Malaria parasites: virulence and transmission as a basis for intervention strategies

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1 Malaria parasites: virulence and transmission as a basis for intervention strategies Matthias Marti Department of Immunology and Infectious Diseases Harvard School of Public Health

2 The global malaria burden today: WHO Map 2007 Countries or areas considered endemic: % at risk worldwide, 84% in Africa 880k fatal cases/year, 800k in Africa

3 The parasite: mal aria and Marsh Fever AA Hebert, 1851: La Malaria Malaria is an ancient human disease

4 Discovery of the malaria parasite in 1880 B Moloch, 1908: Laveran s fight against malaria A Laveran, 1880/81: Oscillaria malaria

5 Discovery of Anopheles mosquitoes as the vector in 1897 Sir Ronald Ross (R Ross, 1897: Mosquito midgut with oocysts, 7 days post feeding)

Malaria parasites are protozoa of the genus Plasmodium, phylum Apicomplexa Of over 120 species of Plasmodium, only five infect humans: Plasmodium falciparum P.

6 Malaria parasites are protozoa of the genus Plasmodium, phylum Apicomplexa Of over 120 species of Plasmodium, only five infect humans: Plasmodium falciparum P. vivax P. ovale P. malariae P. knowlesi The above five Plasmodium species differ in: Geographical distribution Clinical features Patterns of drug resistance Epidemiology

7 The parasite life cycle in human and mosquito (Miller et al., Nature 2002) - Successions of asexual and sexual replication ensure survival and genetic diversity - Pathology is linked to asexual replication in human red blood cells

a result of synchronization through host

the host cell results in membrane networks

9 I. Asexual red blood cell stage development (Aikawa et al 1977; Marti et al 2005) Cycle length 24h or multiples thereof (48, 72h; depending on species) as a result of synchronization through host circadian rhythm Large-scale remodeling of the host cell results in membrane networks and RBC surface alterations Represents vast majority of parasite stages in the host and is linked to most of morbidity and mortality of the disease

10 P.falciparum invades different RBC stages through multiple invasion pathways More efficient invasion is linked to higher parasitemia

11 P.falciparum infected RBC sequester in deep tissues - Presence of rings stages in the peripheral blood - Enrichment of later stages in tissues (Marchiafava and Bignami, 1894)

12 Sequestration depends on cytoadherence of irbc (MacPherson,1984) Identification of knobs as attachment sites for irbc (Trager et al 1966)

13 Cytoadherence is mediated by recpetor ligand interactions - PfEMP1 is localized to knobs and the major ligand for cytoadherence - Cytoadherence assays identify host receptors in vitro: ICAM-1, CD36, CSA etc

ICAM-1 labeling (brown) and sequestered parasites (Silamut et al 1999).

14 Organ-specific sequestration can be linked to pathology: cerebral malaria and placental malaria Endothelial activation in a malaria infected brain shown by ICAM-1 labeling (brown) and sequestered parasites (Silamut et al 1999). irbc in the intervillous space, some cytoadhere to trophoblasts via CSA (Brabin et al 2004)

15 II. Development of transmission stages Cycle length similar to asexual development except for P.falciparum Upon ingestion by the mosquito: formation of a female macrogamete and 8 male flagellated microgametes Gametocytemia usually very low (1-5% of all parasites)

16 Developing transmission stages are absent from the blood circulation Where and how are they sequestering??

17 Transmission stages can be detected in autopsy case tissues pldh in Brain pldh in Spleen pldh in Spleen (PM96) pldh in Heart PF16 in Spleen (PM96)

18 Developing transmission stages are enriched in the bone marrow Quantitative IHC qrt-pcr

efficient cytoadherence has been measured so

19 Host cell alterations determine tissue enrichment Developing transmission stages are less deformable than healthy RBC and transmission competent mature stages No efficient cytoadherence has been measured so far The biology of the transmission stages is distinct from the asexual parasite

III. Development within the mosquito vector

Exflagellating male gametocytes (IFA/phase)

