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Sensory Neurons & Host Defense

Keeping with my long-standing interest in understanding the earliest mechanisms responsible for Type 2 immunity and host responses to parasitic helminths, we have recently turned our attention to the nervous system. Nociceptors are a heterogeneous population of skin sensory neurons (responsible for pain and itch) that upon activation release neurotransmitters and neuropeptides, which are molecules that possess immunomodulatory function(s). This raises the intriguing possibility that nociceptors may participate in host protection against skin-penetrating larval stages of various helminth species. Most of the published work describing experimental infection with skin-penetrating helminths uses a hypodermic needle to administer the infectious inoculum, which bypasses the epidermal and dermal skin layers. Because the afferent endings of nociceptors are in the epidermis and dermis, the role of nociceptors in host protective immunity remains unexplored. To address this gap, we have developed a percutaneous infection procedure in mice that allows us to study a variety of helminth species with a skin penetrating larval stage (i.e., Strongyloides ratti, S. mansoni and N. brasiliensis). We can quantify numbers of infectious larvae that enter or fail to penetrate skin, thereby providing a readout by which to interrogate the level of host protection.

Our preliminary data in the S. ratti model shows that during primary infection of WT mice, up to 80% of S. ratti infectious stage larvae (iL3) penetrate the skin, whereas only 20-30% penetrate during secondary infection. Moreover, mice genetically deficient in the major cation channel in nociceptors called transient receptor potential vanilloid 1 (TRPV1) show significant defects in resistance to worm entry during both primary and secondary challenge infection. It is entirely possible that skin nociceptors directly sense helminth-derived products, and/or that helminth products interfere with nociceptor function as an evasion strategy. To address these possibilities, we have also established primary neuronal culture systems to study neuron activation as measured by calcium influx (in collaboration with Bruce Freedman, PhD). Preliminary studies reveal that pre-exposure of dorsal root ganglia (structures containing nociceptor cell bodies) to excretory secretory (ES) products from two helminth species (S. ratti and S. mansoni) suppresses calcium influx in TRPV1+ neurons, suggesting that worm secretions impair neuron activation. We are currently in the process of establishing whether and if so, which worm ES products modulate distinct subpopulations of nociceptors responsible for pain and/or itch. This work is being done in close collaboration with Ishmail Abdus-Saboor, Ph.D.

References

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  2. Rani, R., Jordan, M. B., Divanovic, S. & Herbert, D. R. IFN-gamma-driven IDO production from macrophages protects IL-4Ralpha-deficient mice against lethality during Schistosoma mansoni infection. Am J Pathol 180, 2001-2008, doi:10.1016/j.ajpath.2012.01.013 (2012).

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  4. Fontana, M. F. et al. JUNB is a key transcriptional modulator of macrophage activation. J Immunol 194, 177-186, doi:10.4049/jimmunol.1401595 (2015).

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  7. Rani, R., Smulian, A. G., Greaves, D. R., Hogan, S. P. & Herbert, D. R. TGF-beta limits IL-33 production and promotes the resolution of colitis through regulation of macrophage function. Eur J Immunol 41, 2000-2009, doi:10.1002/eji.201041135 (2011).

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  22. Hung, L. Y., Pastore, C. F., Douglas, B. & Herbert, D. R. Myeloid-Derived IL-33 Limits the Severity of Dextran Sulfate Sodium-Induced Colitis. Am J Pathol 191, 266-273, doi:10.1016/j.ajpath.2020.11.004 (2021).

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