Studies on Helminth Immunity: I. Comparison between Lumenal and Tissue Phases of Infection in the White Mouse by Hymenolepis Nana (Cestoda: Hymenolepididae)

Donald HeynemanUniversity of California, Los Angeles

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Summary and Conclusions

The present study tested the importance of tissue contact by a growing parasite in initiating a host response, and the need of such contact for effective resistance against a reinfection. The mouse tapeworm Hymenolepis nana, which utilizes either a tissue-phase pattern of growth or a lumenal one, was used as the experimental tool.

It was initially confirmed that egg infections of H. nana are strongly immunogenic against a challenge infection by the same parasite at the same stage of development, i.e., egg infections serve to immunize the host against an egg challenge. Natural age immunity was found to be relatively ineffective and premunition to be of some importance in adding to the host's resistance against reinfection, but to an uncertain degree. Considerable variation in normal host infectivity emphasized the importance of host strain and various environmental factors that may influence the parasite's infectivity or the host's ability to resist infection.

The second phase utilized an initiating or immunizing feeding of eggs, as before, but challenged this immunity with cysticercoids previously developed in beetles. Since these larvae undergo further development only in the host's intestinal lumen, the question of tissue immunity acting against a lumen-dwelling parasite was subjected to test. The results proved that such an effect can indeed take place, though to a less striking degree than does the resistance against a tissue-invading form (penetration of mucosa by hexacanth larvae hatching from eggs). More dramatic was an unexpected but consistent finding in previously uninfected mice fed cysticercoids. These cysticercoid infections proceeded to proliferate a new generation by autoinfection, resulting after 25 days in infection levels many times that originally fed. Autoinfection, confined as it is to cysticercoid infections in nonimmune hosts, implies that an egg infection is self-limiting as it initiates a tissue reaction and resistance against subsequent infection by eggs. The initial infection by cysticercoids developed in beetles involves no tissue phase; hence, no immediate immunogenic contact with host cells results, and no protective response occurs. Therefore, when these lumenal worms mature, their eggs, which can hatch locally and are immediately infective, do so, invade nearby unprotected villi and develop by the direct cycle. The result is readily apparent—a teeming mass of young worms newly emerged from sites of development in the villi and now returned to the intestinal lumen as a second generation. This is an autoinfection—a process extremely rare in helminth life cycles. Though eggs for the reinfection could have been derived from ingestion of infective mouse feces, from anal washing, or from a source of contamination outside the mouse rather than the hatching of eggs produced by worms within the host, it seems less likely than does internal reinfection or true autoinfection, judging from the precise timing of appearance of reinfections. Experimental verification that true autoinfection can occur has appeared elsewhere.

The immunogenic powers of an initial cysticercoid infection in protecting the mouse host against a challenge egg infection was tested in phase 3. These 5 experiments tested the effect of a primary cysticercoid infection on the egg challenge by varying the period between the 2 infections and the mode of reading the results (as adult worms or as cysticercoids within the host villi).

These experiments demonstrated a marked reduction in the challenge infection, however, measured, following cysticercoid feedings. Results are interpreted, however, not in terms of a direct immunizing effect of the cysticercoids, but on the capacity of these cysticercoids to multiply within the host, producing an autoinfection from eggs hatched in situ. These eggs then act as do eggs fed or consumed by the host in the usual manner. They hatch in the small intestine to release hexacanths (oncospheres), the clawing, penetrating larvae that invade and develop inside the mucosal villi. This invading action and subsequent development, rather than the presence of lumen-dwelling adults derived from the original cysticercoid feeding, produce the observed host resistance. The net effect is the same as that noted in the preceding experiments—direct tissue contact stimulates the immune response, and this response is strongly effective against a challenging tissue invasion under a variety of experimental conditions.

The final phase tested the effect of a primary infection with cysticercoids against a challenging infection with additional cysticercoids. Again, autoinfection provided the clue to otherwise anomolous results. Wherever autoinfection was clearly observed or could logically be deduced, a resulting immunity was seen to follow. This immunity was, therefore, traced to the tissue invasion resulting from the oncospheres of the reinfection generation developing within the host intestinal mucosa. Wherever reinfection clearly did not occur or could not logically be deduced, the results demonstrated a complete lack of protection by the host against a challenging infection with cysticercoids. Such challenge larvae developed in the normal proportion (about 75% of cysts fed), with worm size, distribution, and percentage autoinfection in about the same proportion as shown by a corresponding dose of cysticercoids fed to previously uninfected control mice. The following conclusions are suggested by these studies:

  1. 1. The direct life cycle of Hymenolepis nana produced by an egg infection with cysticercoids developing in mouse villi is highly immunogenic.
  2. 2. This immunity is particularly marked against a challenging infection by eggs that hatch and release tissue-invading oncospheres. Penetration and subsequent development of these larvae is strongly resisted by the immunized host.
  3. 3. Immunity so induced is still effective, but to a markedly lesser extent, against lumen-dwelling cysticercoids developing to that stage by the indirect cycle in an insect intermediate host. Subsequent growth and strobilization of the young worm, confined to the intestinal lumen, is less affected by antibodies concentrated in mucosal cells than are larvae of the direct cycle which develop in these tissues. The intestinal zone invaded by oncospheres is generally the anterior third; whereas, that in which adults develop is the last few centimeters anterior to the cecum.
  4. 4. Autoinfection, which can occur in approximately 50 to 70% of nonimmune mice fed cysticercoids of H. nana, may produce 1,500 or more adult worms from an initial infection of 10 to 25 cysticercoids. Such autoinfections do not occur in mice previously infected by eggs. Furthermore, the reinfection appears to be selflimited to 1 or 2 generations, since larvae of the new generation develop in host mucosal tissues and thereby elicit host responses that prevent penetration of oncospheres of another generation.
  5. 5. The indirect life cycle of H. nana, in which cysticercoids develop in an insect and complete their development in a vertebrate host, is in itself not immunogenic in the final host. However, when an autoinfection occurs with its resultant tissue invasion by freshly hatched oncospheres of a second generation, the immunity is as strong as that following an initial feeding of eggs to the host.
  6. 6. When no autoinfection occurs, an initial cysticercoid infection does not induce protection against a challenge infection by cysticercoids of the same worm.
  7. 7. It is concluded that intimacy of tissue contact is of prime importance in stimulating a host response to parasitism by H. nana. These findings accord with views developed earlier that a locally effective antibody concentration results from close and continual association between host cells and a rapidly metabolizing parasite.

Author Notes

Present address: United States Naval Medical Research Unit Number Three, c/o American Embassy, Cairo, Egypt, U.A.R.