Recent advances in functional genomics for parasitic nematodes of mammals

Abstract

Human-parasitic nematodes infect over a quarter of the world's population and are a major cause of morbidity in low-resource settings. Currently available treatments have not been sufficient to eliminate infections in endemic areas, and drug resistance is an increasing concern, making new treatment options a priority. The development of new treatments requires an improved understanding of the basic biology of these nematodes. Specifically, a better understanding of parasitic nematode development, reproduction and behavior may yield novel drug targets or new opportunities for intervention such as repellents or traps. Until recently, our ability to study parasitic nematode biology was limited because few tools were available for their genetic manipulation. This is now changing as a result of recent advances in the large-scale sequencing of nematode genomes and the development of new techniques for their genetic manipulation. Notably, skin-penetrating gastrointestinal nematodes in the genus Strongyloides are now amenable to transgenesis, RNAi and CRISPR/Cas9-mediated targeted mutagenesis, positioning the Strongyloides species as model parasitic nematode systems. A number of other mammalian-parasitic nematodes, including the giant roundworm Ascaris suum and the tissue-dwelling filarial nematode Brugia malayi, are also now amenable to transgenesis and/or RNAi in some contexts. Using these tools, recent studies of Strongyloides species have already provided insight into the molecular pathways that control the developmental decision to form infective larvae and that drive the host-seeking behaviors of infective larvae. Ultimately, a mechanistic understanding of these processes could lead to the development of new avenues for nematode control.

CRISPR-mediated Transfection of Brugia malayi

“…number of parasitic worm species (for reviews see [12][13][14]). Most of the studies that have applied CRISPR to parasitic worms have been conducted using Strongyloides spp., which have the advantage of having free-living stages in their lifecycle.…”

CRISPR/Cas9: A new tool for the study and control of helminth parasites

“…[20,45] Usually, CRISPR/Cas9-mediated gene editing only affects one of the two alleles of a target gene; therefore, several breeding cycles are required to generate offspring with homozygous mutants. [19] However, conducting many breeding cycles with parasitic helminths is difficult due to the challenges in the host passage of mutant worms and this will be discussed further below.…”

“…[5][6][7][8][9] CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, however, is a powerful genetic approach for interrogating the genomes and defining the function of key genes in various organisms by triggering specific and heritable genome editing, not only in somatic cells but also in germ-line cells. [10][11][12][13][14][15][16][17][18][19][20][21][22][23] Utilizing CRISPR/Cas9 technology for the study of parasitic worms sets the scene for effectively characterizing helminth gene products, thereby providing improved understanding TA B L E 1 Use of the CRISPR/Cas9 editing system in helminths Successful adaptation of CRISPR/Cas9 in parasitic helminths provides a molecular genetic toolbox for identifying novel drug targets or vaccine candidates, thereby accelerating the pace towards more effective ways to prevent and treat the diseases caused by these worms.…”

Complementary Approaches to Understand Anthelmintic Resistance Using Free-Living and Parasitic Nematodes

“…Currently, genome editing in nematodes is mostly limited to Caenorhabditis species. Some work in genome editing in parasite species has been performed successfully in Strongyloides spp [78][79][80][81][82][83][84]. When these technologies are further optimized and can be performed in H. contortus, the cycle of discovery can be greatly improved and expanded.…”