The neural basis of heat seeking in a human-infective parasitic nematode
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles
Soil-transmitted parasitic nematodes infect over a billion people and cause devastating morbidity, primarily in the world’s most socioeconomically disadvantaged communities. The skin-penetrating Strongyloides stercoralis is estimated to infect at least 610 million people globally, nearly three times as many people as malaria. Previous studies have shown that both mosquitoes and parasitic worms actively seek out human hosts using body heat. However, while much is known about the mechanisms that enable mosquitoes and other insect vectors to target humans, virtually nothing was known about how parasitic worms locate hosts.
I investigated the molecular and cellular mechanisms underlying temperature-driven host seeking in parasitic nematodes using S. stercoralis. Using CRISPR-Cas9 mutagenesis, I found that heat seeking by S. stercoralis infective larvae (iL3s) is dependent on a cGMP signaling pathway that is conserved across free-living and parasitic nematodes. I identified the primary thermosensory neurons in S. stercoralis and characterized their responses to thermal stimuli by applying single-cell genetic targeting, cell-type specific neural silencing, and genetically-encoded fluorescent biosensors for the first time in any endoparasitic animal. These neurons display unique thermal response properties that support the ability of parasitic worms to engage in long-distance host targeting using body heat. I investigated the molecular substrates that contribute these unique response properties: I identified the thermoreceptor proteins confer parasite-specific sensitivity to body heat, and revealed evidence that additional molecular elements of the cGMP signaling cascade are regulated by temperature in a parasite-specific manner.
Together, these results are the first direct evidence that the sensory neurons of parasitic worms exhibit unique molecular adaptations that allows them to target humans, a finding with important implications for efforts to develop new therapeutic strategies for nematode control.
Host: Beth Buffalo