S. mansoni

To transmit their eggs, S. mansoni adult pairs migrate to the venous vasculature around the intestines; eggs laid here can pass through the blood vessel wall, through the wall of the intestine, and into the intestinal lumen. From here, eggs exit the body with feces. Fig 2 shows that the adult S. mansoni worms in the blood vessels of the liver are presented with some choices when migrating to such egg laying sites in the mesenteries. For instance, from the hepatic portal vein the worm pairs (taking route #1, Fig 2) could enter the splenic vein, then turn into the inferior mesenteric vein, then move down either the left colic vein or one of the sigmoidal veins. The distal venules derived from these vessels are intimately associated with the descending and sigmoid colon, and parasite eggs laid in these locations could pass through the blood vessel wall, through the wall of the intestine, and into the intestinal lumen. Alternatively, the adults could migrate from the hepatic portal vein into the superior mesenteric vein, then deviate down the right colic or ileocolic veins to lay eggs in the venules of the ascending colon (route #2). Worms could also travel to the transverse colon through the middle colic vein (not depicted).

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Fig 2. Diagrammatical representation of the hepato-portal and associated vasculature showing possible routes of migration (yellow arrows) of schistosomes from the blood vessels of the liver to their egg laying sites.

From the hepatic portal vein, pathway “1” indicates parasites entering the splenic vein, then the inferior mesenteric vein to the venules of the descending colon. Pathway “2” indicates parasites entering the superior mesenteric vein to right colic vein and the venules of the ascending colon. Pathway “3” indicates parasites leaving the superior mesenteric vein via the jejunal and ileal veins to the venules draining the small intestine (jejunum and ilium). Pathway “4” indicates parasites traveling via the inferior mesenteric vein into the superior rectal (hemorrhoidal) vein to the venules of the rectum. Finally, pathway “5” indicates parasites migrating beyond the vasculature of the rectum via the rectal venous plexus through the uterine and vaginal venous plexuses (in females, as illustrated, or the prostatic venous plexus in males, not shown) into the vesicle venous plexus draining the bladder. Image credit: Thanks to Taoli Shen for illustrating Fig 2.

https://doi.org/10.1371/journal.pntd.0007951.g002

From the superior mesenteric vein, the parasites could otherwise move via the jejunal and ileal veins to the venules draining the small intestine (jejunum and ilium) to lay eggs (route #3). It is clear that S. mansoni adults avail of all of these pathways because parasite eggs are deposited throughout the entire length of the intestinal tract of infected experimental animals [22–24]. Indeed, this is the case even in mice infected with just a single pair of worms; this means that worm pairs move extensively all along the complex venous system, draining the murine intestinal tract [25]. In addition, using in vivo microscopy, worms have been directly observed to move constantly in the mesenteric veins of their murine hosts [12].

Fig 3A shows adult S. mansoni worms (indicated by the arrows) in the blood vessels of the exposed mesenteries of a 7-week infected mouse. Fig 3B is a hematoxylin and eosin–stained longitudinal section of a schistosome-infected mouse blood vessel showing the female worm within the gynaecophoric canal of the male. This image highlights the snugness of fit of the parasite couple; the vascular endothelium surrounding the worms is indicated by arrows.

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Fig 3.

(A) Exposed mesenteries of a 7-week infected female Swiss Webster mouse showing intravascular adult S. mansoni worms (indicated by arrows). (B) Hematoxylin and eosin–stained, formalin-fixed section of a blood vessel of a 7-week infected female Balb/c mouse containing an adult S. mansoni couple. The male worm and his female partner (within his gynaecophoric canal) are both indicated. The vascular endothelium bounding the worm couple is indicated by arrows.

