Skin-penetrating nematodes have a love-hate relationship with carbon dioxide

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Globally, over 600 million people are infected with the skin-penetrating threadworm, Strongyloides stercoralis, mostly in tropical and subtropical regions with poor sanitation infrastructure. Infections are treated with ivermectin, but some nematodes are starting to develop resistance to this first-line drug. UCLA biologists have discovered that the nematodes respond differently to carbon dioxide at different stages in their life cycle, which could help scientists find ways to prevent or cure infections by targeting the CO2-sensing pathway. In the United States, the most well-known skin-penetrating parasitic worm, called a nematode, is the hookworm. But globally, it is estimated that over 600 million people are infected with the skin-penetrating threadworm, also known as Strongyloides stercoralis. This species is found mostly in tropical and subtropical regions with poor sanitation infrastructure. Skin-penetrating nematodes are excreted in the feces of an infected host, and then enter the ground to wait for a new host. When they infect a new host, they can cause serious illnesses.

Currently, infections are treated with ivermectin, but some nematodes are starting to develop resistance to this first-line drug. New medications are needed, and UCLA neurobiologists might have just found a clue needed to inspire their design.

In a paper published in Current Biology, UCLA researchers report that S. stercoralis threadworms respond differently to carbon dioxide at different stages in their life cycle. They also identified a pair of neurons and a gene that detects CO2 in these parasites, and showed how to manipulate them for further research. Because CO2 is found abundantly in tissues such as the lungs and intestine, the discovery could help scientists find ways to prevent or cure infections by targeting the CO2-sensing pathway.

“Skin-penetrating nematodes encounter high CO2 concentrations throughout their life cycle, both in fecal and soil microenvironments and inside the host body,” said corresponding author and UCLA professor of microbiology, immunology and molecular genetics Elissa Hallem. “Our results suggest that responses to carbon dioxide play an important role in how these parasites interact with human hosts as they pass through the different stages of their life cycle and establish an infection.”

The threadworm infection cycle begins when immature larvae excreted in host poop develop into larvae. The infective larvae then crawl off the poop and into the soil to search for a host to infect. After finding a host and entering the host through the skin, the nematodes travel through the host’s body and are thought to pass through the lungs. They ultimately migrate to the small intestine, where they reside as parasitic adults and lay eggs. The larvae that hatch from these eggs are excreted, and the cycle begins again. 

The UCLA researchers found that infective larvae are repelled by CO2, while noninfective larvae and adults have a neutral reaction. Young nematodes migrating inside the body are attracted to CO2.

“CO2 repulsion in the infective larvae may initiate host-seeking by driving them off of host feces, where CO2 levels are high,” said Navonil Banerjee, a postdoctoral researcher in the Hallem lab and the first author of the study. “And CO2 attraction in worms already inside the body might direct them toward the lungs and intestines, which are high in CO2.”

Hallem, Banerjee and colleagues discovered these reactions by exposing threadworms at different stages of the life cycle to CO2 and studying their behavior. They then identified neurons that detect CO2 and promote associated behavioral responses. They found that these neurons express a receptor called GCY-9, which is known to help nematodes sense CO2. By removing the gene that encodes GCY-9, the threadworms were unable to detect CO2, showing that this gene is necessary for behavioral responses to CO2.

The identification of chemosensory mechanisms that shape the interaction between parasitic nematodes and their human hosts may help scientists design new drugs that target the CO2-sensing pathway. For example, drugs that block GCY-9 function may impair the ability of parasitic worms to navigate within the body by disrupting their ability to detect CO2, which in turn could prevent an infection from establishing or reduce the severity of an existing infection. Future studies will identify additional genes in the CO2-sensing pathway that could act as molecular targets for new antiparasitic drugs.

The research was funded by the National Institutes of Health. 

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