Hookworms Evade Host Immunity by Secreting a Deoxyribonuclease to Degrade Neutrophil Extracellular Traps

Tiffany Bouchery,Mati Moyat,Javier Sotillo,Solomon Silverstein,Beatrice Volpe,Gillian Coakley,Theodora-Dorita Tsourouktsoglou,Luke Becker,Kathleen Shah,Manuel Kulagin,Romain Guiet,Mali Camberis,Alfonso Schmidt,Arne Seitz,Paul Giacomin,Graham Le Gros,Venizelos Papayannopoulos,Alex Loukas,Nicola L Harris

doi:10.1016/j.chom.2020.01.011

Abstract

Hookworms cause a major neglected tropical disease, occurring after larvae penetrate the host skin. Neutrophils are phagocytes that kill large pathogens by releasing neutrophil extracellular traps (NETs), but whether they target hookworms during skin infection is unknown. Using a murine hookworm, Nippostrongylus brasiliensis, we observed neutrophils being rapidly recruited and deploying NETs around skin-penetrating larvae. Neutrophils depletion or NET inhibition altered larvae behavior and enhanced the number of adult worms following murine infection. Nevertheless, larvae were able to mitigate the effect of NETs by secreting a deoxyribonuclease (Nb-DNase II) to degrade the DNA backbone. Critically, neutrophils were able to kill larvae invitro, which was enhanced by neutralizing Nb-DNase II. Homologs of Nb-DNase II are present in other nematodes, including the human hookworm, Necator americanus, which also evaded NETs invitro. These findings highlight the importance of neutrophils in hookworm infection and a potential conserved mechanism of immune evasion.

Highlights

Hookworms, including Necator americanus (Na) and Ancylostoma duodenale, are highly successful nematode parasites that represent an evolutionarily ancient disease; evidence of infection has been found in human fossils dating between 4,000 and 7,000 years old (Araujo et al, 1988)
A large body of research has demonstrated that neutrophils actively form neutrophil extracellular traps (NETs) in response to an array of pathogens—including bacteria, fungi, viruses, and protozoa (Yipp and Kubes, 2013)
Hookworm Infection of the Skin Elicits Rapid Neutrophil Swarming Myeloid cell recruitment from the blood to extravascular sites of tissue damage is a hallmark of the early innate immune response

Summary

Introduction

Hookworms, including Necator americanus (Na) and Ancylostoma duodenale, are highly successful nematode parasites that represent an evolutionarily ancient disease; evidence of infection has been found in human fossils dating between 4,000 and 7,000 years old (Araujo et al, 1988). Neutrophils are highly abundant granulocytes that rapidly enter sites of infection, inflammation, or damage They have long been known to contribute to pathogen resistance through multiple mechanisms including phagocytosis, production of reactive oxygen species, and the release of granules containing toxic mediators. Activated neutrophils were observed to release extracellular nucleic acids decorated with histones and granular proteins, termed neutrophil extracellular traps (NETs) (Brinkmann et al, 2004). Since their discovery, a large body of research has demonstrated that neutrophils actively form NETs (a process known as NETosis) in response to an array of pathogens—including bacteria, fungi, viruses, and protozoa (Yipp and Kubes, 2013). Several groups have reported formation of NETs around other large pathogens, including

Methods

Results

Discussion

Conclusion