“Centennial Reflections – a distinguished parasitologist reflects on a paper published in their field in Parasitology 100 years ago”

Coccidiosis in humans – the past 100 years: A Revision of the Coccidia Parasitic in Man

BY: J. P. Dubey, United States Department of Agriculture, Agricultural Research Service, Beltsville Agricultural Research Service, Animal Parasitic Disease Laboratory, Building 1001, BARC-East, Beltsville, MD 20705-2350, USA.

It is an honor for me to comment on the paper “Revision of the coccidia parasitic in man by Clifford Dobell, Parasitology 11: 147-197, 1919”. Before commenting on the paper, I would like to say a few words about this mighty parasitologist of his time. Clifford Dobell (1886-1949) was famous enough to have his obituary published in the journal Nature (Shortt, 1950) –a rare distinction for a parasitologist. He received an unusual education, but the point I want to make is that education never goes to waste. He was brilliant enough to be admitted to the University of Cambridge, England. He originally wanted to become a veterinarian but changed his mind to become a medical doctor. After 2 years of medical school, he changed his mind again to pursue Natural Sciences. He studied protozoa under Professor Sedwick, who was head of the Zoological Laboratory at Cambridge. He also received training in protozoological techniques in Prof. Schaudinn’s laboratory in Germany.  He studied zoology (under J.J. Lister), physiology, biochemistry, and bacteriology under G.H.F. Nuttall who were leaders in microbiology at that time. Dobell used his extensive knowledge to publish on intestinal protozoa of humans (Hoare and Mackinnon, 1950).

Returning to the main topic of Dobell’s 50-page paper in Parasitology, the first 32 pages are devoted to a critical review of coccidia parasitic in humans. Coccidian-like bodies were noted in human feces/tissues as early as 1858, however, descriptions were inadequate, and mistakes had been copied over from one text book to other. Dobell consulted original publications and documented what had been said by earlier scientists. Dobell concluded that human coccidia belong to genera Isospora (containing 2 sporocysts, each with 4 sporozoites) and Eimeria containing 4 sporocysts, each with 2 sporozoites. He recognized an entity which spurred a legacy of needed further examination, ultimately leading to discovery of uncontemplated biodiversity including major veterinary, zoonotic, and anthroponotic parasites (none precisely corresponding to the taxon that he named, but all needing to be understood by clinicians, biologists, and the like).

Eimeria infections in humans:

From the time of the discovery of the first parasitic protozoa (believed to be Eimeria stiedae) in the bile duct of a rabbit in 1674 by the Dutch scientist, Antony van Leeuwenhoeck (who discovered the microscope), many have studied the parasite including reports in humans (Levine, 1973). The structures noted in human liver were misidentified as E. stiedae by several scientists; there are no archived specimens. In 1919, Dobell  named two new species of Eimeria, E. wenyoni and E. oxyspora. Eimeria wenyoni was named in honor of Wenyon (1915) who had found it in feces of 1 of 556 humans. Eimeria oxyspora was found by Dobell in feces of a single person who had visited the Far East. Currently, Eimeria species, including those named by Dobell, are now considered pseudoparasites, resulting from the ingestion of food contaminated with feces of animals, mostly rodents. This topic is not discussed further.

Isospora infections in humans:

At the time of Dobell’s paper, nothing was known of the endogenous life cycle stages of Isospora in humans. There were no archived specimens, and descriptions of oocysts in feces were vague. There were uncertainties concerning the name Isospora hominis and Isospora bigemina. Some authorities regarded that there were three subspecies of I. bigemina as: I. bigemina var hominis (in humans), var canis (in dogs), and var felis (in cats). Dobell (1919) published a drawing of a bell-shaped sporulated oocyst of I. hominis that he saw in human feces.

Progress on Isospora hominis and other species of human coccidia in the last 100 years

Bell-shaped Isospora sp. oocysts of Dobell

Wenyon (1923) proposed the name Isospora belli for the large, bell-shaped 25-30 x 12-15 µm oocysts in human feces that Dobell illustrated in his paper; in retrospect, I wished it was named I. dobelli. Despite the characteristic shape of its oocysts, I. belli continued to be misdiagnosed as Isospora hominis (Jarpa Gana, 1966; Smitskamp and Oey-Muller, 1966). Until the 1970’s, Isospora species were considered non-host-specific with a direct fecal-oral transmission cycle (Dubey, 2018). When the life cycle of Sarcocystis was discovered in 1972, it became clear that the parasite I. hominis was a mixture of more than two species of Sarcocystis with an obligatory two-host cycle involving cattle and pigs as intermediate hosts and humans as definitive hosts (reviewed in Dubey et al., 2016)—more discussion later. Additionally, Isospora spp. of cats were found to have a tissue cyst stage in extra-intestinal organs of intermediate/transport/paratenic hosts as well as in the definitive host (Frenkel and Dubey, 1972; Dubey and Frenkel, 1972), leading to the creation of a new genus, Cystoisospora (Frenkel, 1977) for Isospora species with a tissue cyst stage. In 1987, the tissue cyst stage of I. belli was discovered (Restrepo et al., 1987). Based on morphologic and phylogenetic relationships with feline and canine Isospora, I. belli was transferred to the genus Cystoisospoira (Barta et al., 2005). Thus, the correct designation for I. belli is Cystoisospora belli (Wenyon, 1923) Frenkel, 1977. Attempts to infect non-human primates, livestock, rodents, and other animals with C. belli were unsuccessful (Jeffery, 1956). Experimental infections in human volunteers (Matsubayashi and Nozawa, 1948; Ferreira et al., 1962) confirmed the direct fecal-oral transmission cycle of C. belli. Human volunteers who ingested sporulated oocysts became infected and excreted unsporulated C. belli oocysts 9 to 17 days later.

