Trypanosomes of the Trypanosoma genus are protozoan haemoflagellates that can infect animals from all vertebrate classes, including warm-blooded mammals and birds as well as cold-blooded amphibians, reptiles, and fish. This genus contains human and animal pathogens, including the intracellular Trypanosoma cruzi (causing Human American Trypanosomiasis or Chagas’ disease), the extracellular T. brucei rhodesiense and T. brucei gambiense (causing Human African Trypanosomiasis or Sleeping Sickness) and T. congolense, T. vivax and T. b. brucei (causing Animal African Trypanosomiasis or Nagana) (Radwanska et al., 2018; Simpson et al., 2006). Among these, salivarian trypanosomes such as T. brucei ssp. live extracellularly in the bloodstream or tissue fluids of their host. For example, T. vivax can multiply rapidly and is evenly distributed throughout the cardiovascular system, T. congolense tends to aggregate in small blood vessels, whereas T. brucei especially can extravasate and multiply in interstitial tissues (reviewed by Magez and Caljon, 2011). Pathologically, anaemia appears to be a factor common to infections with most if not all trypanosomes although with different underlying causative mechanisms. These include, among others, erythrophagocytosis by macrophages (Cnops et al., 2015; Guegan et al., 2013), hemodilution (Naessens, 2006), erythrolysis through intermembrane transfer of variant surface glycoprotein (VSG) from trypanosomes to erythrocytes (Rifkin and Landsberger, 1990), oxidative stress from free radicals (Mishra et al., 2017) and mechanical damage through direct interaction of trypanosomes with erythrocytes surface (Boada-Sucre et al., 2016).

Immunologically, infections with trypanosomes are often associated with dysfunction and pathology related to exacerbated innate and adaptive immune responses (reviewed by Radwanska et al., 2018; Stijlemans et al., 2016). Initially, it was believed that antibody-dependent complement-mediated lysis was the major protective mechanism involved in early parasite control (Krettli et al., 1979; Musoke and Barbet, 1977). However, later studies revealed that at low antibody levels, trypanosomes can efficiently remove surface-bound antibodies through an endocytosis-mediated mechanisms (Engstler et al., 2007), and that complement C5-deficient mice are able to control the first-peak parasitaemia similarly to wild-type mice (La Greca et al., 2014). Instead, innate immune mediators such as IFNγ, TNFα, and nitric oxide (NO) were shown to be indispensable for the control of first-peak parasitaemia, through direct and indirect mechanisms (reviewed by Radwanska et al., 2018). In the early phase of infection, the timely induction of IFNγ by NK, NKT, and CD8⁺ cells Cnops et al., 2015 followed by the production of TNFα and NO by IFNγ-primed macrophages (Baral et al., 2007; Iraqi et al., 2001; Lopez et al., 2008; Lucas et al., 1994; Magez et al., 1993; Magez et al., 2007; Magez et al., 2006; Magez et al., 2001; Magez et al., 1999; O'Gorman et al., 2006; Sternberg and Mabbott, 1996; Wu et al., 2017) leads to effective control of first-peak parasitaemia. Glycosyl-inositol-phosphate soluble variant surface glycoproteins (GPI-VSG) released from the surface of trypanosomes were found to be the major inducers of TNFα in macrophages, and that such response could be primed by IFNγ (Coller et al., 2003; Magez et al., 2002). When macrophages would encounter GPI-VSG prior to IFNγ exposure, however, their TNFα and NO response would dramatically be reduced (Coller et al., 2003) which, depending on the timing, could either lead to macrophage unresponsiveness or prevent exacerbated inflammatory responses during the first-peak of parasite clearance. Altogether, these data made clear that an early innate immune response is crucial to control the acute phase of trypanosome infection, but that its tight regulation is critical to ensure parasite control as opposed to pathology.

