Immunomodulation by IPSE/alpha-1, an excretory/secretory protein from Schistosoma mansoni eggs

Infektionen mit Helminthen können den Wirt vor der Entwicklung chronisch-entzündlicher Erkrankungen schützen. So ist bei S. mansoni das Ei-Stadium immunregulatorisch wirksam. Die zahlreich in den Mesenterialvenen des Wirts abgelegten Eier wandern durch das Darmepithel in das Darmlumen und induzieren Granulome. Sie schädigen die Blutgefäß- und Darmwand und eröffnen damit Eintrittspforten für intestinale Mikrobiota. Hier scheint IL-4 essentiell für die Entzündungskontrolle zu sein: IL-4- und IL-4Rα-defiziente Mäuse versterben bei einer Schistosomen-Infektion rasch an einer exzessiven Darmentzündung. Beachtlich ist, dass die Eier ein Glykoprotein, IPSE/alpha-1, sezernieren, welches Basophile zur Freisetzung von IL-4 stimuliert. Die Frage war: Ist IPSE/alpha-1 über die Induktion von basophilem IL-4 an der Suppression einer überschießenden intestinalen Entzündung im Zuge einer Infektion mit S. mansoni beteiligt? In der Kokultur hemmten IPSE/alpha-1-aktivierte humane Basophile IL-4-vermittelt und zellkontaktunabhängig die Freisetzung proinflammatorischer Zytokine (IL-1β, IL-6 und TNF) aus LPS-aktivierten Monozyten – auch im Kontext mit PBMC. Die simultane Stimulation der Basophilen über FcεRI-gebundenes IgE (via IPSE/alpha-1) und über TLR4 (via LPS) führte zu einer synergistisch erhöhten IL-4-Freisetzung. Ferner entwickelten die inflammatorischen Monozyten in Gegenwart der aktivierten Basophilen einen M2-typischen antiinflammatorischen Phänotyp mit erhöhter Expression von CD206 und CD209. Mittels immunhistologischer Untersuchungen an Geweben S. mansoni-infizierter Mäuse konnten zudem Basophile in Ei-Granulomen in Darm und Leber nachgewiesen werden, womit von den Schistosomen-Eiern sezerniertes IPSE/alpha-1 unmittelbar auf die Basophilen wirken könnte. Insgesamt unterstützen diese Daten die Hypothese, dass IPSE/alpha-1 und Basophile zusammen mit LPS substantiell an der durch S. mansoni-Eier vermittelten intestinalen Entzündungskontrolle beteiligt sein könnten.Infections with helminths may protect the host against the development of chronic inflammatory diseases. In schistosomes, it is the egg stage which exhibits immunoregulatory capacities. S. mansoni eggs, which are deposited in high numbers in the host’s mesenterial vasculature, migrate through the intestinal epithelium to the gut lumen promoted by inflammatory events such as granuloma formation, tissue destruction and invasion of intestinal microbiota. In these events, IL-4 seems to be essential for inflammation control since S.mansoni-infected mice deficient in IL-4 or IL-4Rα die early from excessive intestinal inflammation. Notably S. mansoni eggs secrete the glycoprotein IPSE/alpha-1 (IL-4 inducing principle from Schistosoma mansoni eggs), which triggers basophils to release IL-4. Therefore the question arose if IPSE/alpha-1, via the induction of basophil IL-4, is involved in the suppression of excessive intestinal inflammation during S. mansoni infection. Upon co-culture IPSE/alpha-1-activated basophils inhibited – mediated by IL-4 and cell-cell-contact independently – the release of pro-inflammatory cytokines (IL-6, IL-1β and TNF) from LPS-activated monocytes and PBMC, respectively. Simultaneous stimulation of basophils via FcεRI-bound IgE (with IPSE/alpha-1) and TLR4 (with LPS) boosted the release of IL-4 from basophils. Furthermore, in presence of activated basophils pro-inflammatory monocytes developed an anti-inflammatory M2-like phenotype with increased surface expression of CD206 and CD209. In addition immunohistological staining of liver and gut sections of S. mansoni-infected mice confirmed the presence of basophils in the egg granuloma allowing IPSE/alpha-1 secreted by schistosome eggs to interact directly with basophils. These findings suggest that IPSE/alpha-1 and basophils along with LPS may play an important role in intestinal inflammation control mediated by S. mansoni eggs

Schistosoma mansoni Egg-Released IPSE/alpha-1 Dampens Inflammatory Cytokine Responses via Basophil Interleukin (IL)-4 and IL-13

Schistosomes control inflammation in their hosts via highly effective mechanisms such as induction of Tregs, Bregs, and alternatively activated macrophages (AAMs). Notably, IPSE/alpha-1, the major secretory product from Schistosoma mansoni eggs, triggers basophils to release interleukin (IL)-4 and IL-13. Both cytokines are essential for AAM induction, suggesting an important role for IPSE/alpha-1 in inflammation control. Here, we show by in vitro co-culture experiments that IPSE/alpha-1-induced basophil IL-4/IL-13 inhibited pro-inflammatory cytokine release from human LPS-activated monocytes. This effect was cell/cell contact-independent but dependent on IL-4, since it was abrogated in the presence of anti-IL-4 antibodies. Importantly, the IPSE/alpha-1-induced IL-4/IL-13 release from basophils was amplified in the presence of LPS. Moreover, monocytes co-cultured in the presence of LPS with IPSE/alpha-1-stimulated basophils adopted an AAM-like phenotype as assessed by elevated expression of CD206 and CD209. The putative in vivo relevance of these findings was supported by immunohistological staining of S. mansoni-infected murine tissue revealing close physical contact between IPSE/alpha-1 and basophils in schistosome egg granulomas. Taken together, we found that IPSE/alpha-1 dampens inflammatory cytokine responses by triggering basophil IL-4/IL-13, in particular in the context of TLR activation, thereby turning inflammatory monocytes into anti-inflammatory AAMs. This might represent a mechanism used by schistosomes to control inflammation in the host

Schistosome Eggs Impair Protective Th1/Th17 Immune Responses Against Salmonella Infection

Countries with a high incidence of helminth infections are characterized by high morbidity and mortality to infections with intracellular pathogens such as Salmonella. Some patients with Salmonella-Schistosoma co-infections develop a so-called "chronic septicemic salmonellosis," with prolonged fever and enlargement of the liver and spleen. These effects are most likely due to the overall immunoregulatory activities of schistosomes such as induction of Tregs, Bregs, alternatively activated macrophages, and degradation of antibodies. However, detailed underlying mechanisms are not very well investigated. Here, we show that intraperitoneal application of live Schistosoma mansoni eggs prior to infection with Salmonella Typhimurium in mice leads to an impairment of IFN-γ and IL-17 responses together with a higher bacterial load compared to Salmonella infection alone. S. mansoni eggs were found in granulomas in the visceral peritoneum attached to the colon. Immunohistological staining revealed IPSE/alpha-1, a glycoprotein secreted from live schistosome eggs, and recruited basophils around the eggs. Noteworthy, IPSE/alpha-1 is known to trigger IL-4 and IL-13 release from basophils which in turn is known to suppress Th1/Th17 responses. Therefore, our data support a mechanism of how schistosomes impair a protective immune response against Salmonella infection and increase our understanding of helminth-bacterial co-infections