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PATOGENESISPATOGENESISMALARIAMALARIA
RACHMAT HIDAYAT, dr. RACHMAT HIDAYAT, dr. M.SiM.Si
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Pokok BahasanPokok Bahasan
• Jenis plasmodium• Respon imun• Mekanisme patogenesis
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PlasmodiumPlasmodiumHidup di tubuh manusia dan tubuh nyamuk• Pada tubuh manusia (asexual). - P falciparum --> M. tropica - P. vivax --> Mal. Tertiana - P. malariae --> Mal. Kuartana - P. ovale --> jarang ada di Indonesia - P. knowlesi• Pada tubuh nyamuk (sexual) -->
sporogoni
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Cara penularan malariaCara penularan malaria
Penderita Anopheles
Anopheles terinfeksiOrang sehat
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SIKLUS HIDUP PARASITSIKLUS HIDUP PARASIT
• Siklus hidup semua parasit malaria pd manusia adalah sama mengalami stadium-stadium yg berpindah dari vektor nyamuk ke manusia dan kembali ke nyamuk lagi
• Terdiri dari:1. siklus hidup pada manusia2. Siklus hidup pada nyamuk anopheles
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Life cycleLife cycleCDC (Center Disease Control,) 2013.
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PlasmodiumPlasmodium development in the mosquito development in the mosquito
Ghosh et al. (2003) Trends in Parasitology 19:94-101.
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Ring-stage trophozoite
Mature trophozoite
Schizont (segmenter)
Free merozoites
Trophozoite maturation
Schizogony
Rupture
Re-invasion
Gametosit
Tubuh nyamuk
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Malaria transmission cycle from Malaria transmission cycle from mosquito to humanmosquito to human
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RESPONS IMUN
Efektif Tidak efektif Patologis • Anemia
• Malaria otak
Sterilisasi Hiperparasitemia •Respiratory-
Infeksi distress
Immune response
Parasitemia
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PATOGENESIS PATOGENESIS MALARIAMALARIA
• MEKANISME OBSTRUKSI KAPILER :– Rosetting ( penggerombolan eritrosit )– Sitoadherensi ( perlekatan eritrosit ke
endothel )• MEKANISME IMUNOLOGIK : pembentukan
sitokin, nitrit oxide • MEKANISME PENINGKATAN TEKANAN
INTRA-CRANIAL • MEKANISME ENDOTOKSIN
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TISSUE DAMAGE CAUSED BY MALARIA INFECTIONTISSUE DAMAGE CAUSED BY MALARIA INFECTION
GENERALBy all Plasmodium
SPECIFICBy P. falciparum
TOXIN
DESTRUCTION OFERYTHROCYTE
ERYTHROCYTESTICKY
CAPILLARY BLOCKINGAnoxia, thrombosis and
hemorrhage
LOCAL DAMAGEBrain, pancreas, intestine
DEGENERATION OFPARENCHYM ORGANS
ORGAN DYSFUNCTION - Heart weakening- Liver dysfunction
ANEMIA,ANOXIA
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MEKANISME PATOGENESISMEKANISME PATOGENESIS• Merozoit Eritrosit EP
– Perubahan struktur & biomolekuler selTransport membran seldeformabilitasRheologi knobNeoantigen sitoadherenSekuestrasi roseting
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ERITROSIT PARASITERITROSIT PARASIT• Memulai proses patologik infeksi
malaria falsiparum• Kemampuan adhesi: endotel
vaskular, eritrosit, EP• Deformabilitas sitoadheren dan
sekuestrasi• Variasi antigenik terlindung dari
mekanisme pertahanan tubuh• Antigen RESA• GPI (toksin malaria)
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ANTIGEN RESAANTIGEN RESA•Stadium cincin•Antibodi parasitemia
Inhibisi parasit•Stadium matur: hilang
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• Deformation of pRBCs resulting in “knobs” on the RBC surface– Plasmodium falciparum
Expressed Membrane Protein (PfEMP1)
– Endothelial cell ligands• CD36• ICAM-1• VCAM-1• P-selectin• Chondroitin sulfate A
