C7 Impact of Ascaris-Plasmodium co-infection on antimalarial treatment outcome, re-infection and antimalarial drug resistance (Mockenhaupt)
|Research Group:||Institute of Tropical Medicine and International Health|
|Address:||Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin|
|Supervisor:||Prof. Dr. med. Frank P. Mockenhaupt|
|Doctoral Researcher:||Welmoed van Loon|
State of the art:
Immunomodulation induced by soil-transmitted helminths (STHs) towards Th2 and regulatory
responses counteracts Th1 reactions, which are needed to control Plasmodium falciparum
density but also contribute to malaria pathology. STH-evoked cross-tolerance of TLRs and
non-cytophilic IgGs add to interaction. In most of early and recent studies, Ascaris infection
had beneficial effects on malaria (incidence, parasite density, severity). Immune
mechanisms, e.g. IL-10 production, contribute to malaria parasite clearance following
treatment, i.e., parasite clearance time (PCT), and to recrudescence rate. Artemisininbased
combination therapy (ACT) is the mainstay of malaria treatment but resistance is
emerging, as can be deduced from delayed PCT, ex vivo assays and molecular markers.
In Africa, this development is beginning. We aim at assessing the impact of concurrent Ascaris
infection on (i) ACT treatment outcome and re-infection in Rwandan children, (ii) PCT and ex
vivo results, (iii) biomarkers of antimalarial immunity and inflammation, and (iv) at determining
ACT resistance markers in populations of differing Ascaris prevalence. This project will identify
the role of Ascaris on antimalarial treatment outcome and emergence of ACT resistance.
Previous own work:
In Huye district, Rwanda, we showed since 2009 that P. falciparum and Ascaris occur in
approx. 25% and 35%, respectively; other STHs are rare (<3%). Plasmodium and Ascaris were
not associated, and no interaction (parasite density, manifestation) was observed. The
1st generation PhD student identified artemisinin resistant P. falciparum strains, confirmed
by ex vivo assays including 200 treated patients (unpublished). The 2nd generation PhD student
is analyzing the respective impact of haemoglobinopathies. Methods needed for the project
are established in the working group including clinical trial conduct, follow-up procedures,
typing of pfmdr1/K13 markers of ACT resistance, Plasmodium-monocyte co-culture stimulation
assays as well as cytokine and immune correlate measurements.
Hypotheses and work plan:
1) Ascaris co-infection influences antimalarial (ACT) efficacy, PCT, antimalarial ex vivo assay
results, and reinfection rates. 2) This can be attributed to variations in cytokines and
antimalarial antibodies in Ascaris co-infection. 3) The prevalence of antimalarial resistance
markers varies with population prevalence of Ascaris.
We will assess ACT efficacy, PCT, and ex vivo artemisinin susceptibility among 200
prospectively recruited patients following WHO protocols. STH infection will be determined by
miniFLOTAC and PCR. Children will be followed up for 6 months to assess reinfection rate
(differentiation from recrudescence by PCR). The degree of antimalarial immunity at initiation
of treatment will be assessed by cytokine levels (e.g., IFNy, ILs-6/10), PBMC/monocyte-P.
falciparum stimulation assays (cytokine read-out), and antimalarial antibodies (e.g., RESA,
MSP19-9) and related to efficacy, ex vivo data and re-infection rates in addition to Ascaris coinfection.
Children with recurring parasitaemia or living in villages of known Ascaris prevalence
(to be confirmed by serology) will be sampled and pfmdr1/K13 markers typed.