Research

Parasitic nematodes infect over one billion people and cause extensive morbidity, particularly in low-resource settings. Our research focuses on the skin-penetrating, human-parasitic nematode Strongyloides stercoralis, which infects ~600 million people worldwide. The infective larvae of S. stercoralis and other skin-penetrating nematodes actively search for hosts to infect and then invade the host by penetrating directly through the skin. The overarching goal of our research is to understand host seeking and host invasion at the levels of genes, neural circuits, and behaviors. A better understanding of these processes may enable the development of novel strategies for nematode control. A few highlights from our recent research are described below.

Skin penetration

Adapted from Patel et al., 2025.

We are investigating the molecular and neural mechanisms that enable the infective larvae of skin-penetrating nematodes to burrow into human skin. Although skin penetration is an essential step of the parasite-host interaction, it remains poorly understood (McClure et al., 2024). We have shown that infective larvae engage in behavioral cycles on skin in which they crawl on the skin surface, repeatedly push against the skin with their heads, and then puncture the skin before penetrating. Skin-penetration behavior is driven by dopamine signaling – disrupting dopamine signaling pharmacologically or genetically using CRISPR severely impairs skin penetration. Moreover, disrupting the TRPN channel gene Sst-trp-4, which encodes a putative mechanoreceptor expressed in the dopaminergic neurons, inhibits skin penetration. TRP-4 is conserved to skin-penetrating hookworms but not humans. Thus, compounds that inhibit TRP-4 could be developed into broad-spectrum topical anthelmintics that block skin penetration by interfering with nematode dopamine signaling (Patel et al., 2025). We are now further investigating the molecular, cellular, and circuit mechanisms that drive skin penetration.

Olfaction

Adapted from Gang et al., 2020.

We are investigating how skin-penetrating nematodes respond to human-associated olfactory cues. We have shown that the infective larvae of S. stercoralis are attracted to a diverse array of human skin and sweat odorants (Castelletto et al., 2014). Many of the odorants that attract S. stercoralis are also mosquito attractants, suggesting that human-parasitic nematodes and mosquitoes respond to some of the same human-emitted olfactory cues (Castelletto et al., 2014). Interestingly, the human-parasitic threadworm S. stercoralis and the human-parasitic hookworm Ancylostoma ceylanicum have highly dissimilar olfactory preferences, suggesting that these two species use distinct strategies to find humans to infect (Gang et al., 2020). Finally, targeted mutagenesis of the S. stercoralis tax-4 gene, which encodes a cyclic nucleotide-gated channel subunit, abolishes attraction to a host-emitted odorant and prevents activation, the process whereby the infective larvae develop inside the host (Gang et al., 2020). Our results suggest an important role for chemosensation in host seeking and infectivity, and provide insight into the molecular mechanisms that underlie these processes. We are now elucidating the neural mechanisms that drive olfactory behavior in S. stercoralis.

Carbon dioxide response

Adapted from Banerjee et al., 2025.

Carbon dioxide is a critical host cue for many parasites, including many parasitic nematodes (Banerjee and Hallem, 2020). We have shown that the responses of S. stercoralis to carbon dioxide vary across life stages, such that it is repulsive to infective larvae but attractive to activated infective larvae (i.e., infective larvae that have entered a host and initiated development inside the host). Carbon dioxide repulsion by infective larvae may drive them off host feces and into the soil environment to host seek, whereas carbon dioxide attraction by activated infective larvae may direct them to high-carbon-dioxide areas of the body such as the lungs and small intestine (Banerjee et al., 2025). In addition, we have shown that both carbon dioxide attraction and carbon dioxide repulsion in S. stercoralis are mediated by a pair of head sensory neurons called the Sst-BAG sensory neurons and the receptor guanylate cyclase Sst-GCY-9, a putative receptor for carbon dioxide. Our results illustrate an important role for carbon dioxide sensing in shaping the life-stage-specific interactions between parasitic nematodes and their hosts, and identify the carbon-dioxide-sensing pathway as a potential target for nematode control (Banerjee et al., 2025).

Thermosensation

Adapted from Bryant et al., 2018.

We have shown that infective larvae respond robustly to thermal gradients. Like C. elegans, parasitic nematodes are capable of engaging in both positive and negative thermotaxis. When traveling up thermal gradients, infective larvae migrate toward host body temperature. Targeted mutagenesis of the S. stercoralis tax-4 gene prevents positive thermotaxis, providing the first insights into the molecular basis of heat seeking (Bryant et al., 2018). More recently, we showed that S. stercoralis thermosensory neurons show unique temperature-encoding strategies and molecular adaptations that drive heat-seeking toward human body temperature (Bryant et al., 2022).

Tool development for S. stercoralis

Adapted from Patel et al., 2024.

We are developing new molecular genetic tools and approaches for studying Strongyloides species. Our understanding of the biology of S. stercoralis and other parasitic nematodes has been limited by the lack of tools for genetic intervention. We developed a method for generating CRISPR/Cas9-mediated targeted gene disruptions in S. stercoralis and the closely related rat parasite Strongyloides ratti (Gang et al., 2017). This enabled us to generate the first homozygous gene knockouts in a parasitic nematode. More recently, we developed an approach for generating the first stable transgenic and knockout lines of S. stercoralis (Banerjee et al., 2025; Patel et al., 2024). We have also developed approaches for neuronal silencing and calcium imaging in S. stercoralis (Bryant et al., 2022; Banerjee et al., 2025).