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PfEMP1 on knob structurePfEMP1 on knob structure
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• Kemampuan adhesif pertahanan hidup parasit
• Sitoadheren molekul adhesif:– EP– Endotel vaskular
SITOADHERENSITOADHEREN
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ERITROSIT TERINFEKSI
ERITROSIT TERINFEKSI
ERITROSIT TIDAK
TERINFEKSI
SEKUESTRASI
ERITROSIT TERINFEKSI
ENDOTEL VASKULER
Pf-EMP-I
knob
Pf-EMP-IHSP-I
ERITROSIT TERINFEKSI CD3
6
ICAM-I
TSP
VCAM
ELAM
ENDOTEL VASKULER
ROSET
PARASIT
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PRBC
Knob
MEKANISME SITOADHERENMEKANISME SITOADHEREN
ENDOTEL
EP
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MEKANISME MOLEKULERMEKANISME MOLEKULER
TSP-Rp
TSP
TSP
TSP-RE
ENDOTEL
PRBC
CD36-GPIV-R TSP &CD36/GPIV-R
CD36/GPIV-R
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MEKANISME PATOGENESISMEKANISME PATOGENESIS
ENDOTELICAM-1 ELAM VCAM TSPCD-36
Pf-EMP-1
PRBC
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MOLEKUL ADHESIF MOLEKUL ADHESIF ENDOTEL VASKULARENDOTEL VASKULAR
• CD-36, trombospondin, ICAM-1, ELAM-1, VCAM-1, E-Selektin, kondroitin sulfat
• Distribusi dan ekspresi tidak sama
• Malaria fatal induksi reseptor endotel sistemik (ICAM-1, E-Selektin)
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PERUBAHAN ENDOTELPERUBAHAN ENDOTEL
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SEKUESTRASISEKUESTRASI• Sitoadheren sekuestrasi EP di
mikrovaskular organ-organ vital:– otak– paru– usus– jantung, dllPatologik malaria berat
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ROSETINGROSETING• 1 EP matur dikelilingi + 10 eritrosit non
parasit• Tidak terdapat pada semua parasit• Dipengaruhi oleh :
– Limpa– Antibodi PfHRP-1– Endemisitas
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MEKANISME PATOGENESIS: ROSSETTINGMEKANISME PATOGENESIS: ROSSETTING
PRBC
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ROSETINGROSETING
• Peranan :– Obstruksi mikrovaskular sitoadheren– Melindungi EP terhadap fagositosis
• Peranan dalam patogenesa malaria berat
• Bukan gambaran yang menonjol
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GPI
, Lymphotoxin
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SITOKINSITOKIN• Malaria berat TNF-, IFN-, IL-1,
IL-6, LT, IL-3• Peranan sitokin• TNF-
Peranan secara lokalTNF perifer proses
patologi
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SITOKINSITOKIN
• TNF- : -Upregulation ligand endothel ICAM-1
- Induksi NO endotel - Glukoneogenesis
hipoglikemia - Diseritropoesis
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SITOKINSITOKIN
• TNF-, IL-6 + : parasitemia, bilirubin,
suhu , roseting
- : trombosit
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Anemia pada infeksi malariaAnemia pada infeksi malariaHemolisis terjadi melalui mekanisme : 1. Sel darah merah terinfeksi lisis oleh karena parasit (stadium sison) 2. Destruksi sel darah merah melalui mekanisme autoimun 3. Sel darah merah terinfeksi dieliminasi di organ limpa 4. Erythropoiesis yang tidak effektif
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INVASI ERITROSIT
RING
TROPOZOITSIZONPECAH
MEROZOITANEMIA
GPI
TNF
DEMAMHIPOGLIKEMI
OBSTRUKSIMIKROVAS.
HIPOXIAHIPOGLIKEMI
SEREBRAL, RENAL, PARU LAIN KOMPLIKASI
EFEK FISIKPADA ERI MANUSIA
EFEKMETABOLIKPARASIT
KNOB, SITOADERDEFORM HILANG
PEMAKAIAN GLUHIPOGLIKEMILAKTIK ASIDOSIS
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INVASI ERITROSIT
RING
TROPOZOITSIZONPECAH
MEROZOIT
GPI
TNF
DEMAMHIPOGLIKEMI
MATURASI.
OBSTRUKSIMIKROVASKULER
SEREBRAL, RENAL, PARU LAIN KOMPLIKASI
K N O B SSEKUESTRASI PERIFER pada PO2 rendah
SICKLING
Replikasi
Hipoglikemi
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UDAH LAH YAAANGANTUK