Parasitic nematodes infect over one billion people worldwide and cause extensive morbidity, particularly in low-resource settings. Our research focuses on the skin-penetrating human parasite Strongyloides stercoralis, which infects over 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. We also study how sensory neural circuits are modulated to drive experience-dependent and context-appropriate behaviors, using both parasitic nematodes and the free-living nematode C. elegans as model systems. A few highlights from our recent research are described below.
Olfaction
Adapted from Gang et al., 2020.
We have shown that the infective larvae of S. stercoralis and other mammalian-parasitic nematodes are attracted to a diverse array of skin and sweat odorants (Castelletto et al., 2014; Lee et al., 2016; Ruiz et al., 2017). 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). More recently, we showed that the human-parasitic threadworm S. stercoralis and the distantly related human-parasitic hookworm Ancylostoma ceylanicum have highly dissimilar olfactory preferences, suggesting that these two species use distinct strategies to target humans (Gang et al., 2020). We also showed that targeted mutagenesis of the S. stercoralis tax-4 gene 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.
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 behavior (Bryant et al., 2022).
Carbon dioxide response
Adapted from Guillermin et al., 2017.
Carbon dioxide is a critical host cue for many parasites, including many parasitic nematodes (Banerjee and Hallem, 2020). We have found that both parasitic nematodes and the free-living nematode C. elegans show flexible responses to carbon dioxide such that it can be either attractive or repulsive depending on age, life stage, environmental context, prior experience, or internal state (Carrillo et al., 2013; Lee et al., 2016; Ruiz et al., 2017; Guillermin et al., 2017; Rengarajan et al., 2019; Banerjee et al., 2023; Banerjee et al., 2024). In C. elegans adults, carbon dioxide response is mediated by the same sensory neuron and a single pathway of downstream interneurons regardless of valence. The activity of these interneurons is subject to experience-dependent modulation, enabling them to drive opposite behavioral responses to carbon dioxide. Thus, the same interneurons contribute to both attractive and aversive responses through modulation of sensory-neuron-to-interneuron synapses (Guillermin et al., 2017; Rengarajan et al., 2019). More recently, we showed that although C. elegans adults and dauer larvae are both attracted to carbon dioxide, distinct neural and molecular mechanisms drive this response at the two life stages. Our results demonstrate that functionally distinct microcircuits are engaged in response to a chemosensory cue at different life stages sharing the same valence state, revealing an unexpected complexity to chemosensory processing (Banerjee et al., 2023; Banerjee et al., 2024).
Tool development for S. stercoralis
Adapted from Castelletto et al., 2020.
We are developing new tools and approaches for studying the molecular and cellular mechanisms that drive host seeking and host invasion in parasitic nematodes. Our understanding of the biology of 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; Castelletto et al., 2020). This enabled us to generate the first targeted gene knockouts in a parasitic nematode. We also developed the Strongyloides RNA-Seq Browser for analysis of Strongyloides gene expression across life stages (Bryant et al., 2021), and the Wild Worm Codon Adapter for codon optimization of transgenes and analysis of codon adaptation at a genome-wide level in Strongyloides and other nematodes (Bryant and Hallem, 2021). More recently, we developed an approach for generating the first stable transgenic lines of S. stercoralis (Patel et al., 2024). We have also developed approaches for neuronal silencing and calcium imaging in S. stercoralis (Bryant et al., 2022).
Adapted from Gang et al., 2020.
Adapted from Bryant et al., 2018.
Adapted from Guillermin et al., 2017.
Adapted from Castelletto et al., 2020.
