Karakterisering van myeloïde cellen tijdens trypanosoom-gemedieerde encefalitis

Karen De Vlaminck Kiavash Movahedi
Aan de hand van verschillende experimentele analyses werd het mechanisme achterhaald dat aan de basis ligt van trypanosoom-gemedieerde encefalitis (herseninflammatie) en werd de rol van het myeloïde cel-compartiment (een subsectie van immuuncellen) in hersenimmunopathologie onderzocht. Onze resultaten bieden een nieuwe kijk op het ziekteverloop van trypanosoominfecties.

Afrikaanse slaapziekte: nieuwe aspecten aan het licht gebracht

AFRIKAANSE SLAAPZIEKTE: NIEUWE ASPECTEN AAN HET LICHT GEBRACHT

Slaapziekte eist jaarlijks het leven van duizenden Afrikanen.

Slaapziekte komt voor in grote delen van sub-Sahara Afrika. De ziekte wordt veroorzaakt door een parasiet, de trypanosoom, die op de mens wordt overgedragen door de tseetseevlieg. Bij infectie ervaren patiënten initieel milde symptomen zoals hoofdpijn en koorts, maar in een later stadium wordt de ziekte gekenmerkt door ernstigere problemen. Patiënten ondervinden dan onder meer neurologische symptomen zoals stoornissen in slaapritme –vandaar de naam slaapziekte. Indien de ziekte niet tijdig wordt behandeld, wordt ze fataal. Zo eist slaapziekte jaarlijks het leven van duizenden Afrikanen.

Uit onderzoek in diermodellen blijkt dat sterfte geen rechtstreeks gevolg is van de parasitaire infectie, maar dat de patiënt eerder bezwijkt onder de schade aangericht door zijn eigen immuunsysteem (immunopathologie). Het immuunsysteem is namelijk een defensiemechanisme van het lichaam dat ons in eerste instantie beschermt tegen ziekteverwekkers zoals trypanosomen, maar tegelijkertijd worden daarbij ook onze lichaamseigen weefsels onder vuur genomen. In het algemeen wordt de doodsoorzaak van slaapziekte toegeschreven aan extensieve leverschade, anemie (tekort aan rode bloedcellen) en meervoudig orgaanfalen.

 

Nieuw aandachtspunt in slaapziekte: de hersenen.

Gezien een laat stadium van infectie gepaard gaat met neurologische problemen, vermoedden wij dat –naast bovengenoemde algemeen veronderstelde doodsoorzaken– ook immunopathologie in de hersenen potentieel een belangrijke rol speelt.

De hersenen worden begrensd door drie barrières: de bloed-hersenbarrière, de bloed-hersenvliesbarrière en de bloed-cerebrospinale vloeistof (CSF)-barrière. Samen zorgen ze ervoor dat de infiltratie van onder meer immuuncellen (cellen van het immuunsysteem) vanuit de bloedsomloop naar de hersenen wordt geblokkeerd. Dit suggereert dat er geen immuuncellen in de hersenen aanwezig zijn. Daar is echter één belangrijke uitzondering op: de microglia. De microglia zijn hersen-residente immuuncellen die reeds sinds de geboorte in de hersenen aanwezig zijn en de hersenomgeving aftasten op zoek naar gevaar. In normale omstandigheden zijn dat dus de enige immuuncellen die in de hersenen aanwezig zijn. Wanneer de hersenomgeving wordt verstoord, daarentegen, bijvoorbeeld bij infectie, kunnen de hersenbarrières hun integriteit verliezen waardoor immuuncellen uit de bloedsomloop de hersenen toch kunnen infiltreren. In dat geval zijn zowel hersen-residente microglia als bloed-gerekruteerde immuuncellen in de hersenen aanwezig.

Over de betrokkenheid van de hersenen in slaapziekte is nog maar weinig geweten en met dit onderzoek beoogden wij daar een substantiële bijdrage aan te leveren. Als model werden de hersenen van trypanosoom-geïnfecteerde muizen bestudeerd.

 

Ons onderzoek: innovatief en baanbrekend.

