Research Sarah Hendrickx

Abstract

Leishmania parasites are transmitted via the bite of infected female sand flies. Inside this vector, parasites have to overcome different hurdles before they can differentiate into their metacyclic, infective form, during a process which is called metacyclogenesis. This PhD project will focus on the identification of Leishmania infantum genes that can influence the development and metacyclogenesis of parasites in the vector and hereby impact successful transmission from sand fly to vertebrate host. As both up- and downregulation of certain genes may result in enhanced transmission, two different methodologies will be applied to identify potential transmission-related genes, both in collaboration with prof. dr. Ouellette (Quebec, Canada). On the one hand, repeated infection of sand flies with an already established Leishmania COSMID library will allow for selection of more transmissible parasites that harbor those specific COSMIDs containing genes providing a benefit in the vector. Genes responsible for these observed gain-of-functions in the sand fly will be unveiled using COSMID sequencing. On the other hand, loss-of-function will be explored in parallel using a similar approach for a recently developed Leishmania CRISPR-Cas9 library. Ultimately, the identification of genes involved in transmission not only will provide useful insights on the transmission process, but it might also open doors for the development of novel transmission-blocking strategies in the future.

Researcher(s)

• Promoter: Caljon Guy
• Co-promoter: Hendrickx Sarah
• Fellow: Van den Broeck Lauren

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Leishmaniasis is a neglected tropical disease which is transmitted through the bite of female sand flies of the genera Phlebotomus and Lutzomyia. Leishmania infection might provoke several changes in the fly's feeding behaviour, such as an increased biting persistence and a greater tendency to feed on multiple hosts, hereby enhancing parasite transmission. However, recent evidence from malaria research now indicates that the composition of the blood meal might have an equally important impact on vector behavior and parasite transmission. Although the involvement of the host's glucose/insulin metabolism is well-accepted for malaria, its potential involvement in Leishmania infection in vivo has barely been investigated before. This project will aim to evaluate the effects of the overall infection burden in the host on (1) the glucose/insulin levels in host blood; (2) the host's attractiveness and transmission potential to naive sand flies; and (3) sand fly survival, sand fly infection dynamics and final transmission potential with emphasis on the role of glucose/insulin.

Researcher(s)

• Promoter: Hendrickx Sarah

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Parasites of the L. donovani complex generally cause severe, life-threatening visceral infections in which the spleen, liver and bone marrow are severely affected. In some cases, infections only result in mild transient cutaneous lesions. The exact reasons why certain Leishmania species remain in the dermis and do not migrate to the internal organs are still largely unknown. Although several parasite-related factors have already been suggested, the involvement of the host and vector have been largely ignored. Next to some phenotypic parasite traits, such as infectivity and multiplication potential, this aberrant skin tropism might be linked to the ineffective development of granuloma in the skin, which generally clear the parasite burden in the skin, driving infection into the viscera. In this project, the complex interplay between the parasite's (epi-)phenotype, the drug and the host's immune reaction will be explored using dermotropic VL strains derived from cutaneous or visceral infections. The impact of the development of skin granulomas upon infection with the different strains will be compared in relation to their tissue tropism and in vivo drug efficacy and relapse potential.

Researcher(s)

• Promoter: Hendrickx Sarah

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Leishmania donovani is a protozoan parasite that is usually the causative agent of visceral leishmaniasis (VL), an infectious disease which is fatal if left untreated and affects internal organs such as liver, spleen and bone marrow. In some cases, however, infection with this specific parasite species is relatively benign and only causes cutaneous lesions which are comparable with the lesions from parasite species causing cutaneous leishmaniasis (CL). Although some parasite-specific genes have been implicated in the visceralizing capacity of L. donovani, the associated phenotypic factors that are responsible for this change in tissue tropism are not well-understood. Past research already compared some phenotypic features, such as resistance to increasing temperatures and oxidative stress, between VL-causing L. donovani parasites and CL–causing L. major parasites. However, because of their evolutionary distance comparing different parasite species may not be completely correct as next to genetic variations, also phenotypic discrepancies unrelated to human pathology could be present. Therefore, this study aims at identifying the parasite-related phenotypic factors associated with visceralization by using two isogenetic strains. These will be created by phenotype-driven passive parasite selection from the target organs involved (skin vs. spleen) in the in vivo hamster model. After repeated selection of parasites with a specific tissue tropism and subsequent population enrichment, the course of infection with both the VL-causing and CLcausing parasites will be evaluated and compared by bioluminescence imaging. To characterize both parasite populations, the expression levels of A2, a virulence factor that has been associated with visceralization, will be compared and the strains will be characterized phenotypically in order to identify possible pitfalls during the visceralization process.

