or whether they are ingested into less threatening environments than other bacteria. As part of these efforts, we discuss how monitoring or recovering bacteria from phagosomes can provide insight into the conditions they have faced. We also encourage the use of unbiased screening approaches to identify bacterial genes that are essential for survival inside neutrophil phagosomes.

The neutrophil oxidant hypothiocyanous acid causes a thiol-specific stress response and an oxidative shift of the bacillithiol redox potential in Staphylococcus aureus

“…After infection of the host, the pathogens are phagocytosed by the cells of our innate immune system, such as macrophages and neutrophils. The phagocytosis of the bacteria is associated with an oxidative burst of activated neutrophils, which is aimed to kill the invading bacteria ( 7 – 10 ). First, the NADPH oxidase is assembled in the phagosomal membrane, which transfers electrons to oxygen to produce reactive oxygen species (ROS), such as superoxide anions at concentrations of 2 mM/s ( 8 – 12 ).…”

Superoxide: The enigmatic chemical chameleon in neutrophil biology

“…A more detailed discussion of how bacteria affect the phagosomal environment is reviewed elsewhere in this issue. 143 The fate of protein chloramines is intriguing because they account for a large proportion of hypochlorous acid generated in the phagosome. We have shown that protein dichloramines breakdown to release bactericidal monochloramine gas (NH 2 Cl).…”

“…To be maximally effective in neutrophil phagosomes, SPIN would have to be present at a similar concentration to that of myeloperoxidase. A more detailed discussion of how bacteria affect the phagosomal environment is reviewed elsewhere in this issue 143 …”

Neutrophils and their friends

“…Capitalizing on skills refined by their adaptations to threats from competing organisms in environmental settings, microbes are not passive victims trapped in phagosomes but rather targets that sense and react to the hostile conditions encountered. Hampton and Dickerhof 12 discuss how microbes can actively undermine neutrophil responses, change surface charge to rebuff attack by cationic antimicrobial peptides, release agents that bind and inactivate antimicrobial mediators (as occurs with MPO inactivation by the staphylococcal peroxidase inhibitor, SPIN), degrade or neutralize oxidants, and repair damage exerted by phagosomal contents. The speed with which organisms adapt to their new environments can be remarkable and, when successful, allow ingested bacteria to persist, alive, within neutrophils.…”

“…Whereas the complex mix of interacting agents within phagosomes and the capacity of ingested microbes to counter the attack together make deciphering how neutrophils kill microbes nearly impossible, the heterogeneity among phagosomes compounds the challenge even further. As reviewed by Hampton and Dickerhof, 12 not all neutrophils in circulation exhibit the same capacity for phagocytosis and, even within the same neutrophil, phagosomes differ with respect to their capacity to generate oxidants. The challenges to understanding fully the most fundamental aspect of phagocyte biology, i.e., killing ingested microbes, seem insurmountable.…”