Allereerst illustreerde ons onderzoek dat herseninfiltratie niet uitsluitend optreedt in een geavanceerd stadium van infectie, zoals algemeen wordt aangenomen, maar reeds vroeg in de infectie. Zowel parasieten als bloed-gerekruteerde immuuncellen (waaronder macrofagen) konden reeds vanaf dag 7 na infectie in de hersenen worden gedetecteerd en in de loop van de infectie bleven hun aantallen toenemen. Gepaard gaande met die progressieve herseninfiltratie, werden de hersen-residente immuuncellen, de microglia, gradueel geactiveerd en vermenigvuldigden zich ter plaatse.

Vervolgens wensten we na te gaan welke infiltratieroute de parasieten en bloed-gerekruteerde immuuncellen gebruikten om de hersenen te infiltreren –m.a.w. welke van de drie hersenbarrières hun integriteit hadden verloren– en of er een ruimtelijk verband was tussen beide. Drie complementaire experimentele analyses identificeerden bloed-CSF-barrièreverstoring als het primaire mechanisme. In een laat stadium van infectie waren namelijk zowel trypanosomen als immuuncellen via het CSF (het vocht waarin de hersenen baden) de hersenen binnengedrongen.

Tot slot werd er gezocht naar een eerste indicatie over de functies van hersen-residente microglia en bloed-gerekruteerde macrofagen –de overheersende immuuncelpopulaties in de hersenen van laat stadium geïnfecteerde muizen. Beide immuuncelpopulaties vertoonden een pro-inflammatoir karakter: ze bevorderden de aantrekking van additionele immuuncellen naar de hersenen. CCR2-knockout muizen[1], die na trypanosoominfectie significant hogere overlevingskansen hebben dan wild type muizen, vertoonden een reductie in het aantal immuuncellen in de hersenen, terwijl het aantal parasieten in de hersenen van beide muismodellen vergelijkbaar was. Bijgevolg lijkt het aannemelijk te veronderstellen dat het pro-inflammatoir karakter van residente microglia en bloed-gerekruteerde macrofagen rechtstreeks bijdraagt tot fatale immunopathologie.

Ter conclusie biedt dit onderzoek dus een nieuwe kijk op het ziekteverloop tijdens trypanosoominfecties. Tot enkele jaren geleden werd in de literatuur namelijk algemeen beschreven dat trypanosomen er pas in een laat stadium van infectie in slagen om via de bloed-hersenbarrière de hersenen te infiltreren. Onze resultaten leveren echter sterk experimenteel bewijs dat dit dogma over het tijdstip waarop en de route waarlangs trypanosomen de hersenen bereiken herzien moet worden. Wij hebben namelijk aangetoond dat herseninvasie reeds tijdens een vroeg stadium van infectie optreedt en dat parasitaire en cellulaire infiltratie via de bloed-CSF-barrière (en niet de bloed-hersenbarrière) aan de basis ligt van de herseninfectie. Bovendien suggereren onze data eveneens dat immunopathologie in de hersenen potentieel dé fatale gebeurtenis vormt, wat ook het huidige paradigma rond de doodsoorzaak van slaapziekte in vraag stelt.

 

De weg naar het uitroeien van Afrikaanse slaapziekte ligt open…

Het voortzetten van ons onderzoek is essentieel in het verder ontrafelen van de tot op heden ondermaats belichte aspecten in slaapziekte, wat potentieel cruciaal is in de zoektocht naar efficiëntere interventiestrategieën. Het uitroeien van slaapziekte zou de gezondheidsproblematiek en de socio-economische toestand op het Afrikaanse continent drastisch verbeteren. Echter, gezien de Westerse wereld quasi zuiver winst-gericht te werkt gaat, gaan algemeen weinig middelen uit naar onderzoek voor Afrikaanse ziektes. Tegenwoordig begint men echter in te zien dat door de huidige handels-, migratie- en reismentaliteit in onze maatschappij, Afrikaanse ziektes snel kunnen overwaaien naar andere werelddelen. Daarom zijn wij hoopvol dat farmaceutische bedrijven en/of overheden in de (nabije) toekomst steeds meer zullen willen investeren in dergelijk onderzoek.

 

[1] CCR2-knockout muizen zijn genetisch gemodificeerde muizen die veel minder monocyten in hun bloedsomloop hebben dan wild type (‘normale’) muizen; ze vertonen dus logischerwijs minder (monocytafgeleide) macrofaagrekrutering naar de hersenen.

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Universiteit of Hogeschool
Master of Science in de Bio-ingenieurswetenschappen
Publicatiejaar
2016
Promotor(en)
Prof. Dr. ir. Jo Van Ginderachter
Kernwoorden
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