Helminth immunoregulation: The role of parasite secreted proteins in modulating host immunity

Abstract

Helminths are masterful immunoregulators. A characteristic feature of helminth infection is a Th2-dominated immune response, but stimulation of immunoregulatory cell populations, such as regulatory T cells and alternatively activated macrophages, is equally common. Typically, Th1/17 immunity is blocked and productive effector responses are muted, allowing survival of the parasite in a “modified Th2” environment. Drug treatment to clear the worms reverses the immunoregulatory effects, indicating that a state of active suppression is maintained by the parasite. Hence, research has focussed on “excretory–secretory” products released by live parasites, which can interfere with every aspect of host immunity from initial recognition to end-stage effector mechanisms. In this review, we survey our knowledge of helminth secreted molecules, and summarise current understanding of the growing number of individual helminth mediators that have been shown to target key receptors or pathways in the mammalian immune system.

Whole-genome sequence of Schistosoma haematobium

“…Chronic infections induce key changes in immune-cell populations, including a dominance of the T helper type 2 (T H 2) cells and a selective loss of effector T-cell activity, against a background of regulatory T cells, alternatively activated macrophages, and T H 2-inducing dendritic cells 22 . Much of the immunomodulatory capacity of schistosomes is attributable particularly to ES products 23 . In the S. haematobium proteome, we identified 55 molecules (20 of which were predicted to be ES proteins) with known immunomodulatory roles in other helminths (Supplementary Note, Supplementary Table 24).…”

Ascaris suum draft genome

“…Notably, the secreted peptidases (such as the M12 'astacins', the S9 and S33 serine proteases, and the C1 and C2 cysteine proteases) are abundantly represented, and have key roles in tissue invasion and degradation (for example, during migration and/or feeding) and/or immune evasion/modulation in many parasites 14,15 .…”

Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations

“…40 It is increasingly believed that the rapid microfilarial clearance following ivermectin dosing results not from the direct impact of the drug but via suppression of the parasite's ability to evade the host's natural immune defense mechanism. [41][42][43][44][45][46][47][48][49] Immunomodulatory agents often display fewer side effects than drugs, as well as producing less opportunity for creation of resistance in target microorganisms, which helps explain the absence of drug resistance in humans.…”