All the findings above took advantage of the availability of several mice models for trypanosome infection using trypanosusceptible or trypanotolerant as well as mutant ‘knock-out’ mice strains. Although mice cannot be considered natural hosts of trypanosomes and do not always recapitulate all features of natural infections, the availability of such models allowed to gain insights into the general biology of trypanosomes, their interaction with and evasion of the host immune system, as well as into various aspects related to vaccine failure, antigenic variation, and (uncontrolled) inflammation (Magez and Caljon, 2011). The use of knock-out strains for example, shed specific light on the role of various cytokines, particularly TNFα, IFNγ, and IL-10, in the control of parasitaemia and in the induction of pathological conditions during infection (reviewed in Magez and Caljon, 2011). It would be ideal to be able to follow, in vivo, the early host responses to the infection and visualise the trypanosome response to the host’s attack. However, due to the lack of transparency of most mammalian hosts, this has not yet been feasible.

We recently reported the establishment of an experimental trypanosome infection of zebrafish (Danio rerio) with the fish-specific trypanosome Trypanosoma carassii (Dóró et al., 2019). In the latter study, by combining T. carassii infection of transparent zebrafish with high-resolution high-speed microscopy, we were able to describe in detail the swimming behaviour of trypanosomes in vivo, in the natural environment of blood and tissues of a live vertebrate host. This led to the discovery of novel attachment mechanisms as well as trypanosome swimming behaviours that otherwise would not have been observed in vitro (Dóró et al., 2019). Previous studies in common carp (Cyprinus carpio), goldfish (Carrassius aurata) and more recently zebrafish, demonstrated that infections with T. carassii present many of the pathological features observed during human or animal trypanosomiasis, including a pro-inflammatory response during first-peak parasitaemia (Kovacevic et al., 2015; Oladiran et al., 2011; Oladiran and Belosevic, 2009) polyclonal B and T cell activation (Joerink et al., 2007; Joerink et al., 2004; Lischke et al., 2000; Ribeiro et al., 2010; Woo and Ardelli, 2014) and anaemia (Dóró et al., 2019; Islam and Woo, 1991; McAllister et al., 2019). These shared features among human and animal (including fish) trypanosomiases suggest a commonality in (innate) immune responses to trypanosomes across different vertebrates.

Zebrafish are fresh water cyprinid fish closely related to many of the natural hosts of T. carassii (Kent et al., 1993; Simpson et al., 2006) and are a powerful model species owing to, among others, their genetic tractability, large number of transgenic lines marking several immune cell types, knock-out mutant lines and most importantly, the transparency of developing embryos allowing high-resolution in vivo visualisation of cell behaviour (Benard et al., 2015; Bertrand et al., 2010; Ellett et al., 2011; Langenau et al., 2004; Lawson and Weinstein, 2002; Page et al., 2013; Petrie-Hanson et al., 2009; Renshaw et al., 2006; White et al., 2008). During the first 2–3 weeks of development, zebrafish are devoid of mature T and B lymphocytes and thus offer a window of opportunity to study innate immune responses (Torraca et al., 2014; Torraca and Mostowy, 2018), especially those driven by neutrophils and macrophages. The response of macrophages and neutrophilic granulocytes towards several viral, fungal and bacterial pathogens has been studied in detail using zebrafish (Cronan and Tobin, 2014; García-Valtanen et al., 2017; Nguyen-Chi et al., 2014; Palha et al., 2013; Ramakrishnan, 2013; Renshaw and Trede, 2012; Rosowski et al., 2018; Torraca and Mostowy, 2018) but never before in the context of trypanosome infections.

Taking advantage of the recently established zebrafish-T. carassii infection model and of the availability of zebrafish transgenic lines marking macrophages and neutrophils as well as il1b- and tnfa-expressing cells, in the current study, we describe the early events of the innate immune response of zebrafish to T. carassii infections. Based on a novel clinical scoring system relying, amongst other criteria, on in vivo real-time monitoring of parasitaemia, we could consistently segregate larvae in high- and low-infected individuals without having to sacrifice the larvae. Between these individuals we always observed a marked differential response between macrophages and neutrophils, especially with respect to their proliferative capacity and redistribution in tissues or major blood vessels during infection. Significant differences were observed in the inflammatory response of macrophages in high- and low-infected individuals and in their susceptibility to the infection. In low-infected individuals, despite an early increase in macrophage number, a mild inflammatory response strongly associated with control of parasitaemia and survival to the infection was observed. Conversely, exclusively in high-infected individuals, we describe the occurrence of large, granular macrophages, reminiscent of foamy macrophages (Vallochi et al., 2018), characterised by a strong inflammatory profile and association to susceptibility to the infection. This is the first report of the occurrence of foamy macrophages during an extracellular trypanosome infection.