Fragmentary information on endogenous stages by examination of human biopsy or post mortem tissues revealed that the life cycle of C. belli was like Eimeria and confined to enterocytes of biliary epithelium from the small intestine (Brandborg et al., 1970) and bile ducts or gallbladder (Benator et al., 1994; Agholi et al., 2016). Schizonts, microgamonts, macrogamonts, and unsporulated oocysts were seen in enterocytes of the small intestine and in the biliary epithelium. More recently, Dubey et al. (2019) described details of asexual and sexual stages of C. belli in bile duct or intestinal epithelium and concluded that these stages were like Cystoisospora of dogs and cats (Dubey, 2018; Dubey and Lindsay, 2019).

Other isosporan oocysts referred as Isospora hominis or Isospora bigemina-var hominis oocysts

Dobell (1919) reviewed previous reports of I. hominis-like parasites with oocysts smaller than 20 µm in diameter, considered I. bigemina. Wenyon (1926) believed that there were two races of I. bigemina, the small race developed in villar enterocytes whereas the large race was in the lamina propria. This confusion continued until the discovery of oocyst in the life cycle of Toxoplasma gondii in 1970; the oocysts were approximately 10 x 12 µm in diameter (reviewed in Dubey, 2009). The small race of I bigemina, developing in the intestinal epithelium of cats turned out to be T. gondii and a new genus, Hammondia with H. hammondi as type species. The parasite developing in enterocytes of dogs turned out to be another species of Hammondia, H. heydorni, and another new genus, Neospora, with N. caninum as the type species (Dubey et al., 2002).

In 1972, the life cycle of Sarcocystis was discovered. Rommel and Heydorn (1972) excreted sporulated oocysts in their feces after ingesting raw pork or beef naturally infected with Sarcocystis; these oocysts were initially considered I. hominis. When the nomenclature was reviewed, the parasite originating from the ingestion of beef was considered Sarcocystis hominis  and the species resulting from the ingestion of pork was considered S. suihominis (see Dubey et al., 1989). Recently, another zoonotic species of Sarcocystis, S. heydorni was named; Dr. Heydorn excreted I. hominis-like oocysts in his feces after eating raw beef infected with Sarcocystis (Dubey, 2015). Unlike other species of coccidia, Sarcocystis oocysts sporulate in the lamina propria of small intestine and fully sporulated oocysts are excreted in feces. Thus, what was I bigemina or I. hominis turned out to be mixture of more than 50 species of coccidia. Retrospectively, I. bigemina is nomen nuda but it took a century to sort it. By accurately documenting the descriptions of coccidia in his memoir, Dobell made it easier for future scientists to investigate this topic.

Article DOI: https://doi.org/10.1017/S0031182000004170
For correspondence, email jitender.dubey@ars.usda.gov

References

Agholi M, Aliabadi E, and Hatam GR (2016) Cystoisosporiasis-related human acalculous cholecystitis: the need for increased awareness. Polish Journal of Pathology 67, 270-276.

Barta JR, Schrenzel MD, Carreno R, and Rideout BA (2005) The genus Atoxoplasma (Garnham 1950) as a junior objective synonym of the genus Isospora (Schneider 1881) species infecting birds and resurrection of Cystoisospora (Frenkel 1977) as the correct genus for Isospora species infecting mammals. Journal of Parasitology 91, 726-727.

Benator DA, French AL, Beaudet LM, Levy CS, and Orenstein JM (1994) Isospora belli infection associated with acalculous cholecystitis in a patient with AIDS. Annals of Internal Medicine 121, 663-664.

Brandborg LL, Goldberg SB, and Breidenbach WC (1970) Human coccidiosis — a possible cause of malabsorption — the life cycle in small-bowel mucosal biopsies as a diagnostic feature. New England Journal of Medicine 283, 1306-1313.

Dobell C (1919) A revision of the coccidia parasitic in man. Parasitology 11, 147-197.