https://doi.org/10.1371/journal.pntd.0007951.g003

Examination of infected humans at autopsy reveals that the adult worms, as in mice, are widely distributed in the colonic venules, in the small intestinal venules, and in the liver and portal vein [26]. While the inferior mesenteric vein is considered the “natural habitat” of S. mansoni, this habitat actually extends to all veins that drain into the hepatic portal system [27]. In keeping with this wide distribution of the worms seen at autopsy, parasite eggs are also found throughout the human intestinal mucosa, with higher proportions of the eggs being reported in the rectum and colon versus the small intestine (ilium and jejunum) [26,28,29]. The presence of S. mansoni eggs in high numbers in the rectum confirms that these worms can migrate down the superior rectal vein to the anorectal plexus to lay eggs (as depicted in Fig 2, route #4) and are by no means confined to the proximal mesenteric veins [27]. Indeed, S. mansoni eggs have been detected even in the bladder and in the urine of infected individuals, showing that the worms can move beyond the anorectal plexus to the vesicle venous plexus (a migration more commonly associated with S. haematobium, see later) [28,30,31]. It has been reported that S. mansoni eggs are excreted in the urine more often in mixed S. mansoni/S. haematobium infections versus in pure S. mansoni infections; S. mansoni eggs have been detected in the urine of 5.6% of people (62/1,146) with a mixed infection but only in 0.7% of people (6/840) with a pure S. mansoni infection [32,33]. However, in another study of 106 pure S. mansoni–infected individuals, a notably higher proportion—14.5% (15 patients)—were found to pass S. mansoni eggs in the urine [30].

Demonstrating the relentless exploratory nature of intravascular schistosomes, parasite eggs have been detected in the spleen, the stomach, the pancreas, and gall bladder of infected humans [28,29,34,35]. Because venous blood flows away from these organs, eggs found there are not passively swept to these sites. The worms actively moved, for instance, to the terminus of the splenic vein and laid eggs there, even though these eggs have no route to the outside to continue the parasite’s life cycle. This finding of wide egg deposition raises the question as to whether S. mansoni females lay eggs directly in the veins of the liver versus, as is usually assumed, that eggs in the liver arrived there by being swept back to this site with the blood flow after having been laid elsewhere. Indeed, the worm couples could potentially begin laying eggs in the portal vessels as soon as they pair and while they are in the process of migrating away from the liver.

Worm distribution can change over the course of infection. For instance, prolonged infection in rhesus macaques (>187 days post-cercarial exposure) is accompanied by a marked shift of S. mansoni worms from colonic venules to venules of the small intestine [36]. The change in worm position is akin to that seen in human subjects with Symmers fibrosis of the liver (a condition not seen in macaques) [26].

S. japonicum

S. japonicum infects several animal species and causes zoonotic disease; the distribution of intravascular worms of this species has been examined in a variety of animals. In all cases, the parasites are found widely distributed throughout the mesenteries (reviewed in [37]), showing that the adult pairs (like S. mansoni) can also navigate via routes 1, 2, 3, and 4 as depicted in Fig 2. Based on the distribution of S. japonicum eggs and the severity of pathological changes along the length of the intestine, there is debate as to the relative importance of these routes in different host species; higher egg density and/or more severe pathology in the small intestine is reported in smaller animal hosts (for instance, mouse, guinea pig [38,39]—suggesting a preference for route 3), whereas higher egg density and/or more severe pathology in the large intestine is reported in larger animal hosts (for instance, goat, sheep, buffalo [38]—suggesting a preference for routes 1 and 2). Humans (large animal hosts) follow this trend; adult worms are localized predominantly in the inferior mesenteric vein and the superior rectal vein and egg numbers are highest in the rectum, the sigmoid colon, and the descending colon [37,40]. As is the case for S. mansoni, infection of mice with a single S. japonicum worm pair also results in parasite eggs scattered throughout the gut, indicating movement of these worms in the venous vasculature along the length of the intestine [41].

Also as seen for S. mansoni, egg deposition in “non-productive” sites such as the spleen and stomach is seen with S. japonicum [40,42]. In addition, there are case reports documenting S. japonicum eggs in the ovary [43], fallopian tube [44], or prostate [45], showing that sometimes S. japonicum worms too can migrate beyond the mesenteric venules [46].

The situation is complicated by the existence of different S. japonicum strains [42]. In one study in rabbits, the preferred oviposition site for a Japanese schistosome strain was found to be the small intestine, whereas the large intestine was preferred in infections with a Philippine strain [47]. In contrast, S. japonicum eggs were found predominantly in the small intestine in capuchin monkeys infected with the Philippine strain and predominantly in the colon in monkeys infected with the Japanese strain [48].

