Overview

Africa faces a host of challenges to health and development: among the most prominent of these burdens are infectious diseases. Two diseases, malaria and AIDS, each take each take approximately three million lives a year, primarily in Africa. Malaria is caused by a particularly crafty parasite, Plasmodium falciparum, which for perhaps ten thousand years has used mosquitoes to transmit itself to humans. Up to 500 million people experience a bout of malaria each year, suffering anemia, weakness, and fever, which greatly limit their ability to work or go to school. Repeated infections are extremely common and can lead to death or cause mental impairment. Even single bouts take the lives of the most vulnerable, including one million children in Africa each year. Unlike AIDS, efforts to influence behavior have little impact on the transmission of malaria: its victims simply live where the parasite's preferred variety of mosquito thrive. Also unlike AIDS, we have effective treatments to cure malaria-or so we thought. In the mid-twentieth century, scientists and public health workers believed they had the tools to conquer malaria: inexpensive chloroquine pills and bed nets with insecticide greatly eased suffering and reduced the spread of the disease. Widespread use of DDT killed the mosquitoes that transmit malaria, but it also unintentionally harmed many other organisms. Now, malaria is on the rise. In the past decades we have seen that the parasite that causes the symptoms of malaria is becoming invulnerable to existing medicines, and the mosquito is demonstrating resistance to insecticides. Resistance to cheap treatments is spreading, and multi-drug resistance is appearing in more and more areas. In recent years, even as it became clear that resistance was spreading, drug companies cut their programs on malaria drug and vaccine development. Drugs to treat diseases that primarily affect poor regions were not expected to result in the spectacular profits shareholders have come to expect.

Malaria in Senegal

Dr. Ousmane Sarr and Ambroise Dioum Ahoudi

Dr. Therese Dieng

Senegal lies in the Sahel-Sudan-type Savannah region of Africa where malaria is mostly hypoendemic to mesoendemic. Malaria transmission in Senegal is mainly seasonal, where the highest degree of transmission occurs during the rainy season (July- November). P. falciparum is the most prevalent species, representing 96% of the cases, followed by P. malariae (3%) and P. ovale (1%). The main vectors are Anopheles arabiensis and An. gambiae. Parasite resistance to the existing antimalarial drugs is well established in Senegal. Chloroquine resistance, which was first reported in 1984/1985, is now very prevalent in Senegal. Drug resistance is emerging as a major problem and training in identifying and tracking new emergent populations is urgently needed. P. falciparum parasite populations in Senegal are highly diverse, with a large number of circulating serotypes and serotype combinations. With the tools provided by the malaria genome project and the methods being developed under the newly NIH-funded program directed by Dr. Wirth it is now possible to study population diversity, and analyze parasite populations from Senegal. The first goal of the initiative would determine the level of parasite diversity by analyzing regions of the genome not predicted to be under selective pressure for polymorphisms. This analysis would be extended to compare nucleotide polymorphism within immune compromised hosts as compared to immune competent ones to test the hypothesis that host immune response alters parasite population structure. The second goal is to examine the expression profiles of specific parasite genes and the potential modulatory effects of the host immunological status. A third goal will be to examine the role of drug resistance and drug pressure on parasite populations in Senegal. Initial studies would involve sampling of parasites for comparison with these baseline estimates of parasite diversity.

Malaria in Nigeria

Dr. Christian Happi

Malaria is a disease which kills about 300,000 Nigerians every year (Annual report of the Federal Ministry of Health, Lagos, Nigeria, 1989). In the absence of an effective malaria vaccine, chemotherapy remains the mainstay for treatment and prevention of the disease.  However, resistance to chloroquine, the most widely used, safest and most affordable antimalarial drug, has accelerated mortality and morbidity caused by Plasmodium falciparum in African children.

Identification of markers of drug resistance is critical both to new drug discovery and for strategies to prevent the emergence and spread of drug resistant organisms.  The goal of the collaborative initiative is to identify molecular determinants of drug response in P. falciparum in Nigeria and to characterize the early events in the emergence of drug resistant parasites.  Field activities of this research are led by Dr. Christian Happi of the Malaria Research Laboratories, Institute of Advanced Medical Research and Training (IAMRAT), College of Medicine, University of Ibadan, Nigeria.  Dr. Happi has trained in Molecular biology with Professor Wirth at the Department of Immunology and Infectious Diseases, Harvard School of Public Health.  

This research is directed at achieving the following specific goals.

