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The Esophageal Gland Mediates Host Immune Evasion by the Human The esophageal gland mediates host immune evasion FROM THE COVER by the human parasite Schistosoma mansoni Jayhun Leea, Tracy Chonga,b, and Phillip A. Newmarka,b,c,1 aRegenerative Biology, Morgridge Institute for Research, Madison, WI 53715; bHoward Hughes Medical Institute, University of Wisconsin–Madison, Madison, WI 53715; and cDepartment of Integrative Biology, University of Wisconsin–Madison, Madison, WI 53715 Edited by Robb Krumlauf, Stowers Institute for Medical Research, Kansas City, MO, and approved June 30, 2020 (received for review April 7, 2020) Schistosomes are parasitic flatworms that cause schistosomiasis, a Within the snail host, cercariae develop organs necessary for neglected tropical disease affecting over 200 million people. infection (e.g., penetration glands) and primordia of organs (e.g., Schistosomes develop multiple body plans while navigating their the digestive tract) required during the next parasitic stage complex life cycle, which involves two different hosts: a mamma- (Fig. 1B). Cercariae also contain approximately five to six stem lian definitive host and a molluscan intermediate host. Their cells that are localized stereotypically: one pair of cells on each survival and propagation depend upon proliferation and differen- side, and one cell medially (7). Previously, we showed that upon tiation of stem cells necessary for parasite homeostasis and infection of the mammalian host and transformation into schis- reproduction. Infective larvae released from snails carry a handful tosomula, these cells begin to proliferate (7), but the fates of of stem cells that serve as the likely source of new tissues as the their progeny were unexplored. In this work, we examine the parasite adapts to life inside the mammalian host; however, the contributions of these stem cells to early intramammalian de- role of these stem cells during this critical life cycle stage remains velopment. Based on the unexpected finding that stem cells unclear. Here, we characterize stem cell fates during early intra- contribute to development of an accessory digestive organ, the mammalian development. Surprisingly, we find that the esopha- esophageal gland, before the rest of the digestive system is geal gland, an accessory organ of the digestive tract, develops formed, we characterize the gland’s function in vivo, revealing a before the rest of the digestive system is formed and blood mechanism for evasion of the host immune system. feeding is initiated, suggesting a role in processes beyond nutrient uptake. To explore such a role, we examine schistosomes that lack Results DEVELOPMENTAL BIOLOGY the esophageal gland due to knockdown of a forkhead-box tran- Stem Cells in Early Schistosomula Generate Parasite–Host Interfaces. Sm-foxA scription factor, , which blocks development and mainte- In flatworms, differentiated cells do not proliferate; thus, genes nance of the esophageal gland, without affecting the development regulated in a cell cycle-dependent manner, such as histone 2b of other somatic tissues. Intriguingly, schistosomes lacking the (h2b), can be used as generic stem cell markers (6, 15–17). Using esophageal gland die after transplantation into naive mice, but h2b as a marker of these cells in cercariae (Fig. 1C) and schis- survive in immunodeficient mice lacking B cells. We show that tosomula (Fig. 1D), we tracked their behavior by examining in- parasites lacking the esophageal gland are unable to lyse ingested corporation of 5-ethynyl-2′-deoxyuridine (EdU) in pulse-chase immune cells within the esophagus before passing them into the experiments either during in vitro transformation or in vivo (SI gut. These results unveil an immune-evasion mechanism mediated Appendix, Fig. S1A and Materials and Methods). The number of by the esophageal gland, which is essential for schistosome survival (h2b+) stem cells remained unchanged during 1 wk of in vitro and pathogenesis. culture, analogous to lung-stage in vivo schistosomula (Fig. 1D), stem cells | host–parasite interaction | foxA | intramammalian parasite development | parasitic helminths Significance chistosomes are parasitic flatworms that cause schistosomi- Schistosomes are parasitic flatworms infecting hundreds of Sasis, a neglected tropical disease affecting over 200 million millions of people. As they alternate between mammalian and individuals (1). Schistosomes reside in the vasculature of a wide molluscan hosts, their survival and propagation depend upon stem cell proliferation and differentiation. Tracking the fate of range of vertebrate hosts; there, they lay eggs that cause in- these stem cells during early intramammalian development, flammation and damage to host tissues, leading to schistosomi- we find that the esophageal gland, an accessory digestive or- asis (2). Their complex life cycle requires passage through gan, develops before the rest of the digestive system is formed molluscan and mammalian hosts (Fig. 1A): aquatic snails release and feeding begins, suggesting