““MALARIA”MALARIA”Binding of Malaria Parasites to Host Binding of Malaria Parasites to Host

cellscells

Advanced cell biology II, class presentationAdvanced cell biology II, class presentationKedar Ghimire,Kedar Ghimire,

April 5, 2006April 5, 2006

EM of a plasmodium

Why do we need to concern about Malaria Why do we need to concern about Malaria and the tiny mosquito?and the tiny mosquito?

• Infects 200-300 million people every Infects 200-300 million people every year!year!

• Kills 1-3 million people!!! Kills 1-3 million people!!!

• Kills one child every 30 seconds!!!!!Kills one child every 30 seconds!!!!!

• Originated in AfricaOriginated in Africa

• In 1898, Ronald Ross discovered In 1898, Ronald Ross discovered plasmodium in Anopheles plasmodium in Anopheles mosquitoes mosquitoes

• In past, common in the whole world In past, common in the whole world and mostly in Rome, name derived and mostly in Rome, name derived from the Italian (male-aria)from the Italian (male-aria)

Brief History of Malaria Brief History of Malaria

Malarial parasiteMalarial parasite

• Caused by four species of Caused by four species of PlasmodiumPlasmodium

• Transmitted by any of 60 species of Transmitted by any of 60 species of Anopheles among 400 speciesAnopheles among 400 species

• Plasmodium Falciparum- the most Plasmodium Falciparum- the most dangerous species and luckily ,the dangerous species and luckily ,the intensely studied oneintensely studied one

Life cycle of Plasmodium Life cycle of Plasmodium • The life cycle of The life cycle of PlasmodiumPlasmodium is is

extraordinarily complexextraordinarily complex

Life cycle of Plasmodium Falciparum

Binding of parasite to mosquito Binding of parasite to mosquito cellscells• Parasites tend to attack specific tissues of Parasites tend to attack specific tissues of

mosquitomosquito• Hypothesis, specific ligands- specific receptors Hypothesis, specific ligands- specific receptors

binding binding • Specific recognition event, evidence is there to Specific recognition event, evidence is there to

support it.support it.• Sporozoites have surface protein called CS protein Sporozoites have surface protein called CS protein

and TRAP.and TRAP.• The protein Saglin- a salivary-gland receptor for The protein Saglin- a salivary-gland receptor for

parasites (its ability to bind the sporozoite surface parasites (its ability to bind the sporozoite surface protein TRAP protein TRAP

• Laminins expressed in the midgut epithelial cells Laminins expressed in the midgut epithelial cells thought to bind malaria parasitesthought to bind malaria parasites

Merozoite invasion of red blood cellsMerozoite invasion of red blood cells

Bannister et al., 1975, Parasitology, 71, 483-491

Apical adhesion

Binding of parasite to Binding of parasite to mammalian host cellsmammalian host cells• Plasmodium sporozoites successfully Plasmodium sporozoites successfully

invades liverinvades liver

• They also express a surface protein They also express a surface protein CS and TRAP(SSP2)- sporozoite CS and TRAP(SSP2)- sporozoite ligands, (STARP, LSA-3)ligands, (STARP, LSA-3)

• CS binds to hepatocyte microvilli on CS binds to hepatocyte microvilli on HSPG and CSPGHSPG and CSPG

 

Change in Rbc‘s shape: knob formation

Entry into red blood cells

Possible explanation for binding of sporozoites to Possible explanation for binding of sporozoites to hepatocyteshepatocytes

http://trc.ucdavis.edu/mjguinan/apc100/modules/Digestive/mammal/liver5/liver.html

Plasmodium and problems for immune Plasmodium and problems for immune systemsystem

• Toxins released during growth, reproduction Toxins released during growth, reproduction or rupture of red blood cellsor rupture of red blood cells

• Malaria parasites hide from immune system Malaria parasites hide from immune system (Nature, 2005)(Nature, 2005)

• Plasmodium falciparumPlasmodium falciparum constantly changes constantly changes the appearance of a protein pfEMP1 it the appearance of a protein pfEMP1 it deposits on infected RBCsdeposits on infected RBCs

• They mainly damage Red blood cellsThey mainly damage Red blood cells

Prospects for Anti malarial vaccines, Prospects for Anti malarial vaccines, drugs, genetic methods????drugs, genetic methods????

