New Tools for Old Questions: How Strictly Human Are “Human Schistosomes”—And Does It Matter?

(See the Brief report by Catalano et al, on pages 429–33.)

Human schistosomiasis has been documented in Egyptian mummies from the time of the early Pharaohs [1]. Efforts to control it in endemic areas have been ongoing since the discovery of the main species of human schistosomes in the early part of the 20th century [2]. Many of these early efforts focused on control of the snail hosts and water engineering, due to the lack of an easily applied, field-applicable drug. During that first golden age of parasitological discovery, there were many investigations to determine whether human-infecting schistosome species were zoonotic and which, if any, other vertebrates could be definitive hosts. Experimental infections of a wide variety of mammalian hosts were undertaken as were field surveys to search for patent infections of human schistosomes in wild or domestic animals. The former studies were critical to establish experimental studies of schistosomes, whereas the latter investigations were focused on determining whether reservoir hosts existed and were capable of transmission to appropriate snails and thus contribute to transmission of human schistosomiasis.

As recounted admirably in the seminal studies and writings of Fujinami and Nakamura [3], Kuntz [4], Nelson [5], and Pitchford [6], very early on it became obvious that Schistosoma japonicum, and to a lesser extent Schistosoma mekongi, both found in the Far East, were clearly zoonotic. Schistosoma japonicum is capable of patency in 40 mammalian species [7], with water buffalos serving as a major reservoir host, and S mekongi can mature in dogs and pigs. For Schistosoma mansoni in Africa, the Middle East, and the Americas, it was learned that several species of primates, rodents, and other mammals would yield egg-producing infections upon experimental exposure and baboons, and some rodent species were frequently found naturally infected in contexts where they could likely contribute to snail infections. In both Brazil and Guadeloupe, rodents have been implicated in long-term studies in maintaining and/or supporting transmission of S mansoni [8, 9]. Even for Schistosoma haematobium, although considered to be largely confined to humans as natural definitive hosts, several rodent species can be experimentally infected. Streptococcus bovis, a close relative of S haematobium, despite its name, has also been recovered from wild rodents. For many of these earlier studies, parasitologists had to rely on the morphology of schistosome eggs or, after necropsy, on anatomical features of adult worm, or of cercariae if experimental snail infections could be achieved. Although it was clear that the human-infecting schistosomes S mansoni and S haematobium could infect and be maintained in certain experimental hosts, the extent to which these species served as reservoirs for transmission to people remained unsettled and largely ignored. In the meantime, there is now evidence of an additional complication as well. The application of new molecular tools has revealed that each species can hybridize with close, nonhuman infecting relatives (Schistosoma rodhaini in the case of S mansoni; S bovis, Schistosoma curassoni, or Schistosoma mattheei in the case of S haematobium) [10]. The possibility that such hybrids might expand human transmission through both new snail and wild mammal reservoir hosts now needs to be investiged.

In the Brief Report by Catalano et al [11] in this issue of the Journal of Infectious Diseases, the authors have addressed this overlooked issue in the public health response to schistosomiasis in sub-Saharan Africa, the Americas, and the Middle East. This article uses molecular identification of the schistosomes found and should reinvigorate substantive discussions on the possibility of zoonotic transmission of human-infecting schistosomes. Hopefully, it will lead to more studies on the potential zoonotic nature of S mansoni and S haematobium in both existing major endemic foci and in areas where transmission may be waning or more precarious. The report by Catalano et al [11] does not provide direct or correlative evidence of such transmission from rodent reservoir hosts to humans, nor does it claim to do so. Likewise, it does not present direct evidence that S haematobium/S bovis hybrids infecting rodents produce miracidia that can infect vector snails. However, the potential is there and certainly warrants further study. Studies of given water contact sites to attempt to correlate the frequency of S mansoni-infected rodents and the prevalence of human S mansoni could be of considerable interest.