a role for this organ beyond cercariae, free-living, infective larvae that swim to find and nutrient uptake. We show that schistosomes lacking the penetrate mammalian host skin. Upon infection, the cercarial esophageal gland die in naive mice but survive in immunode- tail is lost at the infection site, and the parasite body transforms ficient mice lacking B cells; they are unable to lyse ingested into a schistosomulum. This early intramammalian-stage parasite immune cells before passing them into the gut. These results immediately faces major challenges as it adapts to this new host unveil an immune-evasion mechanism, which is essential for environment: it must migrate from the skin into the bloodstream, schistosome survival and pathogenesis. then through the lungs, to reach its niche in the hepatic vascu- Author contributions: J.L. and P.A.N. designed research; J.L. and T.C. performed research; lature (3). There, it will begin feeding on blood, which fuels J.L. analyzed data; and J.L. and P.A.N. wrote the paper. growth, sexual maturation, and reproduction. Failure at any step The authors declare no competing interest. would disrupt the life cycle, yet it manages these challenges, even This article is a PNAS Direct Submission. in the face of the host’s immune system (4, 5). Recent work has This open access article is distributed under Creative Commons Attribution-NonCommercial- identified heterogeneous populations of schistosome stem cells NoDerivatives License 4.0 (CC BY-NC-ND). – (6 10) and described their roles in asexual reproduction (7, 11), 1To whom correspondence may be addressed. Email: [email protected]. ’ tegument (the parasite s outer surface) production during ho- This article contains supporting information online at https://www.pnas.org/lookup/suppl/ meostasis (12, 13), and germ cell development (7, 8, 10, 14). Thus, doi:10.1073/pnas.2006553117/-/DCSupplemental. stem cells help drive schistosome viability and transmission. www.pnas.org/cgi/doi/10.1073/pnas.2006553117 PNAS Latest Articles | 1of11 Downloaded by guest on September 26, 2021 A B water sporocysts egg mouth opening (m) esophagus (e) eg primordial vs esophageal gland (eg) (meg4.1+) body ventral schistosomulum sucker (vs) miracidium primordial gut (g) (cathepsin B+) X tail Schistosoma mansoni life cycle m gut e eg cercaria g germinal schistosomulum juvenile adult male female vs intra-mammalian cells skin lung mesenteric veins 50 μm development 0-3 days ~1 week ~2-4 weeks > 5 weeks DAPI PNA phalloidin merge C h2b DAPI D E 20 n.s 10 cells 15 h2b+ 10 5 M 5 number of total EdU+ cells 0 number of 01234 vs 0 R L cercariae D3 D7 D7 days of continuous EdU labeling 10 μm - D1 - D6 - D11 (lung) N (worms) 11 11 10 11 F h2b EdU DAPI EdU pulse: D0-D3; chase 4 days G tsp2 EdU DAPI EdU pulse: D0-D3; chase 4 days *p=0.0002 50 of total EdU+ cells of total tsp2+ cells 100 *p=0.01 *p=0.02 of total EdU+ cells of total h2b+ cells 25 n.s 50 +EdU+ cells +EdU+ cells tsp2 h2b % % 0 0 D3 D7 D3 D7 10 μm days post-transformation D3 D7 D3 D7 10 μm days post-transformation N = 10 12 N = 10 12 H meg4.1 cathepsin B DAPI I EdU DAPI (lung stage, D8) 1 1 2 12meg4.1 cathepsin B lung stage 100 2 80 60 1 +EdU+ worms 2 40 20 meg4.1 % 0 012345 days (post-EdU Injection) 10 μm 10 μm 10 μm 7/13 12/12 N = 8 9 10 8 Fig. 1. Stem cells drive early development of the schistosome esophageal gland. (A) Life cycle of Schistosoma mansoni. eg, esophageal gland; vs, ventral sucker. Each worm schematic depicts the esophageal gland (magenta-filled bean shapes), gut branches that stretch posteriorly (magenta outlines), and the ventral sucker (dark gray disk). The intramammalian developmental curve was adapted from ref. 40. (B) Anatomical features of schistosomula. (Top) Sche- matic view of a schistosomulum with the primordial digestive tract outlined. Genes expressed in distinct parts of the digestive tract are indicated. (Bottom) Day 1 posttransformation schistosomulum stained with PNA lectin and phalloidin, maximum-intensity projection (MIP). PNA (cyan) labels cercarial penetration gland used for mammalian skin penetration; this gland is largely unused after mechanical removal of tails. Phalloidin staining (magenta) labels muscular features surrounding the primordial digestive tract. (C) h2b fluorescence in situ hybridization (FISH) in cercaria, MIP. R and L, right and left, each showing pairs of h2b+ stem cells; M, medially located stem cell. vs, ventral sucker, indicated by white circles throughout (C–I). (D) Quantification of h2b+ cells in cercariae and schistosomula at various time points in vitro and in vivo (lung) (SI Appendix, Fig. S1A). Gray lines: Mean ± SD. Statistical analysis: one-way ANOVA. (E) Quantification of EdU+ cells at indicated days posttransformation after continuous EdU labeling in vitro. Mean ± SD. (F, Left) h2b FISH and EdU − labeling at day 3 or 7 posttransformation in vitro, MIP. Arrowheads: double-positive cells; Arrows: h2b+ EdU cells. (Right) Percent of h2b+ EdU+ cells over total − EdU+ cells (black) or h2b+ cells (gray); mean ± SD.
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