In this study, we describe the differential response of macrophages and neutrophils in vivo, during the early phase of trypanosome infection of larval zebrafish. Considering the prominent role of innate immune factors in determining the balance between pathology and control of first-peak parasitaemia in mammalian models of trypanosomiasis (Magez and Caljon, 2011; Radwanska et al., 2018; Stijlemans et al., 2017), the use of transparent zebrafish larvae, devoid of a fully developed adaptive immune system, allowed us to investigate the early events of the innate immune response to T. carassii infection in vivo. After having established a clinical scoring system of infected larvae, we were able to consistently differentiate high- and low-infected individuals, each associated with opposing susceptibility to the infection. In high-infected larvae, which fail to control first-peak parasitaemia, we observed a strong inflammatory response associated with the occurrence of foamy macrophages and susceptibility to the infection. Conversely, in low-infected individuals, which succeeded in controlling parasitaemia, we observed a moderate inflammatory response associated with resistance to the infection. Altogether these data confirm that also during trypanosome infection of zebrafish, innate immunity is sufficient to control first-peak parasitaemia and that a controlled inflammatory response is beneficial to the host.

Using transgenic lines marking macrophages and neutrophils, total cell fluorescence and cell proliferation analysis revealed that T. carassii infection triggers macrophage division, particularly in low-infected individuals. Although to a much lesser extent, neutrophils also responded to the infection by dividing. The total number of neutrophils, however, was comparatively low and likely did not contribute to the total cell fluorescence measured in our whole larvae analysis. It cannot be excluded however, that neutrophils’ viability was affected by the infection and that the number of newly divided neutrophils is only slightly higher than the dying ones. Although neutrophils were recently implicated in promoting the onset of tsetse fly-mediated trypanosome infections in mouse dermis, macrophage-derived immune mediators, such as NO and TNFα were confirmed to played a more prominent role in the control of first-peak parasitaemia and in the regulation of the overall inflammatory response (Caljon et al., 2018).

