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Experimental models such as laboratory mice or model cell culture systems have the great advantage to mechanistically answer biological questions. This proven strategy is used by Ngwa and colleagues who used in vitro differentiation of Plasmodium falciparum gametocytes to describe epigenetic changes due to histone acetylation that are likely relevant during parasite transmission from human host to vector (Ngwa et al.). Interaction of parasite and host factors can also reliably be studied in experimental models. Here, Dunst and colleagues identified the microfilament tethering factor moesin as an interacting partner of P. falciparum GPI purified from blood stages parasites (Dunst et al.). The authors show that absence of moesin influences neither life cycle progression nor malaria-related pathology, calling for further studies to identify GPI-binding recognition factors in the host. Analyses in mouse parasites illustrate key elements of the tool-boxes available to parasitological research in experimental model organisms.

This tool-box is also exploited in the contribution by Souza et al.. They apply a murine model of microbial sepsis to test the collateral damage by a pro-inflammatory immune response elicited by a persisting preexisting Toxoplasma gondii infection. The study on neutrophils in cerebral inflammation due to Toxoplasma infection contributed by Biswas and coworkers highlights another benefit of using laboratory mouse models, namely the broad range of antibodies available to identify and characterize specific immune cell subsets, based on signature proteins and cytokines (Biswas et al.). This allowed the authors to show that two distinct populations of inflammatory neutrophils act together to diminish parasite infiltration into the brain and reduce experimental cerebral toxoplasmosis.

Deciphering of immune cell interaction and cellular networks of host responses to parasites often rely on laboratory models. In this RT Bock and colleagues define so-called Th2/1 hybrid cells that combine lineage transcription factors and cytokine expression patterns of CD4⁺ Th1 as well as Th2 cells as integral parts of the immune response to nematodes (Bock et al.). Along the same line, Ahmed and colleagues analyze changes of the nematode-specific T cell response in a coinfection setting with an opposing pathogen (Ahmed et al.). In the helminth field the vast possibilities of working with the free-living model nematode Caenorhabditis elegans are often exploited to extrapolate findings to parasitic nematodes. Here, Midha et al. review the current knowledge and potential new directions to study reciprocal interactions of nematodes with their microbial environment (Midha et al.).

Cell culture and animal models for parasitic diseases often remain suboptimal, and their correlation with the infection of the host species of interest is a frequent matter of debate. Dunst and coworkers review present knowledge on the relevance of cytokines in the etiology of cerebral malaria (Dunst et al.). Although the respective murine model can only offer an incomplete assessment of this major complication of human malaria, it permits the fine resolution of molecular mechanisms involved in the development of cerebral malaria. Dunst et al. integrate findings from the murine experimental malaria model with in vitro observations and results of clinical studies to deduce a potential sequence of pathophysiological events that entails the activation of endothelial cells and leukocyte recruitment and ultimately leads to permeability of the blood-brain barrier and neuroinflammation. Acknowledging the difficulties to establish a suitable model host for human P. falciparum, Cunha and colleagues present a Chlodronate-liposome-based protocol for new world common squirrel monkeys (Saimiri sciureus) to render these hosts susceptible to experimental P. falciparum inoculations by depletion of phagocytes (Cunha et al.). This might substitute the current common practice of surgical splenectomy.

Giardia duodenalis is a cause of chronic diarrheal disease globally, but not every infected host develops symptoms. Pathogenic mechanisms, such as the breakdown of intestinal barriers, have been primarily investigated using human intestinal cell lines, such as CaCo-2 cells. Kraft and colleagues attempt a critical analysis of the value of the latter as a model of pathogenesis based on literature and own observations (Kraft et al.). They propose that this set up rather models asymptomatic colonization and may serve to screen for till date elusive non-host, non-parasite factors precipitating disease.

An appraisal of limitations and pitfalls, underexplored virtues and promises of small rodent models is contributed by Ehret and colleagues. They review illustrative examples and discuss the translational potential of non-standard rodent resources, such as collaborative crosses of Mus musculus, humanized mice, and wildtype rodents (Ehret et al.).

Arguably, instructive models to test novel malaria vaccine candidates would be of very high translational relevance. A vaccine to prevent human malaria is WHO's target by the year 2030 (WHO, 2016b). Two contributions to this RT discuss malaria vaccines. Jaurige and Seeberger review examples, strategy and status of vaccines consisting of carbohydrate antigens against malaria, but also against toxoplasmosis and leishmaniasis (Jaurige and Seeberger). The idea of a live attenuated vaccine has a long history in malaria research. Irradiated or chemically attenuated parasites have been used but may not be the ultimate solution. In that context, Kreutzfeld and coworkers discuss the promise that genetically attenuated Plasmodium spp., which do not develop beyond the liver stages, hold with respect to inducing a protective immune response (Kreutzfeld et al.). They conclude that realizing the potential of such parasites requires earnest investment into murine models to improve their relevance for translation.

We hope that this RT sparks interest for parasitic infections, which remain a research priority in medicine, veterinary medicine, and public health.

SH, TA, and KM were the three editors of the research topic and thus put together the editorial for the RT “Parasite Infections: From experimental models to natural systems.”