Neutrophils cast extracellular traps in response to protozoan parasites

Abstract

Release of extracellular traps by neutrophils is a now well-established phenomenon that contributes to the innate response to extracellular bacterial and fungal pathogens. The importance of NETs during protozoan infection has been less explored, but recent findings suggest an emerging role for release of neutrophil-derived extracellular DNA in response to this class of microbial pathogens. The present review summarizes findings to date regarding elicitation of NETs by Toxoplasma gondii, Plasmodium falciparum, Eimeria bovis, and Leishmania spp.

Keywords: anti-microbial defense; extracellular traps; neutrophils; protozoan parasite; toxoplasma.

FIGURE 1

Outline of NET formation. (1) Initiation of NETosis generally occurs through engagement of cell surface receptors. For parasites such as Toxoplasma, the receptor ligand interaction is not known. While invasion itself is not required, it is possible that adhesion enables high local concentrations of parasite ligands that trigger the NET cascade. (2) Evidence indicates involvement of the Raf–MEK–ERK pathway during NET formation elicited by several stimuli, including Toxoplasma. In most cases, NADPH oxidase is also involved (not shown here). (3) Signaling to the nucleus results in chromatin modification. Histone citrullination mediated by peptidylarginine deiminase (PAD) appears to be a prerequisite for NET release. (4) Concurrent with chromatin decondensation, the nuclear membrane disintegrates. (5) This results in mixing of cytoplasmic, granule (yellow and red circles) and nuclear contents. (6) Finally, DNA with associated histones and granule molecules are released into the extracellular environment entrapping microbes in the vicinity. For protozoa such as Toxoplasma this results in some parasite killing, but the major effects of NETs may be to interfere with invasion. There is evidence that other protozoa such as Leishmania donovani possess mechanisms to avoid NET-mediated killing.

FIGURE 2

NET formation triggered by Toxoplasma. Human peripheral blood neutrophils were co-incubated with Toxoplasma in the presence of cytochalasin D to prevent invasion. 4 hrs later, cells were fixed and stained with antibody to the tachyzoite surface molecule SAG-1 (pseudo-colored red). PMN nuclei and NETs were visualized using DAPI (pseudo-colored yellow).