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 ~600 million people worldwide. S. stercoralis and many other parasitic nematodes have an infective larval stage that actively searches for hosts to infect using a wide array of host-emitted sensory cues. An overarching goal of our research is to understand how parasitic nematodes use host-emitted sensory cues to find and infect hosts. We aim to understand host seeking and host infection 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 current 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 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 behaviors in S. stercoralis andS. ratti.
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. We also showed that targeted mutagenesis of the S. stercoralis tax-4 gene prevents positive thermotaxis, providing the first insights into the molecular basis of host seeking (Bryant et al., 2018). We are now investigating the molecular pathways and neural circuits that drive thermosensory behaviors in S. stercoralis.
Carbon dioxide response
Adapted from Guillermin et al., 2017.
Carbon dioxide (CO2) 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 CO2 such that CO2 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). In C. elegans, CO2 response is mediated by the same sensory neuron and a single pathway of downstream interneurons regardless of valence. The CO2-evoked activity of these interneurons is subject to experience-dependent modulation, enabling them to drive opposite behavioral responses to CO2. 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). We are now further investigating the neural mechanisms that determine CO2 response valence. We are also investigating the neural basis of CO2 response in Strongyloides.
Tool development for Strongyloides
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 infectivity 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 S. ratti (Gang et al., 2017; Castelletto et al., 2020). This enabled us to generate the first targeted gene knockouts in a parasitic nematode. We are now using this system to disrupt a number of different genes to identify signaling pathways that drive host seeking and infectivity. We are also developing other tools and approaches for studying neural circuit function in parasitic nematodes.
Adapted from Gang et al., 2020.
Adapted from Bryant et al., 2018.
Adapted from Guillermin et al., 2017.
Adapted from Castelletto et al., 2020.
