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

Advanced cell biology II, class presentation Advanced cell biology II, class presentation Kedar Ghimire, Kedar Ghimire,

April 5, 2006 April 5, 2006

EM of a plasmodium

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

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

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

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

• • Originated in Africa Originated in Africa

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

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

Brief History of Malaria Brief History of Malaria

Malarial parasite Malarial parasite

• • Caused by four species of Caused by four species of Plasmodium Plasmodium

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

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

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

extraordinarily complex extraordinarily complex

Life cycle of Plasmodium Falciparum

Binding of parasite to mosquito cells Binding of parasite to mosquito cells

• • Parasites tend to attack specific tissues of mosquito Parasites tend to attack specific tissues of mosquito

• • Hypothesis, specific Hypothesis, specific ligands ligands- - specific receptors binding specific receptors binding

• • Specific recognition event, evidence is there to support it. Specific recognition event, evidence is there to support it.

• • Sporozoites Sporozoites have surface protein called CS protein and have surface protein called CS protein and TRAP. TRAP.

• • The protein The protein Saglin Saglin- - a salivary a salivary- -gland receptor for parasites gland receptor for parasites (its ability to bind the (its ability to bind the sporozoite sporozoite surface protein TRAP surface protein TRAP

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

Merozoite Merozoite invasion of red blood cells invasion of red blood cells

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

Apical adhesion

Binding of parasite to mammalian Binding of parasite to mammalian host cells host cells

• • Plasmodium Plasmodium sporozoites sporozoites successfully successfully invades liver invades liver

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

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

Change in Rbc‘s shape: knob formation

Entry into red blood cells

Possible explanation for binding of Possible explanation for binding of sporozoites sporozoites to to hepatocytes hepatocytes

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

Plasmodium and problems for immune system Plasmodium and problems for immune system

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

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

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

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

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

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

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

• • Genetically engineered mosquitoes Genetically engineered mosquitoes

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

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

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

bears receptors for the bears receptors for the circumsporozoite circumsporozoite protein, Cell, Cell press protein, Cell, Cell press • • Kappe Kappe S. et al (2001), Exploring the S. et al (2001), Exploring the transcriptome transcriptome of the malaria of the malaria sporozoite sporozoite stage , stage ,

PNAS PNAS • • Fidock Fidock DA DA, , Bottius Bottius E E, , Brahimi Brahimi K K, , Moelans Moelans II II, , Aikawa Aikawa M M, , Konings Konings RN RN, , Certa Certa U U, , Olafsson Olafsson P P, ,

Kaidoh Kaidoh T T, , Asavanich Asavanich A A, et al.,1994, Mol , et al.,1994, Mol Biochem Biochem parasitol parasitol • • Daubersies Daubersies P P, , Thomas AW Thomas AW, , Millet P Millet P, , Brahimi Brahimi K K, , Langermans Langermans JA JA, , Ollomo Ollomo B B, , BenMohamed BenMohamed

L L, , Slierendregt Slierendregt B B, , Eling Eling W W, , Van Van Belkum Belkum A A, , Dubreuil Dubreuil G G, , Meis Meis JF JF, , Guerin Guerin- -Marchand Marchand C C, , Cayphas Cayphas S S, , Cohen J Cohen J, , Gras Gras- -Masse H Masse H, , Druilhe Druilhe P P.et .et al, 2000, al, 2000, Nature Nature- -Medicine Medicine

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

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

• • http://www.bio.davidson.edu/Courses/Immunology/Students/Spring20 http://www.bio.davidson.edu/Courses/Immunology/Students/Spring2003/Lafontaine/m 03/Lafontaine/m alariawebpage.htm alariawebpage.htm

• • http://en.wikipedia.org/wiki/Chloroquine http://en.wikipedia.org/wiki/Chloroquine • • http://www.wellcome.ac.uk/en/malaria/TheParasite/pfantv1.html http://www.wellcome.ac.uk/en/malaria/TheParasite/pfantv1.html

• • http://www.anobase.org/embo_meeting/2005/abstracts/JacobsLorena. http://www.anobase.org/embo_meeting/2005/abstracts/JacobsLorena.pdf pdf

THANK YOU ALL FOR YOUR KIND ATTENTION, QUESTIONS?