The observation that in low-infected individuals the number of macrophages was significantly increased by 4–5 dpi, the time point at which clear differences in parasitaemia were apparent between the two infected groups, suggests a role for macrophages, or for macrophage-derived factors in first-peak parasitaemia control. Phagocytosis however, can be excluded as one of the possible contributing factors since motile T. carassii, similar to other extracellular trypanosomes (Caljon et al., 2018; Saeij et al., 2003; Scharsack et al., 2003), cannot be engulfed by any innate immune cell (Video 7). A strong inflammatory response is also not required for trypanosomes control, since in low-infected individuals, only moderate il1b or tnfα expression was observed, mostly in macrophages, as assessed using transgenic zebrafish reporter lines. Our data are in agreement with several previous studies using trypanoresistant (BALB/c) or trypanosusceptible (C57Bl/6) mice that revealed the double-edge sword of pro-inflammatory mediators such as TNFα or IFNγ during trypanosome infection in mammalian models (reviewed by Radwanska et al., 2018; Stijlemans et al., 2007). These studies showed that a timely but controlled expression of IFNγ, TNFα, and NO, contributed to trypanosomes control via direct (Daulouède et al., 2001; Iraqi et al., 2001; Lucas et al., 1994) or indirect mechanisms (Kaushik et al., 1999; Magez et al., 2007; Magez et al., 2006; Mansfield and Paulnock, 2005; Namangala et al., 2001; Noël et al., 2002). Conversely, in individuals in which an uncontrolled inflammatory response took place, immunosuppression and inflammation-related pathology occurred (Namangala et al., 2009; Namangala et al., 2001; Noël et al., 2004; Stijlemans et al., 2016). The stark contrast between the mild inflammatory response observed in low-infected individuals and the exacerbated response observed in high-infected larvae, strongly resembles the opposing responses generally observed in the aforementioned studies in mice. Owing to the possibility to monitor the infection at the individual level, it was possible to observe such responses within a population of outbred zebrafish larvae. Although we were unable to investigate the specific role of Tnfα during T. carassii infection of zebrafish, due to the unavailability of tnfα-/- zebrafish lines or the unsuitability of morpholinos for transient knock-down at late stages of development, we previously reported that recombinant zebrafish (as well as carp and trout) Tnfα, are all able to directly lyse T. brucei (Forlenza et al., 2009). In the same study, we reported that also during Trypanoplasma borreli (kinetoplastid) infection of common carp, soluble as well as transmembrane carp Tnfα play a crucial role in both, trypanosome control and susceptibility to the infection. Thus, considering the evolutionary conservation of the lectin-like activity among vertebrate’s TNFα (Daulouède et al., 2001; Forlenza et al., 2009; Lucas et al., 1994; Magez et al., 1997), it is possible that the direct lytic activity of zebrafish Tnfα may have played a role in the control of first-peak parasitaemia in low-infected individuals. In the future, using tnfα-/- zebrafish lines, possibly in combination with ifnγ reporter or ifnγ-/- lines, it will be possible to investigate in detail the relative contribution of these inflammatory mediators in the control of parasitaemia as well as onset of inflammation.

Video 7

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There are multiple potential explanations for the inability of high-infected larvae to control parasitaemia and the overt inflammatory response. Using various comparative mice infection models, it became apparent that while TNFα production is required for parasitaemia control, a timely shedding of TNFα Receptor-2 (TNFR2) is necessary to limit TNFα-mediated infection-associated immunopathology (Radwanska et al., 2018). Furthermore, during T. brucei infection in mice and cattle, continuous cleavage of membrane glycosyl-phosphatidyl-inisotol (GPI)-anchored VSG (mVSG-GPI) leads to shedding of the soluble VSG-GIP (sVSG-GPI), while the di-myristoyl-glycerol compound (DMG) is left in the membrane. While the galactose-residues of sVSG-GPI constituted the minimal moiety required for optimal TNFα production, the DMG compound of mVSG contributed to macrophage overactivation (TNFα and IL-1β secretion) (Magez et al., 2002; Magez et al., 1998; Sileghem et al., 2001). Although T. carassii was shown to possess a surface dominated by GPI-anchored carbohydrate-rich mucin-like glycoproteins, not subject to antigenic variation (Lischke et al., 2000; Overath et al., 2001), components of its excreted/secreted proteome, together with phospholipase C-cleaved GPI-anchored surface proteins, have all been shown to play a role in immunogenicity (Joerink et al., 2007), inflammation (Oladiran and Belosevic, 2010; Oladiran and Belosevic, 2009; Ribeiro et al., 2010) as well as immunosuppression (Oladiran and Belosevic, 2012). Thus, the over-activation caused by the presence of elevated levels of pro-inflammatory trypanosome-derived moieties, combined with the lack of a timely secretion of regulatory molecules (e.g. soluble TNFR2) that could control the host response, may all have contributed to the exacerbated inflammation observed in high-infected individuals.

Given the differential response observed in low- and high-infected individuals, especially with respect to macrophage distribution and activation, we attempted to investigate the specific role of macrophages in the protection or susceptibility to T. carassii infection. To this end, the use of a cross between the Tg(mpeg1:Gal4FF)^gl2 (Ellett et al., 2011) and the Tg(UAS-E1b:Eco.NfsB-mCherry)^c26 (Davison et al., 2007) line, which would have allowed the timed metronidazole (MTZ)-mediated depletion of macrophages in zebrafish larvae, was considered. Unfortunately, in vitro analysis of the effect of MTZ on the trypanosome itself, revealed that trypanosomes are susceptible to MTZ, rendering the nfsB line not suitable to investigate the role of macrophages (nor neutrophils) during this particular type of infection. Alternatively, we attempted to administer liposome-encapsulated clodronate (Lipo-clodronate) as described previously (Nguyen-Chi et al., 2017; Phan et al., 2018; Travnickova et al., 2015). In our hands, however, administration of 5 mg/ml Lipo-clodronate (3 nl) to five dpf larvae (instead of 2–3 dpf larvae), led to the rapid development of oedema.