S. haematobium

S. haematobium, unlike the other two major human-infecting schistosome species, migrates primarily to the veins surrounding the bladder (the vesicle venous plexus) and causes urinary schistosomiasis. The route taken is not often described, but Fig 2 (route #5) shows one relatively direct path of migration for the adult pairs from the hepatic portal vein: first into the splenic vein, then into the inferior mesenteric vein. This vein runs directly into the superior rectal (hemorrhoidal) vein, which leads to a collection of interconnected vessels known as the rectal venous plexus. This plexus connects with another series of interconnected vessels draining the reproductive organs (the uterine and vaginal venous plexuses in females [illustrated in Fig 2] and the prostatic venous plexus in males) which, in turn, connect with the network of vessels draining the bladder (the vesicle venous plexus). The abundant interconnections (anastomoses) between these different venous plexuses in the pelvis facilitate worm movement. These vessels largely lack valves and so offer a network of unrestricted routes for the worms to, and through, the urogenital organ systems. Schistosome eggs laid in the vesicle venous plexus can traverse the blood vessel wall, as well as the wall of the bladder, to enter the lumen of the bladder and can then exit the body with urine. In keeping with this, most of the S. haematobium adult worms seen at autopsy are found in the blood vessels of the bladder, and the highest percentage of eggs in the organs are likewise found in the bladder (followed by the ureter) [31]. Egg distribution is observed to be uneven in the lower urinary tract (i.e., bladder and urethra) and focal egg deposition is considered to be more characteristic of light infections, while heavy worm burdens result in eggs being laid more evenly throughout the region [49].

S. haematobium adults, however, are by no means confined to the urinary tract. In one study examining 46 cases at autopsy, adult S. haematobium were located in roughly equal proportions in the mesenteric and portal veins (47%) compared to the bladder (48%) [31] and, in keeping with this distribution, considerable numbers of S. haematobium eggs were found in the colon [31], a finding that is commonly observed in humans [28,29,34] and in a variety of primates [50]. While a majority of S. haematobium eggs in the intestine are seen in the rectum, the fact that eggs are also located in the cecum, appendix, and small intestine demonstrates that S. haematobium too can migrate down the superior mesenteric vein from the liver (Fig 2, route #3)—a route from which the worms cannot progress directly to the bladder (Fig 2) [28,29,31,35,51].

Fig 2 shows the extensive interconnected network of veins in the pelvis through which the parasites can migrate. It appears that the worms lay eggs throughout this network even though, in many cases, there is little prospect for those eggs to exit the body and continue the parasite’s life cycle. For instance, in infected women, eggs can be found in the cervix, uterus, vagina, fallopian tubes, and ovaries, all contributing to the widespread pathology collectively called female genital schistosomiasis [31,35,52–54], and all essentially dead-end sites for the worms in terms of parasite transmission. In a meta-analysis of the anatomical distribution of female genital schistosomiasis based on histopathological and postmortem studies in various endemic areas, the worms displayed no strong and consistent preference for a specific female genital organ [55]. For instance, of all eggs found in the genital organs, the percentage found in the cervix varied from 7% to 62% in different studies; the percentage found in the fallopian tubes varied from 7% to 32%, and in the vagina from 10% to 78% [55].

In men, S. haematobium eggs can be found at autopsy in the epididymis, prostate, seminal vesicles, vas deferens, and testes [31,34,35,52,56], leading to male genital schistosomiasis with, as in females, little prospect for easy egg egress from the body from these genital sites. As in women, in men, too, the worms show no strong preference for localization in any specific genital site. Eggs in the prostate have been reported from 14% to 100% of cases, and eggs in the seminal vesicles from 55% to 100% [52,57].

Emphasizing once more the relentless migratory tendencies of schistosomes, note that in cases of S. mansoni infection too, parasite eggs can sometimes be found in all of the female and male genital organs just listed but, in comparison with S. haematobium infection, in much reduced numbers [31,57].

Finally, it is worth noting that once schistosomes reach the anorectal plexus there is relatively easy access to systemic venous blood flow from the middle and inferior rectal veins, or the pelvic venous system to the inferior vena cava. Eggs that distribute into systemic blood circulation via these routes can get trapped, for instance, in the capillary beds of the lungs [58,59]. In one histological autopsy study, 59% of 108 cases had eggs in the lungs, 94% of these being S. haematobium (and the remainder mixed S. haematobium and S. mansoni). Here, S. mansoni was only found in the lungs when the bladder was affected [28]. Eggs of all species, and indeed adult worms, can also be found in a variety of other tissues, including the brain and spinal cord, with S. japonicum—the most prolific egg producer among the human schistosomes—being more commonly found in the brain [28,34,40,60].