Hijacking the Immune System

Staphylococcus aureus (S. aureus) evades clearance by the immune system by hijacking the very traps it produces, transforming these same traps into a toxic compound according to a paper published in Science.¹ Scientists from the University of Chicago (Chicago, USA) used high performance liquid chromatography coupled to mass spectrometry (HPLC–MS) to identify the toxin as 2’-deoxyadenosine (dAdo).

Bacterial invasion of tissue triggers an array of processes as part of the immune response, in an attempt to first contain and then destroy an infection. S. aureus can permanently colonize the human body without causing harmful effects, usually on the skin and within the nose causing boils or abscesses. However, if it enters the blood stream it can result in blood poisoning, endocarditis, and meningitis among other conditions.

S. aureus tissue infections are characterized by abscesses formed by immune cells cornering off the infection for clearance by a specific type of cell known as a macrophage — so-called “big eaters” that roam the body clearing away infections. The traps are released by neutrophils (neutrophil extraceullar traps [NETs]) in an attempt to contain the infection until the arrival of the macrophage. In the case of S. aureus however, there is no macrophage activity and the infection remains uncleared.

To investigate this mystery, S. aureus was co-cultured alongside immune cells, including neutrophils and macrophages. When NET production was activated, the macrophage began to die suggesting the production of a toxin by the bacterium. The team performed HPLC–MS to identify this toxin as 2’-deoxyadenosine (dAdo). Combining these results with data from genetic experiments using mutant strains of S. aureus, the team deduced that the bacterium converted NETs to dAdo that is toxic to macrophages.

Olaf Schneewind, senior author of the paper, said: “These bacteria have endowed themselves with weapons to not only anticipate every immune defense, but turn these immune defenses against the host as well.” He added: “Sooner or later almost every human gets some form of S. aureus infection. Our work describes for the first time the mechanism that these bacteria use to exclude macrophages from infected sites.”

So what does this mean for drug development? Theoretically, scientists could target this mechanism of evasion using therapeutic proteins to block bacterial enzymes involved in the transformation of NETs by S. aureus. This is promising but requires a lot more work.

Reference

1. V. Thammavongsa et al., Science342, 863–866 (2013).