Researcher(s)

• Promoter: Hendrickx Sarah

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Sarah Hendrickx graduated with great distinction in 2010 in Biomedical Sciences at the University of Antwerp. Under the supervision of prof. Louis Maes at the Laboratory for Microbiology, Parasitology and Hygiene (LMPH), she performed her master thesis entitled 'Use of Leishmania reporter strains for in vitro and in vivo evaluation of antileishmanial drugs'. This way, she became actively involved in the ongoing research on the Leishmania parasite and encouraged her to pursue her research ambitions as a PhD student on an ongoing project at LMPH. After one year, she applied for and obtained the position of mandate assistant. Sarah became responsible for teaching several practical courses, such as 'Parasitology' (Biomedical Sciences and Veterinary Sciences); 'Immunochemistry and Cell Culture' (Biomedical Sciences) and 'Microbiology' (Veterinary Sciences). Despite these ample teaching activities and two maternity leaves, she finalized her PhD thesis, entitled "Emergence of drug resistance in visceral leishmaniasis treatment - Will paromomycin and miltefosine stand the test of time?" in December 2015. Her thesis focused on the emergence of resistance of the Leishmania parasite against all currently used antileishmanial drugs, highlighting the need to combat future emergence of resistance against the few remaining effective antileishmanials. She successfully applied for a FWO-postdoc position and a FWO-Krediet aan Navorsers to continue the work in visceral leishmaniasis in addition of establishing her own independent research line within LMPH with focus on the cutaneous variant of the disease that has not yet been covered at LMPH up until now. In order to obtain sufficient funding for this, she applied for an additional FWO-Krediet aan Navorsers earlier this year. Note: All the chapters of her PhD have been published in high impact international journals

Researcher(s)

• Promoter: Hendrickx Sarah

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Amphotericin B (AmB) is currently implemented as first-line treatment for visceral leishmaniasis (VL) in large parts of the world, while the use of miltefosine (MIL) is endorsed as second option, either in mono- or in combination therapy. However, a cumulative number of treatment failures is being reported, necessitating repeated treatments that may obviously facilitate emergence of resistance. As isolates from clinical relapse patients still demonstrate a 'drug susceptible' phenotype, factors other than intrinsic drug resistance may likely influence treatment outcome. Next to some phenotypic parasite traits, such as infectivity and multiplication potential, treatment failure has also been linked to a decreased drug exposure in particular parasite niches, such as in liver granulomas preventing sterile cure upon drug exposure. In this project, the complex interplay between the parasite's (epi-)phenotype, the drug and the host's immune reaction will be explored using syngeneic VL strains derived from a cure, relapse and resistant background. The impact of the development of granulomas upon infection with the different strains will be compared in relation to the in vitro and in vivo drug efficacy and relapse potential.

Researcher(s)

• Promoter: Hendrickx Sarah

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Amphotericin B (AmB) is currently implemented as first-line treatment for visceral leishmaniasis (VL) in large parts of the world, while the use of miltefosine (MIL) is endorsed as second option, either in mono- or in combination therapy. However, a cumulative number of treatment failures is being reported, requiring the need for repeated treatments that will facilitate emergence of resistance. As isolates from clinical relapse patients generally still demonstrate a 'drug susceptible' phenotype, factors other than intrinsic drug resistance may likely influence treatment outcome. For MIL, increased infectivity and metacyclogenesis potential of the infecting parasites has been suggested, while preliminary observations from our laboratory indicate similarities for AmB. Treatment failure has also been linked to a decreased drug exposure in particular parasite niches, such as in liver granulomas precluding sterile cure upon drug exposure. In this project, the complex interplay between the parasite's (epi-)phenotype, the drug and the host's immune system will be explored using syngeneic VL strains derived from a cure, relapse and resistant background. More in particular, virulence will be compared in the sand fly vector and in in vitro and in vivo laboratory models. The impact of the development of granulomas upon infection with the different strains will be compared in relation to the in vitro and in vivo drug efficacy and relapse potential.

Researcher(s)

• Promoter: Maes Louis
• Co-promoter: Caljon Guy
• Fellow: Hendrickx Sarah

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project