Helminth derived factors inhibit neutrophil extracellular trap formation and inflammation in bacterial peritonitis

Abstract

Despite their protective antimicrobial function, neutrophil extracellular traps (NETs) have been implicated in propagation of inflammatory responses in several disease conditions including sepsis. Highly diffusible exogenous ROS produced under such inflammatory conditions, can induce exuberant NETs, thus making inhibition of NETs desirable in inflammatory diseases. Here we report that helminth parasite excretory/secretory factors termed as parasitic ligands (PL) inhibit ROS-induced NETs by blocking the activation of nonselective calcium permeable channel Transient Receptor Potential Melastatin 2 (TRPM2). Therapeutic implication of PL mediated blockage of NET formation was tested in preclinical model of septic peritonitis, where PL treatment regulated neutrophil cell death modalities including NET formation and mitigated neutrophil mediated inflammatory response. This translated into improved survival and reduced systemic and local bacterial load in infected mice. Overall, our results posit PL as an important biological regulator of neutrophil functions with implications to a variety of inflammatory diseases including peritonitis.

Hookworm infections: Reappraising the evidence for a role of neutrophils in light of NETosis

“…Hookworms express several antioxidant enzymes, such as SODs, which could interfere with the process of NET formation (Figure 1). Interestingly, extracts of the tapeworm Mesocestoides corti were shown to block the formation of stress‐induced NETs 53 . In this study, parasite products were co‐cultured with neutrophils in the presence of H 2 O 2 , and a reduction in NETs was observed.…”

“…Interestingly, extracts of the tapeworm Mesocestoides corti were shown to block the formation of stress‐induced NETs. 53 In this study, parasite products were co‐cultured with neutrophils in the presence of H 2 O 2 , and a reduction in NETs was observed. The authors then further determined that ES products block the Transient Receptor Potential Cation Channel Subfamily M Member 2 (TRPM2) as well as downstream autophagy pathways.…”

“…Interestingly, extracts of the tapeworm Mesocestoides corti were shown to block the formation of stress-induced NETs. 53 In this study, parasite products were co-cultured with neutrophils in the presence In this section, we have shown that hookworms have evolved a considerable defense arsenal against neutrophil activity, both blocking recruitment as well as neutrophil effector functions. We therefore argue that this reflects a selective pressure exerted by neutrophils on parasite fitness.…”

Heme-Oxygenase-1 Attenuates Oxidative Functions of Antigen Presenting Cells and Promotes Regulatory T Cell Differentiation during Fasciola hepatica Infection

“…On the other hand, Schistosome infection relates to an immense oxidative stress by the host that is not sufficient to control infection [ 49 ]. Further data demonstrated that excretory/secretory factors from Mesocestoides corti inhibit ROS-induced neutrophil extracellular traps, showing that the parasite could use this mechanism to attenuate the effects induced by ROS [ 50 ]. It should be highlighted, however, that although oxidative mechanisms are induced by helminth parasite infections, their detrimental role in the parasite itself as well as in the host surroundings is not well-established yet [ 51 , 52 , 53 ].…”

Communication is key: Innate immune cells regulate host protection to helminths

“…Further, Bouchery et al, showed that NETs released following an N. brasiliensis challenge can directly impair larval viability and the parasites combat this response by secreting DNAse II (123). The ability of helminthderived products to inhibit NET formation was also shown by Chauhan et al that demonstrated that Mesocestoides corti ES products were sufficient to inhibit NET formation in the context of bacterial peritonitis (131). Moreover, it was reported that neutrophils and eosinophils require myeloperoxidase and major basic protein to kill S. stercoralis larvae in vitro (93).…”