Invade or die: behaviours and biochemical mechanisms that drive skin penetration in Strongyloides and other skin-penetrating nematodes

Abstract

Skin-penetrating nematodes, including the human threadworm Strongyloides stercoralis and hookworms in the genera Necator and Ancylostoma, are gastrointestinal parasites that are a major cause of neglected tropical disease in low-resource settings worldwide. These parasites infect hosts as soil-dwelling infective larvae that navigate towards hosts using host-emitted sensory cues such as odorants and body heat. Upon host contact, they invade the host by penetrating through the skin. The process of skin penetration is critical for successful parasitism but remains poorly understood and understudied. Here, we review current knowledge of skin-penetration behaviour and its underlying mechanisms in the human parasite S. stercoralis, the closely related rat parasite Strongyloides ratti, and other skin-penetrating nematodes such as hookworms. We also highlight important directions for future investigations into this underexplored process and discuss how recent advances in molecular genetic and genomic tools for Strongyloides species will enable mechanistic investigations of skin penetration and other essential parasitic behaviours in future studies. This article is part of the Theo Murphy meeting issue 'Strongyloides: omics to worm-free populations'.

Keywords: Strongyloides; astacins; hookworms; sensory behaviour; skin penetration; skin-penetrating nematode.

Figure 1.

The life cycle of Strongyloides stercoralis. Parasitic adults reside and reproduce in the host small intestine. Their progeny exit the host in faeces as L1 larvae and then undergo either homogonic (direct) or heterogonic (indirect) development [20]. L1 larvae following the homogonic path develop through two larval stages before developmentally arresting as third-stage infective larvae (iL3s). The iL3s host seek and then invade hosts by skin penetration [21]. Inside the host, the iL3s resume development and molt twice to become parasitic adults. L1 larvae following the heterogonic path molt four times to become free-living adults. The free-living adults are amenable to genetic manipulation by intragonadal microinjection [22,23]. All progeny of the free-living adults develop into iL3s. Strongyloides stercoralis can also undergo an autoinfective cycle, in which the nematodes complete their life cycle inside the same host (not shown) [20]. The figure was generated using Canva, BioRender and Adobe Illustrator.

Figure 2.

The structure of mammalian skin and potential routes of skin invasion used by hookworms. Mammalian skin or cutaneous tissue is composed of the epidermis, the dermis and various appendages [–38]. The epidermis is avascular and is composed primarily of keratinocytes, which are stacked in multiple layers [–39]. The outermost layer of the epidermis, termed the stratum corneum, is formed by dead keratinocytes. The epidermis and the dermis are separated via a protein-rich basement membrane [40]. The dermis is vascularized and fibrous, and is the place of origin of several skin appendages, including hair follicles and sweat glands [38]. The cutaneous tissue lies on top of the subcutaneous tissue or hypodermis; the hypodermis is composed of fat and traversed by circulatory vessels [41,42]. The structures in the skin that are relevant to skin penetration are labelled A-I and listed in legend 1. Hookworm iL3s follow different routes to travel into and through the skin. As indicated in legend 2, the diamonds depict two possible points of entry that iL3s might use to invade the epidermis, lines depict distinct paths of migration of iL3s through the tissue, arrows indicate the direction of migration of iL3s, and circles depict points where iL3s might enter the circulatory fluid. Whether Strongyloides spp. follow similar migratory routes during skin penetration remains to be determined. The figure was generated using BioRender and Adobe Illustrator.

Figure 3.

The astacin gene family is highly expanded in Strongyloides species. A phylogenetic dendrogram of the astacin genes of selected nematode species. Strongyloides ratti contains a large expansion of the astacin gene family. The figure is reprinted from Hunt et al. [101].