Besides differences between the overall macrophage and neutrophil (inflammatory) response, the differential distribution of these cells was also investigated in vivo during infection utilising the transparency of the zebrafish and the availability of transgenic lines marking the vasculature. Neutrophils were never observed inside the cardinal caudal vein although in infected individuals they were certainly recruited and were observed in close contact with the outer vessel’s endothelium. Conversely, macrophages could be seen both outside and inside the vessel and the total proportion differed between high- and low-infected individuals. While in low-infected individuals the majority of macrophages recruited to the cardinal caudal vein remained outside the vessel in close contact with the endothelium, in high-infected individuals the majority of macrophages were recruited inside the caudal vein and were tightly attached to the luminal vessel wall. To our knowledge, such detailed description of the relative (re)distribution of neutrophils and macrophages, in vivo, during a trypanosome infection, has not been reported before.

Interestingly, exclusively in high-infected individuals, by 4 dpi large, round, dark, and granular cells were observed, already under the bright field view, in the lumen of the cardinal caudal vein. These cells were confirmed to be foamy macrophages with high cytoplasmic lipid content. Foam cells, or foamy macrophages have been named after the lipid bodies accumulated in their cytoplasm leading to their typical enlarged morphological appearance (Dvorak et al., 1983), but are also distinguished by the presence of diverse cytoplasmic organelles (Melo et al., 2003). Foam cells have been shown to be typical of atherosclerotic plaques associated to various inflammatory metabolic diseases (e.g. hyperlipidemia, diabetes, insulin resistance and obesity) as well as cancer (e.g. Papillary renal cell carcinoma, Esophageal xanthoma and non-small cell lung carcinoma) and autoimmune diseases e.g. multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis (reviewed in Guerrini and Gennaro, 2019; Saka and Valdivia, 2012). Besides inflammatory diseases, they have also been associated with several (intracellular) infectious diseases, including Leishmaniasis, Chagas disease, experimental malaria, toxoplasmosis, tuberculosis and other intracellular bacterial infections (reviewed in Guerrini and Gennaro, 2019; López-Muñoz et al., 2018; Vallochi et al., 2018) but never before with (extracellular) trypanosome infection. For example, during T. cruzi infection of rat, increased numbers of activated monocytes or macrophages were reported in the blood or heart (Melo and Machado, 2001). Interestingly, trypanosome uptake was shown to directly initiate the formation of lipid bodies in macrophages, leading to the appearance of foamy macrophages (D'Avila et al., 2011). During human Mycobacterium tuberculosis infections, foamy macrophages play a role in sustaining the presence of bacteria and contribute to tissue cavitation enabling the spread of the infection (Russell et al., 2009). Independently of the disease, it is clear that foamy macrophages are generally associated with inflammation, since their cytoplasmic lipid bodies are a source of eicosanoids, strong mediators of inflammation (Melo et al., 2006; Wymann and Schneiter, 2008). In turn, inflammatory mediators such as Prostaglandin E2 benefit trypanosome survival, as shown in Trypanosoma, Leishmania, Plasmodium, and Toxoplasma infections (reviewed in Vallochi et al., 2018). Our results are consistent with these reports as we show the occurrence of foamy macrophages exclusively in individuals that developed high parasitaemia, characterised by a strong pro-inflammatory response, and ultimately succumbed to the infection. Although we did not systematically investigate the exact kinetics of parasitaemia development in correlation with foamy macrophages occurrence, during our in vivo monitoring, we consistently observed that the increase in trypanosome number preceded the appearance of foamy macrophages. It is possible that, in high-infected individuals, foamy macrophages are formed due to the necessity to clear the increasing concentration of circulating trypanosome-derived moieties or of dying trypanosomes. The interaction with trypanosome-derived molecules, including soluble surface (glyco)proteins or trypanosome DNA, may not only be responsible for the activation of pro-inflammatory pathways, but also for a change in cell metabolism. The occurrence of foamy macrophages has been reported for intracellular trypanosomatids (T. cruzi, Leishmania), and arachidonic acid-derived lipids were reported to act as regulators of the host immune response and trypanosome burden during T. brucei infections (López-Muñoz et al., 2018). To our knowledge, our study is the first to report the presence of foamy macrophages during an extracellular trypanosome infection.

