Interleukin-25-mediated resistance against intestinal trematodes does not depend on the generation of Th2 responses

Abstract

Interleukin-25 (IL-25) plays a major role in resistance against intestinal helminth infections as initiator of protective Th2 responses. However, recent studies have challenged the contribution of this cytokine in both the polarization of the response towards a Th2 phenotype and the parasite rejection. We have used the experimental model Echinostoma caproni-ICR mice to investigate the participation of this cytokine in resistance to intestinal helminths. ICR mice are characterized by their inability to respond with IL-25 production in primary infections with E. caproni, causing susceptibility associated with a Th1 response. However, mice are refractory to infection in presence of IL-25 in relation to a type 2 phenotype. Herein, we show that dynamics of resident microbiota appears to be crucial in IL-25 production. Moreover, IL-25 seems to play a pivotal role in the polarization to Th2 in primary responses, but also appears to participate in the generation of memory mechanisms making unnecessary the participation of IL-25 in memory responses for the development of Th2 milieu. However, resistance to E. caproni infection does not depend on the generation of a Th2 phenotype, but exclusively depends on the presence of IL-25, operating autonomously from the type 2 response in the generation of resistance.

Changes in resident microbiota associated with mice susceptibility or resistance to the intestinal trematode Echinostoma caproni

“…Susceptibility of mice to E. caproni infection depends on the ability of the host to respond to IL-25 production (Muñoz-Antoli et al ., 2016 a ; Álvarez-Izquierdo et al ., 2020 a ). Primary infections become chronic and characterized by elevated levels of inflammation and tissue damage in relation to the lack of IL-25 production (Muñoz-Antoli et al ., 2007).…”

“…However, mice develop partial resistance to secondary infection in relation to the innate production of IL-25 as a consequence of the curation of the primary infection (Muñoz-Antoli et al, 2016a, 2016b. Furthermore, Álvarez-Izquierdo et al (2020a) demonstrated that type gut microbiota (Zaph et al, 2008;Sawa et al, 2011;Donaldson et al, 2015;Watanabe et al, 2017). IL-25-mediated intestinal immune regulation is impaired in mice in the absence of microbiota (Sawa et al, 2011;Donaldson et al, 2015;Watanabe et al, 2017).…”

“…However, mice develop partial resistance to secondary infection in relation to the innate production of IL-25 as a consequence of the curation of the primary infection (Muñoz-Antoli et al, 2016a, 2016b. Furthermore, Álvarez-Izquierdo et al (2020a) demonstrated that type 2 response to secondary E. caproni infection in mice was unable to develop resistance in the absence of IL-25, confirming the requirement of IL-25 for resistance and showing that the role of this cytokine is not limited to regulatory functions, but also has a critical effector role in the resistance. However, the factors that determine the upregulation of IL-25 are not known, but there are several lines of evidence suggesting that it can be driven by resident gut microbiota (Zaph et al, 2008;Sawa et al, 2011;Donaldson et al, 2015;Watanabe et al, 2017).…”

“…In highly compatible hosts, such as mice, primary infection becomes chronic, while pharmacological healing of the primary infection induces a sudden production of IL-25. Secondary infection in the presence of IL-25 results in partial resistance to the challenge infection (Muñoz-Antoli et al, 2016a, 2016bÁlvarez-Izquierdo et al, 2020aÁlvarez-Izquierdo et al, , 2020b. Herein, we analyse the changes in resident microbiota induced by primary E. caproni infection in mice, cure of the primary and secondary infections with the aim to gain further insight into the potential role of microbiota in the production of IL-25 and resistance to infection.…”

Neglected food-borne trematodiases: echinostomiasis and gastrodiscoidiasis

“…Resistance to echinostome infections has been traditionally associated with the development of Th2 responses, mainly mediated by interleukin 4 (IL-4) and/or IL-13 (Brunet et al ., 2000; Toledo and Fried, 2005; Sotillo et al ., 2011; Cortés et al ., 2017 b ; Toledo et al ., 2019). However, recent studies suggest that resistance depends on the ability of the host to maintain the mucosal homoeostasis in a process mediated by IL-25 (Muñoz-Antoli et al ., 2016; Álvarez-Izquierdo et al ., 2020 a , 2020 b ). Resistance is associated with hyperplasia of local tuft cells and production of IL-25 which operates by facilitating the maintenance of the epithelial homoeostasis that could be ultimately responsible for parasite rejection (Muñoz-Antoli et al ., 2016; Cortés et al ., 2017 b ; Álvarez-Izquierdo et al ., 2020 a , 2020 b ).…”