An update on Cryptosporidium biology and therapeutic avenues

Abstract

Cryptosporidium species has been identified as an important pediatric diarrheal pathogen in resource-limited countries, particularly in very young children (0-24 months). However, the only available drug (nitazoxanide) has limited efficacy and can only be prescribed in a medical setting to children older than one year. Many drug development projects have started to investigate new therapeutic avenues. Cryptosporidium's unique biology is challenging for the traditional drug discovery pipeline and requires novel drug screening approaches. Notably, in recent years, new methods of oocyst generation, in vitro processing, and continuous three-dimensional cultivation capacities have been developed. This has enabled more physiologically pertinent research assays for inhibitor discovery. In a short time, many great strides have been made in the development of anti-Cryptosporidium drugs. These are expected to eventually turn into clinical candidates for cryptosporidiosis treatment in the future. This review describes the latest development in Cryptosporidium biology, genomics, transcriptomics of the parasite, assay development, and new drug discovery.

Keywords: Cryptosporidium; Drug targets; Genomics; Therapeutics; Virulence factors.

Fig. 1

Cryptosporidium parvum life cycle. a The excystation of a single oocyst releases four infective sporozoites. Using gliding motility as a means of locomotion, the sporozoites ultimately reach the microvilli of the intestinal epithelial cells. b The parasite remains in the microvillar region inside a parasitophorous vacuole in the plasma membrane of the host. c The sporozoites develop into spherical trophozoites. d Trophozoites undergo merogony, to form Type-I meront, consisting of 8 merozoites. Meront ruptures and infective merozoites are released to infect other nearby cells. e Type-II meront formed from a type-I meront contains four merozoites, but instead of continuing the infection cycle, each merozoite now undergoes gametogony, giving rise to either a (f) microgamont or a (g) macrogamont. h Each micro or macro gamont ultimately gets fertilized to produce a zygote. The zygote, after undergoing sporogony, produces an oocyst containing four sporozoites. It is covered with either a thick or a thin wall. i The thick-walled oocyst is released into the intestinal lumen eventually being excreted out, ready to infect a new host (j) The thin-walled oocyte, on the other hand, can re-infect the same host in a process called autoinfection. (Adapted with modification from CDC, Atlanta, GA, USA. https://www.cdc.gov/dpdx/cryptosporidiosis/index.html). The figure was created with the help of Adobe Illustrator 2020 software

Fig. 2

Novel therapeutics against Cryptosporidium. a Structures of AN7973, a benzoxaborole (Lunde et al. 2019), and b triacsin-C targeting acyl-coenzyme-A synthetases have been employed against the parasite (Guo et al. 2014). c The structure of compound K11777 targeting the cysteine proteases has also been employed against the parasite (Ndao et al. 2013). d The structure of atorvastatin, a statin compound, having DrugBank database ID: DB01076, in combination with nitazoxanide (NTZ), has been tested for a synergistic approach against the parasite-infected mice (Madbouly Taha et al. 2017). e Oleylphosphocholine (OlPC), an alkylphosphocholine, has also been employed against the parasite-infected immunocompromised mice (Sonzogni-Desautels et al. 2015)