The possibility to detect the occurrence of large, granular cells already in the bright field and the availability of transgenic lines that allowed us to identify these cells as macrophages, further emphasizes the power of the zebrafish model. It allowed us to visualise in vivo, in real time, not only their occurrence but also their differential distribution with respect to other macrophages or neutrophils. Observations that we might have missed if we for example were to bleed an animal, perform immunohistochemistry or gene expression analysis. Thus, the possibility to separate high- and low-infected animals without the need to sacrifice them, allowed us to follow at the individual level the progression of the infection and the ensuing differential immune response.

In the future, it will be interesting to analyse the transcription profiles of sorted macrophage populations from low- and high-infected larvae. Given the marked heterogeneity in macrophage activation observed especially within high-infected individuals, single-cell transcriptome analysis, of foamy macrophages in particular, may provide insights in the differential activation state of the various macrophage phenotypes. Furthermore, the zebrafish has already emerged as a valuable animal model to study inflammation and host-pathogen interaction and can be a powerful complementary tool to examine macrophage plasticity and polarisation in vivo, by truly reflecting the complex nature of the environment during an ongoing infection in a live host. Finally, the availability of (partly) transparent adult zebrafish lines (Antinucci and Hindges, 2016; White et al., 2008), may aid the in vivo analysis of macrophage activation in adult individuals.

Altogether, in this study, we describe the innate immune response of zebrafish larvae to T. carassii infection. The transparency and availability of various transgenic zebrafish lines, enabled us to establish a clinical scoring system that allowed us to monitor parasitaemia development and describe the differential response of neutrophils and macrophages at the individual level. Interestingly, for the first time in an extracellular trypanosome infection, we report the occurrence of foamy macrophages, characterised by a high-lipid content and strong inflammatory profile, associated with susceptibility to the infection. Our model paves the way to investigate which mediators of the trypanosomes are responsible for the induction of such inflammatory response as well as study the conditions that lead to the formation of foamy macrophages in vivo.

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 4, 5, 6, 7, and 9.

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Author details

1. Sem H Jacobs

   1. Cell Biology and Immunology Group, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands
   2. Experimental Zoology Group, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands

   Contribution

   Conceptualization, Data curation, Formal analysis, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7482-3438

2. Eva Dóró

   Cell Biology and Immunology Group, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands

   Present address

   Institute of Physiology, Faculty of Medicine, University of Pécs, Pécs, Hungary

   Contribution

   Data curation, Formal analysis, Visualization, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

3. Ffion R Hammond

   Cell Biology and Immunology Group, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands

   Present address

   Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom

   Contribution

   Formal analysis, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

4. Mai E Nguyen-Chi

   DIMNP, CNRS, University of Montpellier, Montpellier, France

   Contribution

   Conceptualization, Supervision, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

5. Georges Lutfalla

   DIMNP, CNRS, University of Montpellier, Montpellier, France

   Contribution

   Conceptualization, Supervision, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

6. Geert F Wiegertjes

   1. Cell Biology and Immunology Group, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands
   2. Aquaculture and Fisheries Group, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

7. Maria Forlenza

   Cell Biology and Immunology Group, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   maria.forlenza@wur.nl

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9026-7320

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