7-21 days in Anopheles vector - Sporogony

development in oocyst, sporoites migrate to

humans - Only 1-20 sporozoites are released with

21 III. Development within the mosquito vector Oocysts on the outside of the midgut Exflagellating male gametocytes (IFA/phase) Sporozoites in the salivary gland - Cycle length 7-21 days in Anopheles vector - Sporogony produces 10,000-15,000 sporozoites - After development in oocyst, sporoites migrate to salivary glands where they become infectious to humans - Only 1-20 sporozoites are released with a blood meal - Oocyst development represents major bottleneck in the malaria life cycle

22 Vector distribution determines parasite distribution - Anopheles present throughout temperate and tropical regions - In Sub-Saharan Africa: Anopheles arabiensis, A. funestus, A. gambiae

Changes in malaria distribution in the last 100 years (Hay et al 2004) Map represents the distribution of the 4 major species Maximum distribution in preintervention aera around 1900, widest range by

23 Changes in malaria distribution in the last 100 years (Hay et al 2004) Map represents the distribution of the 4 major species Maximum distribution in preintervention aera around 1900, widest range by P.vivax Since 1900 risk area has been reduced by 50% Through successful eradication efforts malaria mostly disappeared from Europe, Russia and USA However: only recently is subsaharan Africa targeted

Current intervention strategies Vaccines Drugs Interventions to control disease RTS,S and GAP.diversity, delivery, mass production? AMA1, MSPs etc diversity?

24 Current intervention strategies Vaccines Drugs Interventions to control disease RTS,S and GAP.diversity, delivery, mass production? AMA1, MSPs etc diversity? All current antimalarials Interventions to control transmission Carter et al, Nat Med 2000?? Primaquine Pfs28, Pfs25, Pfs230 and Pf48/45 efficacy? No effective vaccine, widespread drug resistance No vaccine/drug blocking transmission

Malaria life cycle bottlenecks as targets for interventions 10 12 10 8 Asexual Blood stages 10 11 Macrogametes Sexual Blood stages Oocysts Rupturing oocyst 10 4

25 Malaria life cycle bottlenecks as targets for interventions Asexual Blood stages Macrogametes Sexual Blood stages Oocysts Rupturing oocyst 10 4 Liver Schizont Sprozoites in glands Liver Schizont ~100 Sporozoites Sporozoites in bite Ookinetes Man Mosquito Man Invasion Alavi et al 2003 Invasion

26 Oct 2007: B & M Gates declare eradication within their life time a goal Priorities for eradication: P.vivax New drugs for mass administration and prophylaxis Vaccines and drugs that interrupt transmission New vector control approaches Better diagnostics and surveillance tools Tool kits to scientifically assess and determine health system readiness for moving from control to elimination efforts New approaches to model outcome - Increase in funding for malaria research - Promising data from the field

27 A reminder from 1955, at the onset of the WHO campaign for eradication While keeping in mind the realities one can nevertheless be confident that malaria is well on its way towards oblivion. Already as a malariologist, I feel premonitory twinges of lonesomeness, and in my own organisation I am now a sort of last survivor. So perhaps it is fitting that I should take this backward glance at the fascinating pages of malaria history. Paul Russell 1955: Man s Mastery of Malaria

28 Acknowledgments Regina Joice Kathrin Buchholz Tom Burke Roger Wiegand Dan Milner Curtis Huttenhower Johanna Daily Manoj Duraisingh & Lab Dyann Wirth & Lab Jacqui Montgomery Jimmy Vareta Mavis Menyere Malcolm Molyneux Rob Heyderman Kim Williamson Terrie Taylor Belinda Morahan Karl Seydel Families of the children involved in the autopsy case study

Malaria. This sheet is from both sections recording and includes all slides and diagrams.

Malaria. This sheet is from both sections recording and includes all slides and diagrams. Malaria This sheet is from both sections recording and includes all slides and diagrams. Malaria is caused by protozoa family called plasmodium (Genus) mainly affect blood system specially RBCs and each