1. Determine genetic correlates of chloroquine sensitivity in P. falciparum isolates from patients treated with chloroquine. The presence of mutations in P. falciparum chloroquine resistance determinant genes (i) pfcrt and (ii) pfmdr1 by DNA sequence analysis. 

2. Validate the role of chloroquine resistance determinants in P. falciparum clones prepared from fresh patients' isolates.

3. Determine the background mutation prevalence in the DHFR and DHPS genes associated with P. falciparum sulfadoxine-pyrimethamine resistance in Nigerian isolates.

4. Establish a site in Nigeria that will serve as the national reference laboratory to study the development and spread of drug resistant Plasmodium falciparum over time in Nigeria.

It is anticipated that through this Collaboration, new tools for monitoring changes in the efficacy of antimalarial drugs over time in Nigeria will be developed.  Ultimately, this collaboration aims at enhancing research capabilities and promoting evidence-based policy on malaria therapy in Nigeria.

CURRENT ACTIVITIES OF THE MALARIA RESEARCH LABORATORIES
ISTITUTE FOR MEDICAL RESEARCH AND TRAINING (IMRAT)
COLLEGE OF MEDICINE, UNIVERSITY OF IBADAN, IBADAN, NIGERIA

The Malaria Research Laboratories at the College of Medicine University of Ibadan is a multidisciplinary research group comprising physicians and scientists. The physical facilities of the Laboratories are located in the Institute for Medical Research and Training (IMRAT). Activities in the laboratories focus on basic and applied research for the control of malaria and reduction of associated morbidity and mortality. The principal areas of research in the Laboratories include:

• Chemotherapy
• development of novel treatment modalities and diagnostic techniques
• epidemiology, community and Public Health education.

The current focus and strength of the Malaria Research Laboratories comprise studies on:

• Pharmacological and clinical efficacy of antimalarial drugs
• Basic laboratory research on chemotherapy, parasitology and molecular biology of malaria parasites
• Application of social sciences in tropical disease control.

Major ongoing research activities at the Malaria Research Laboratories are currently focusing on: 1) Monitoring the in vivo efficacy of antimalarial drugs combinations (artesunate-amodiaquine and artemether-lumefantrine) used as first line treatment for malaria in Nigerian children; 2) Determination of in vitro susceptibility profiles of patients isolates of Plasmodium falciparum to antimalarial drugs either alone or in combination using different methodologies; 3) Identification and validation of new molecular markers of Plasmodium falciparum resistance to antimalarial drugs (including artemisinin derivatives) in fresh isolates obtained from children with malaria in Nigeria 4) pharmacovigilence of antilamarual drugs and 5) Home management of malaria.

The Malaria Research Laboratories also devotes effort to training community health workers, young physicians, scientists and graduate students in tropical disease research. Clinicians and scientists trained by the group are currently participating in various aspects of health care, research, medical education and decision making in Nigeria. The group is also working in collaboration with National and Oyo State Malaria Control Programmes. Thus, results of research at the Malaria Research Laboratories are made available to the OyoState and National Malaria Control Programmes for promotion of evidence-based antimalarial drug policies in Nigeria.

Malaria in Malawi

Malawi Dr. Danny Milner, Jr. is a Clinical Fellow in Pathology at the Brigham &Women's Hospital and the Pathology Department at the Harvard Medical School. Dr. Milner has been a consultant pathologist with the Blantyre Malaria Project, Queen Elizabeth Central Hospital, Blantyre, Malawi since March of 2000. The team in Blantyre is involved in a long-term study of the clinicopathological correlates of fatal malaria in order to elucidate the underlying pathogenesis. Dr. Milner's focus will be parasite-specific contributions to fatal malaria infections. As a first step, he plans to define the genetic diversity of P. falciparum parasites in Malawi, and compare it to the genome of an established laboratory strain (3D7). The comparison may help to identify genes critical to parasite survival in the human host and to calculate the evolutionary age of the strains of P. falciparum in Malawi. A second goal is to define parasite-specific contribution to malaria pathogenesis by comparing mRNA expression profiles from different organs within the same patient, and from the same organ in different patients. P. falciparum is the only one of the four species of parasite infecting man that sequesters; mature forms of the intraerythrocytic parasite adhere tightly to endothelial cells in the microvasculature of various tissues. Dr. Milner's comparisons will elucidate which genes, if any, are differentially expressed in sequestration associated with pathology vs. sequestration alone and which are differentially expressed in the parasites of patients with fatal malaria vs. patients with incidental parasitemias (who die for other reasons). The expression arrays could also identify any genes uniquely expressed in Malawi, compared to other geographic sites.