• Anti-malarial vaccines- not yet Anti-malarial vaccines- not yet

• Chloroquine, mefloquine etc- resistance and side Chloroquine, mefloquine etc- resistance and side effectseffects

• Genetically engineered mosquitoes Genetically engineered mosquitoes

• Organisations funding the malarial research- Organisations funding the malarial research- UNDP, WHO, The Wellcome trust, Gates UNDP, WHO, The Wellcome trust, Gates foundation etcfoundation etc

ReferencesReferences• Sultan AA, Molecular mechanisms of malaria sporozoite motility and invasion of host Sultan AA, Molecular mechanisms of malaria sporozoite motility and invasion of host

cells,1999, Int Microbiolcells,1999, Int Microbiol• Cerami C. et al (1992), The basolateral domain of the hepatocyte plasma membrane Cerami C. et al (1992), The basolateral domain of the hepatocyte plasma membrane

bears receptors for the circumsporozoite protein, Cell, Cell press bears receptors for the circumsporozoite protein, Cell, Cell press • Kappe S. et al (2001), Exploring the transcriptome of the malaria sporozoite stage , Kappe S. et al (2001), Exploring the transcriptome of the malaria sporozoite stage , PNASPNAS • FidockFidock DA DA, , BottiusBottius E E, , BrahimiBrahimi K K, , MoelansMoelans II II, , AikawaAikawa M M, , KoningsKonings RN RN, , CertaCerta U U, , OlafssonOlafsson P P, ,

KaidohKaidoh T T, , AsavanichAsavanich A A, et al.,1994, Mol Biochem parasitol, et al.,1994, Mol Biochem parasitol• DaubersiesDaubersies P P, , Thomas AWThomas AW, , Millet PMillet P, , BrahimiBrahimi K K, , LangermansLangermans JA JA, , OllomoOllomo B B, , BenMohamedBenMohamed L L, ,

SlierendregtSlierendregt B B, , ElingEling W W, , Van Van BelkumBelkum A A, , DubreuilDubreuil G G, , MeisMeis JF JF, , Guerin-Guerin-MarchandMarchand C C, , CayphasCayphas S S, , Cohen JCohen J, , Gras-Masse HGras-Masse H, , DruilheDruilhe PP.et al, 2000, .et al, 2000, Nature-MedicineNature-Medicine

• http://www.rph.wa.gov.au/labs/haem/malaria/history.htmlhttp://www.rph.wa.gov.au/labs/haem/malaria/history.html• http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/J/Junctions.htmlhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/J/Junctions.html• http://news.bbc.co.uk/2/hi/health/4419835.stmhttp://news.bbc.co.uk/2/hi/health/4419835.stm• Consuelo Pinzon-Ortiz. Et al, 2005, Consuelo Pinzon-Ortiz. Et al, 2005, The binding of the circumsporozoite protein to The binding of the circumsporozoite protein to

cell surface proteoglycans is required for plasmodium sporozoite attachment to cell surface proteoglycans is required for plasmodium sporozoite attachment to target cells, J. Biol. Chemtarget cells, J. Biol. Chem

• http://www.bio.davidson.edu/Courses/Immunology/Students/Spring2003/Lafontaine/http://www.bio.davidson.edu/Courses/Immunology/Students/Spring2003/Lafontaine/malariawebpage.htmmalariawebpage.htm

• http://en.wikipedia.org/wiki/Chloroquinehttp://en.wikipedia.org/wiki/Chloroquine• http://www.wellcome.ac.uk/en/malaria/TheParasite/pfantv1.htmlhttp://www.wellcome.ac.uk/en/malaria/TheParasite/pfantv1.html• http://www.anobase.org/embo_meeting/2005/abstracts/JacobsLorena.pdfhttp://www.anobase.org/embo_meeting/2005/abstracts/JacobsLorena.pdf

THANK YOU ALL FOR YOUR KIND ATTENTION,QUESTIONS?