Encephalitozoon cuniculi is a microsporidial parasite of mammals with world-wide distribution. An important cause of neurologic and renal disease in rabbits, E. cuniculi can also cause disease in immunocompromised people.

Its current accepted name is Nosema cuniculi.

E. cuniculi is a microsporidial, unicellular, obligate intracellular, eukaryotic, parasite. It belongs to the phylum Microsporidia. Microsporidia are parasitic fungi infecting many animal groups. Lacking mitochondria and peroxysomes, they were first considered a deeply branching protist lineage that diverged before the endosymbiotic event that led to mitochondria. The discovery of a gene for a mitochondrial-type chaperone combined with molecular phylogenetic data later implied that microsporidia are atypical fungi that lost mitochondria during evolution. The genome reflects this dependency, with significant gene loss across biosynthetic and metabolic pathways. In veterinary taxonomy, E. cuniculi has been placed within the genus Encephalitozoon due to its unique life cycle characteristics and infection patterns across multiple host species

The genome consists of approximately 2.9-megabases (Mbs) in 11 chromosomes, with a total of 1,997 potential protein-coding genes. Genome compaction is reflected by reduced intergenic spacers and by the shortness of most putative proteins relative to their eukaryote orthologues. At the time of publication (2001), only 44% of the proteins had a function assigned to them. the latest reference proteome in Uniprot (2021) lists 2041 proteins with ~620 proteins annotated as "uncharacterized", about 200 without annotation (e.g. "UPF0329 protein ECU06_1620") and another ~150 or so that are annotated as having some "domain" (including domains of unknown function) and numerous proteins of "probable" and "putative" function plus dozens with "similarity" to characterized proteins. Hence, even 20 years after the genome sequence was published, about 50% of the E. cuniculi proteome remains uncharacterized or poorly understood.

The strong host dependence is illustrated by the lack of genes for some biosynthetic pathways and for the tricarboxylic acid cycle. Phylogenetic analysis lends substantial credit to the fungal affiliation of microsporidia. Because the E. cuniculi genome contains genes related to some mitochondrial functions (for example, Fe-S cluster assembly), it is possible that microsporidia have retained a mitochondrion-derived organelle.

The infective form of microsporidia (E. cuniculi) is a resistant spore which can survive for a long time in the environment. The spore extrudes its polar tubule and infects the host cell. The spore injects the infective sporoplasm into the eukaryotic host cell through a polar tube. Inside the cell, the sporoplasm undergoes extensive multiplication. This multiplication occurs either by merogony (binary fission) or schizogony (multiple fission). Host cell mitochondria often cluster around the developing parasite, suggesting a role in parasite development or nutrient acquisition. Microsporidia develop by sporogony to mature spores in the cytoplasm or inside parasitophorous vacuole. During sporogony, a thick wall is formed around the spore. The thick wall formed provides resistance to adverse environmental conditions. Once the spores increase in number and completely fill the cytoplasm of the host's cell, the cell membrane is disrupted and releases the spores to the surroundings. These free mature spores can infect new cells thus continuing the cycle. Vertical transmission has also been reported in rabbits, with spores transmitted transplacentally or during birth.

E. cuniculi has undergone an evolutionary process of genome reduction that has affected all major DNA repair pathways. DNA double-strand breaks are one of the most detrimental forms of DNA damage, as they can cause genome fragmentation if not repaired. More than half of the proteins that ordinarily participate in the two double strand break repair pathways, homologous recombinational repair and non-homologous end joining, are absent in E. cuniculi compared to other related species. The remaining proteins are all involved in additional cellular functions (such as meiosis).

First identified in rabbits, E. cuniculi infections have been reported worldwide in over 20 mammalian species, including humans. Prevalence in pet rabbits is high, with 23–75% having antibodies to the disease. Studies of healthy dogs have found a 0–38% prevalence. Cats appear to be relatively resistant to the organism, although experimental infections in kittens with feline leukemia virus have been described. Recent guidelines from European researchers confirm that cats can serve as hosts under certain conditions, such as immunosuppression. E. cuniculi also infects rodents, and the organism has been detected in the feces of 13% of pet birds. A small percentage of healthy people have antibodies to the organism, indicating previous exposure. Seroprevalence rates are higher in immunocompromised people, and in those who live in or have visited tropical countries. Most infections do not result in clinical disease.