Development of B cell memory and antibody responses to malaria
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
| (Primary) | Infection and Immunity | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Infection and Immunity | .(JavaScript must be enabled to view this email address) |
Details of project
During blood-stage replication, merozoites invade red blood cells through a complex multi-step process that requires initial contact of the parasite with the red blood cell surface followed by apical reorientation of the merozoite, tight junction formation, and final entry into the red blood cell.
While initial attachment is thought to involve antigens expressed on the surface of the parasite such as merozoite surface protein-1 (MSP-1), invasion appears to be mediated through the binding of molecules located in the parasite’s apical organelles. Thus merozoite surface antigens are potential targets of protective immunity and experimental evidence suggests that antibodies directed against some of these surface molecules are able to inhibit parasite invasion into the red blood cell.
This project will examine the development of B cell responses to MSP-1 in fatal and self-resolving rodent malaria models to determine whether lethal infections are associated with defects in the induction of humoral immune responses. To that end, frequencies of high affinity anti-MSP-1 antibody secreting cells will be determined in the spleen and the bone marrow. The capacity of antibodies generated after fatal or mild-malaria infection to inhibit invasion of Plasmodium parasites will be also evaluated in in vitro assays. This project will reveal new insights into the cellular basis of delayed acquisition of immunity to malaria.
Project references
- Urban BC, et al. Fatal Plasmodium falciparum malaria causes specific patterns of splenic architectural disorganization. Infect Immun. 2005 73:1986-1994.
- Carvalho LJ, Ferreira-da-Cruz MF, Daniel-Ribeiro CT, Pelajo-Machado M and Lenzi HL. Germinal center architecture disturbance during Plasmodium berghei ANKA infection in CBA mice. Malar J. 2007 6:59.
- Hansen DS, Siomos M-A, de Koning-Ward T, Buckingham L, Crabb BS and Schofield L. CD1d-restricted NKT cells contribute to the splenomegaly associated with B cell expansion and enhance parasite-specific antibody responses in murine malaria. Eur J Immunol. 2003 33:2588-2598.
- de Koning-Ward TF, et al. A new rodent model to assess blood stage immunity to the Plasmodium falciparum antigen merozoite surface protein 119 reveals a protective role for invasion inhibitory antibodies. J Exp Med. 2003 198:869-875.
Research interests
Malaria is one the most serious infectious diseases of humans with 500 million clinical cases annually. The infection is transmitted to vertebrate hosts by the bite of female Anopheles mosquitos that are infected with protozoan parasites of the genus Plasmodium.
After an initial period of replication in the liver, the asexual parasite life-cycle starts when merozoites are released from liver cells and invade red blood cells. The blood stage of the Plasmodium parasite is entirely responsible for malaria-associated pathology. Clinical symptoms of malaria include respiratory distress, renal failure, pulmonary oedema and cerebral involvement.
In endemic areas, the most susceptible population to symptoms associated with severe malaria are children under the age of 5, who experienced a few parasitic infections. Individuals living in endemic areas develop clinical immunity after many years of repeated exposure. This form of protection does not result in sterilising immunity but prevents symptomatic episodes and severe disease by substantially reducing parasite burden.
Naturally acquired immunity seems to predominantly target blood-stage parasites and antibodies are considered the main effector mechanisms required to control parasitemia. Yet several studies have shown that antibodies to malarial antigens are inefficiently generated and rapidly lost in the absence of exposure to the parasite, which suggest a defect in malaria-specific B cell memory and long-lived antibody responses.
Our group is investigating the development and maintenance of B cell responses to malaria in humans as well as animal infection models. We also aim to identify specific antigenic targets of immunity to malaria in human populations as well as the effector mechanism by which protective antibodies facilitate control of parasite burden.
Selected publications
- Hansen DS and Schofield L. Natural T regulatory cells in malaria: host or parasite allies? PLoS path. 2010 Apr 29;6(4):e1000771.
- Nie CQ, Bernard NJ, Norman MU, Amante FH, Lundie RJ, Crabb BS, Heath WR, Engwerda CR, Hickey MJ, Schofield L and Hansen DS. IP-10-mediated T cell homing promotes cerebral inflammation over splenic Immunity to malaria infection. PLoS Path. 2009 5(4): e1000369.
- Nie CQ, Bernard NJ, Schofield L and Hansen DS. CD25+ CD4+ T regulatory cells suppress T cell function and inhibit the development of parasite-specific to TH1 responses involved in cerebral malaria pathogenesis. Infect. Immun. 2007 75:2275-2282.
- Hansen DS, Evans KJ, D’ombrain MC, Bernard NJ, Sexton AC, Buckingham L, Scalzo AA and Schofield L. The Natural Killer Complex regulates malarial pathogenesis and influences acquired immune responses to Plasmodium berghei. Infect. Immun. 2005 73:2288-2297.
- Hansen DS, Siomos M-A, Buckingham L, Scalzo AA and Schofield L. Regulation of murine malarial pathogenesis by CD1d-restricted NKT Cells and the Natural Killer Complex. Immunity. 2003 18:391-402.
Research theme
Infectious diseases
Scientific discipline
- Immunology
Keywords
Malaria, antibodies, immunity