Dubey JP (2009) The evolution of the knowledge of cat and dog coccidia. Parasitology 136, 1469-1475.

Dubey JP (2015) Foodborne and waterborne zoonotic sarcocystosis. Food and Waterborne Parasitology 1, 2-11.

Dubey JP (2018) A review of Cystoisospora felis and C. revolta-induced coccidiosis in cats. Veterinary Parasitology 263, 34-48.

Dubey JP and Frenkel JK (1972) Extra-intestinal stages of Isospora felis and I. rivolta (Protozoa: Eimeriidae) in cats. Journal of Protozoology 19, 89-92.

Dubey JP and Lindsay DS (2019) Coccidiosis in dogs – 100 years of progress. Veterinary Parasitology 266, 34-55.

Dubey JP, Barr BC, Barta JR, Bjerkås I, Björkman C, Blagburn BL, Bowman DD, Buxton D, Ellis JT, Gottstein B, Hemphill A, Hill DE, Howe DK, Jenkins MC, Kobayashi Y, Koudela B, Marsh AE, Mattsson JG, McAllister MM, Modrý D, Omata Y, Sibley LD, Speer CA, Trees AJ, Uggla A, Upton SJ, Williams DJL, and Lindsay DS (2002) Redescription of Neospora caninum and its differentiation from related coccidia.  International Journal for Parasitology 32, 929-946.

Dubey JP, Calero-Bernal R, Rosenthal BM, Speer CA, and Fayer R (2016) Sarcocystosis of Animals and Humans. 2^nd edn. CRC Press. Boca Raton, Florida., pp.1-481.

Dubey JP, Evason K, and Walther Z (2019) Endogenous development of Cystoisospora belli in intestinal and biliary epithelium of humans. Parasitology http://doi.org/10.1017/S003118201900012X,

Dubey JP, Speer CA, and Fayer R (1989) Sarcocystosis of Animals and Man. CRC Press, Boca Raton, Florida. pp. 1-215.

Dubey JP, van Wilpe E, Calero-Bernal R, Verma SK, and Fayer R (2015) Sarcocystis heydorni n. sp. (Apicomplexa: Sarcocystidae) with cattle (Bos taurus) and human (Homo sapiens) cycle. Parasitology Research 114, 4143-4147.

Ferreira LF, Coutinho SG, Argento CA, and da Silva J (1962) Experimental human coccidial enteritis by Isospora belli Wenyon, 1923. A study based on the infection of 5 volunteers. Hospital. (Rio J.) 62, 795-804.

Frenkel JK (1977) Besnoitia wallacei of cats and rodents: with a reclassification of other cyst-forming isosporoid coccidia. Journal of Parasitology 63, 611-628.

Frenkel JK and Dubey JP (1972) Rodents as vectors for feline coccidia, Isospora felis and Isospora rivolta. Journal of Infectious Diseases 125, 69-72.

Hoare CA and Mackinnon DL (1950) Clifford Dobell, 1886-1949. Biographical Memoirs of Fellows of the Royal Society 35-61. https://doi.org/10.1098/rsbm.1950.0004

Jarpa Gana A (1966) Coccidiosis humana. Biologica 39, 3-26.

Jeffery GM (1956) Human coccidiosis in South Carolina. Journal of Parasitology 42, 491-495.

Levine ND (1973) Introduction, history, and taxonomy. In: Hammond DM and Long PL. The coccidia, Eimeria, Isospora, Toxoplasma, and related genera 1-22.  Baltimore, Univeristy Park Press

Matsubayashi H and Nozawa T (1948) Experimental infection of Isospora hominis in man. American Journal of Tropical Medicine and Hygiene 28, 633-637.

Restrepo C, Macher AM, and Radany EH (1987) Disseminated extraintestinal isosporiasis in a patient with acquired immune deficiency syndrome. American Journal of Clinical Pathology 87, 536-542.

Rommel M and Heydorn AO (1972) Beiträge zum Lebenszyklus der Sarkosporidien. III. Isospora hominis (Railliet und Lucet, 1891) Wenyon, 1923, eine Dauerform der Sarkosporidien des Rindes und des Schweins. Berliner und Münchener tierärztliche Wochenschrift 85, 143-145.

Shortt HE (1950) Obituary: Dr. Clifford Dobell, F.R.S. Nature (4189), 219.

Smitskamp H and Oey-Muller E (1966) Geographical distribution and clinical significance of human coccidiosis. Tropical and Geographical Medicine 18, 133-136.

Wenyon CM (1915) Another human coccidium from the Mediterranean War area. Lancet. II. page 1404.

Wenyon CM (1923) Coccidiosis of cats and dogs and the status of the Isospora of man. Annals of Tropical Medicine and Parasitology 17, 231-288.

Wenyon CM (1926) Coccidia of the genus Isospora in cats, dogs and man. Parasitology 18, 253-266