Strongyloides infection in rodents: immune response and immune regulation

Abstract

The human pathogenic nematode Strongyloides stercoralis infects approximately 30-100 million people worldwide. Analysis of the adaptive immune response to S. stercoralis beyond descriptive studies is challenging, as no murine model for the complete infection cycle is available. However, the combined employment of different models each capable of modelling some features of S. stercoralis life cycle and pathology has advanced our understanding of the immunological mechanisms involved in host defence. Here we review: (i) studies using S. stercoralis third stage larvae implanted in diffusion chambers in the subcutaneous tissue of mice that allow analysis of the immune response to the human pathogenic Strongyloides species; (ii) studies using Strongyloides ratti and Strongyloides venezuelensis that infect mice and rats to extend the analysis to the parasites intestinal life stage and (iii) studies using S. stercoralis infected gerbils to analyse the hyperinfection syndrome, a severe complication of human strongyloidiasis that is not induced by rodent specific Strongyloides spp. We provide an overview of the information accumulated so far showing that Strongyloides spp. elicits a classical Th2 response that culminates in different, site specific, effector functions leading to either entrapment and killing of larvae in the tissues or expulsion of parasitic adults from the intestine.

Th2/1 Hybrid Cells Occurring in Murine and Human Strongyloidiasis Share Effector Functions of Th1 Cells

“…Here we confirm that experimental murine and natural human infections by threadworms are predominantly associated with Th2 responses (Chiuso-Minicucci et al, 2010; Anuradha et al, 2015; Breloer and Abraham, 2016). Mice infected with S. ratti displayed locally and systemically increased frequencies of Th2 cells and only low signs of intestinal immunopathology, which is in line with the mostly asymptomatic course of threadworm infections in human patients (Siddiqui and Berk, 2001; Vadlamudi et al, 2006; Montes et al, 2010).…”

Differences in the Importance of Mast Cells, Basophils, IgE, and IgG versus That of CD4+T Cells and ILC2 Cells in Primary and Secondary Immunity to Strongyloides venezuelensis

“…We found that T and B cell-deficient Rag2 -/-mice exhibited a 20-day delay (i.e., requiring 32 days in total) in cessation of S. venezuelensis egg excretion during primary infections and a 25-day delay (i.e., requiring 37 days in total) in the secondary infection (versus no eggs detected during secondary infections in any of the wild-type mice) (Fig. 3A), underscoring the importance of an adaptive immune response for effective secondary immune responses to this nematode (8,11,13,14,41,(46)(47)(48). In addition, we confirmed that the number of adult worms in the intestines on day 8 of the primary infection was significantly higher in the Rag2 -/-mice than in the corresponding wild-type mice (Fig.…”

“…We also examined whether MCs and/or basophils contribute to cessation of S. venezuelensis egg excretion during secondary infections. Several studies indicated that, in secondary nematode infections of wild-type mice, the larvae can be trapped in the skin and lungs before reaching the intestines, as reported for S. venezuelensis (39)(40)(41), Strongyloides ratti (41), and Nippostrongylus brasiliensis (42)(43)(44). In this study, we assessed fecal egg numbers as an indicator of whether larvae could reach the intestines and then produce eggs.…”

Strongyloides

“…The interaction of Strongyloides with its host immune response is key to understanding the harm that it can cause to hosts, and the immunobiology of Strongyloides is reviewed here by Minka Breloer and David Abraham (Breloer and Abraham, 2016). In common with other helminths a Th2 response dominates host anti- Strongyloides responses.…”

“…But, this results in different, site-specific effects acting against either migrating larvae within the host tissues or against parasitic adults in the host gut. The effectors acting against parasitic adults are mast cells [activated by the cytokines interleukin (IL)-3 and IL-9] and anti- Strongyloides immunoglobulin E (IgE) and IgG responses (Breloer and Abraham, 2016). The developmental choices of the Strongyloides life cycle are in part controlled by the host immune response (Viney and Kikuchi, 2016), and understanding what aspects of the host immune response Strongyloides sense, and how they sense it, to make these life cycle decisions is unknown, and something that deserves to be investigated.…”