Trickle infection and immunity toTrichuris muris

Abstract

13 The majority of experiments investigating the immune response to gastrointestinal helminth 14 infection use a single bolus infection. However, in situ individuals are repeatedly infected with low 15 doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with 16 low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected 17 by a gradual increase in worm burden followed by a partial expulsion. Flow cytometry revealed 18 that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided 19 with an increase in Type 2 cytokines. The development of resistance following trickle infection 20 was associated with increased worm expulsion effector mechanisms including goblet cell 21 hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells 22 reversed resistance confirming their importance in protective immunity following trickle infection. 23In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris 24 trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following 25 the development of resistance.26 These data support trickle infection as a robust and informative model for analysis of immunity to 27 chronic intestinal helminth infection more akin to that observed under natural infection conditions 28 and confirms the importance of CD4+ T cell adaptive immunity in host protection. 29 30 Author Summary 31 Infection with parasitic worms (helminths) is a considerable cause of morbidity in humans.32 Understanding how we respond to infection is crucial to developing novel therapies. Laboratory 33 models of helminth infection have been a valuable tool in understanding fundamental immune 34 responses to infection. However, typically an individual mouse will be infected with a large, single-35 dose of the parasite. This is in contrast to the natural scenario in which individuals will receive 36 frequent low level exposures. What is unknown is how repeated infection alters the development 37 of immunity to infection. We have developed a laboratory model to tackle this question. We 38 infected mice with the model helminth Trichuris muris on a weekly basis and assessed a range of 39 responses in comparison with a more traditional infection system. We found striking differences 40 in the dynamics of the infection, the host immune response, and in changes to host gut microbial 41 populations. Our study shows how resistance to helminth infection can develop over time in 42 response to repeat infection, and provides a model system that better reflects human immunity to 43 this parasite. 45 Introduction46 Gastrointestinal (GI) dwelling nematodes infect approximately 1 billion people worldwide causing 47 significant ill health (1). Prevalence is high in endemic areas although intensity of infection varies 3 48 with age, suggesting acquired immunity develops, although sterile immunity is rare and individuals 49 ar...

Myeloid A20 is critical for alternative macrophage polarization and type-2 immune-mediated helminth resistance

“…Recently, deletion of A20 in macrophages was reported to suppress IL-33-dependent expansion of lung ILC2s, type-2 cytokine production, and eosinophilia (14). Since ILCs do not play a prominent role during T. muris expulsion, in contrast to other parasite infections such as N. brasiliensis and H. polygyrus infection (42), our data indicate that A20 acts as an essential mediator of alternative macrophage polarization and subsequent adaptive immunity in response to T. muris infection. A20 deficiency leads to default classical macrophage activation and type-1 immune polarization.…”