Trickle infection and immunity to Trichuris muris

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.

Immunity to Soil-Transmitted Helminths: Evidence From the Field and Laboratory Models

“…Therefore, during a trickle infection the concentration of these alarmins may increase with each subsequent challenge until a threshold concentration is reached that is sufficient to drive a protective response. This notion is consistent with the slow but progressive increase in Th2-associated responses observed during T. muris trickle (139). Further, damage-inducing microparticles have been previously shown to act as potent adjuvants capable of driving innate and antigen-specific Th2 immune responses in vivo comparable in efficacy to Alum (153,154), as does mechanical abrasion (155).…”

“…We have recently reported a detailed characterization of a long-term trickle infection with T. muris (139). By performing weekly infections of 20 embryonated T. muris eggs in C57BL/6 mice we observed infection kinetics that closely mimicked those seen in human T. trichiura infection.…”

“…Worm burden rose steadily with subsequent infections for 9 weeks, however, at 11 weeks we observed a decrease in worm burden and an absence of very early larval stages in the caeca of infected mice. This apparent acquisition of immunity correlated with an increase in Th2associated immune responses including goblet cell hyperplasia, Muc5ac expression, and accelerated epithelial turnover (139). Importantly, depletion of CD4 + cells during the period of expulsion after trickle, removes protection.…”

“…During trickle infection a transition occurs between susceptibility to infection and subsequent resistance to future challenges. In the case of T. muris this transition is dependent upon the number of doses, with fewer doses being insufficient to generate a protective immune response given the same exposure time (139). This would suggest that it is parasite burden, not the length of exposure that is essential in driving a shift in immune response.…”

Immunoregulatory molecules secreted byTrichuris muris

“…During natural infection, T. muris is acquired by repeated low dose infections. Using a trickle infection approach in the laboratory, Glover et al (2019) showed that there was a steady build up in worm burden coincident with a dominant Th1 response until partial protective immunity was acquired due to the development of a stronger Th2 response. This suggests that adult parasites are present before effective IL-13-mediated immunity is acquired and thus copious p43 is secreted into the intestinal niche, which would bind IL-13 from the developing Th2 response, effectively delaying host protection.…”