Abstract
The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data establish trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection.
Highlights
Gastrointestinal (GI) dwelling nematodes infect approximately 1 billion people worldwide causing significant ill health[1]
Laboratory models of helminth infection have been a valuable tool in understanding fundamental immune responses to infection
Our study shows how resistance to helminth infection can develop over time in response to repeat infection, and provides a model system that better reflects human immunity to this parasite
Summary
Gastrointestinal (GI) dwelling nematodes infect approximately 1 billion people worldwide causing significant ill health[1]. Rodents are given a single, and sometimes a second, infection composed of an unnaturally large dose of infectious stages. This approach has been extremely informative and established that such a robust parasite challenge stimulates the host to generate host protective responses, dominated by Type 2 immunity. Whilst single bolus infections in the laboratory have been central to defining paradigms of resistance and susceptibility, one major discrepancy between these models and natural infection in man, and rodents, is that individuals are infected repeatedly with low dose infections throughout their lifetime and STH are chronic, non-resolving infections. Studies of repeated low dose nematode infections of rodents are rare [9,10]
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