Because of the progress now being made on the control of schistosomiasis, it is time, if not past time, to consider the possible zoonotic potential of S mansoni and S haematobium. This is especially true as some approach consideration of the next steps to move toward the elimination of this scourge. Over the last 16 years, the World Health Assembly has issued multiple resolutions calling for the control and eventual elimination of human schistosomiasis. These welcome acknowledgments of the global importance of schistosomiasis have been accompanied by World Health Organization guidelines outlining its control and elimination by preventive chemotherapy with praziquantel, snail control, and provision of water and sanitation. Annual or biennial mass drug administration by national Neglected Tropical Disease programs with the assistance of the donation of praziquantel by Merck AG and multiple bilateral programs have begun to bring down the prevalence and intensity of schistosome infections across much of Africa. Likewise, ongoing national programs over multiple decades in China and Egypt have curtailed transmission of schistosomiasis to focal areas of very low prevalence and seek to eliminate schistosomiasis transmission.

As indicated above, it is well appreciated that for the zoonotic species S japonicum and S mekongi, actual interruption of transmission will require attention to both domestic and wild animals that can support patent infections and, thus, contribute to continuing transmission to humans. This is the basis of China’s (1) program to replace water buffalos with tractors and (2) studies in the Philippines on vaccine development of water buffalos against schistosome infections.

The situation with S mansoni is somewhat less clear, but there is no question this species can patently infect baboons and wild and peridomestic rodents [12, 13]. The latter should not be surprising because most experimental studies undertaken around the world with S mansoni rely on rodent-maintained specimens. Nevertheless, cognitively acknowledging this and then either demonstrating its potential epidemiological significance or accommodating it in one’s public health planning are quite different things. When asked about the potential problem that might arise in public health campaigns should S mansoni transmission prove to be zoonotic, we propose that an appropriate response should be as follows: “This has not been shown to be a problem……yet, but this inconvenient possibility needs to be evaluated.” The article by Catalano et al [11] adds to and begins to fold back the covers on the possibility that the “yet” in this response should at least lead to more extensive evaluation. Although not designed to demonstrate transmission from rodents to humans, the report by Catalano et al [11] does demonstrate that rodent infections with S mansoni and human infections with S mansoni clearly coexist, which has also been reported in East Africa [14].

Outside of the laboratory, S haematobium has consistently been observed to patently infect only people and is not considered a zoonosis. However, the article by Catalano et al [11] indicates that the S haematobium/S bovis hybrids that they and others have studied over the past several years can infect rodents. This potential example of what might occur due to hybrid vigor is unsettling from the public health perspective, because it opens the prospect of new potential avenues for transmission accomplished by a mixing of the attributes of different schistosome taxa.

The time to begin to consider the possibility of animal reservoirs and determine whether they actively contribute to transmission to humans is now. It is likely that their role at the present time may not be critical, because human-to-snail-to-human transmission is currently efficient and almost certainly the primary mode by which humans now become infected. However, that word yet is still there to confront us. As current programs successfully bring prevalence and intensity in people to very low levels, will animal reservoirs harboring S mansoni or S haematobium (or possibly hybrid versions) be sufficient to continue transmission to humans? Is it also conceivable that increased transmission through reservoir hosts could alter fundamental properties—like virulence—for parasites that had previously been shaped evolutionarily by interactions with humans? We simply do not know. The use of molecular tools to identify schistosomes in the studies reported by Catalano et al [11] represents a way forward if we are to understand the potential role(s) of animal reservoirs in the transmission of schistosomes most often referred as only using humans as definitive hosts. Clever additions to the molecular tool kit, including the means to detect the definitive host of origin or to determine whether rodent-borne vs human-borne parasites have non-overlapping cycles of transmission, would be most welcome. It is encouraging to see new tools brought into use to solve old questions raised over 100 years ago by those who thought deeply about the biology and life cycles of these debilitating helminth pathogens.

Notes

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

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