Background

Hookworm larvae migrate from the skin to the lungs, before finally reaching the intestine, where they complete their maturation into adult worms and start to reproduce. Immunity against hookworms arise during each of these developmental phases and following both primary and secondary infections (Bouchery et al., 2017). Whilst the host immune responses against the lung and intestinal phases of the parasite infection are well characterised, the skin response has only been partially characterised as current models that utilize the rodent hookworm, Nippostrongylus brasiliensis (Nb), traditionally deliver the infectious larvae via the subcutaneous route of infection bypasses the skin de-facto. To counteract this problem, we developed two methods of infection that allow investigation of the skin-penetrating phase. These models utilize an intradermal infection of infective larvae, allowing the delivery of a controlled dose of the parasite, or the topical application of larvae mimicking the natural skin penetration of hookworms (Gharib, 1955).

Hookworms undergo their transition from a free-living organism to an infective parasite as they migrate through the skin and as such this is the first site where the parasite needs to express products aimed at the modulation of the host immune response. Indeed, we have recently used the protocols described herein to demonstrate the production of a DNAse II by skin penetrating hookworm larvae which acts to degrade neutrophil extracellular traps and thus evade killing by host neutrophils (Bouchery et al., 2020). It is likely that many additional interactions occur between the host and the parasite within the skin but that these remain to be characterised. Further study of such interactions could provide an important avenue for the identification of new vaccine targets against hookworms. Furthermore, the study of immunomodulatory events that occur early after infection could provide potential new treatments against inflammatory diseases.

The skin penetration route is already widely employed in experimental studies of Schistosomiasis infection (Winkel et al., 2018; Haas and Haeberlein, 2009), and we expect our methodology could easily be adapted to other skin penetrating helminths, such as Strongyloides spp (Jannasch et al., 2015).