The causative agent of severe malaria in humans, Plasmodium falciparum, facilitates immune evasion by extensive antigenic diversity. Mutation and recombination have resulted in a highly diverse collection of pathogenic types and sub-types that co-circulate within a community. Even during the course of a single infection, P. falciparum escapes detection and destruction by the immune system by displaying an enormous variety of antigenic variants. Some of the most important determinants for immune evasion and malaria pathology are the variant surface antigens (VSA), and specifically the var gene encoded family of erythrocyte membrane proteins PfEMP1. These highly polymorphic proteins mediate cytoadhesion of the infected erythrocytes to a variety of host cell receptors, which can lead to sequestration of parasitized red blood cells in the deep vasculature and is associated with severe malaria pathologies. We are interested in studying the evolution, population dynamics and clinical significance of antigenic diversity, both at the population level and during in vivo infections, and try to understand its effect on the multifaceted epidemiology of P. falciparum malaria.
At the population level. P. falciparum infections have a wide range of pathological outcomes: young children under the age and 5 and pregnant women are at particular risk of developing severe and life-threatening malaria, whereas older children and adults frequently harbour parasites with no clinical symptoms. Immunity against severe malaria might be acquired after a few infections only , and different clinical features, such as severe malaria anaemia or cerebral malaria, generally follow distinct age profiles in the population. This has led to the theory of malaria being caused by independently transmissible ‘strains’ [2,3], with each P. falciparum strain defined by its antigenic repertoire and maintained despite high rates of recombination through immune-mediated selection . By combining mathematical tools with serological and genome sequence data, we are investigating the role of immune selection on the evolution and maintenance of such population structures, with particular emphasis on var genes and var gene repertoires [5,6,7]. This should help elucidate the observed associations between acquired immunity, gene expression and malaria pathology.
Within the host. P.falciparum evades the adaptive immune response and establishes chronic infections by a process called antigenic variation, which involves mutually exclusive, transcriptional switches between the ~60 members of the var multi-gene family. This process is thought to underlie the successive waves of parasitaemia that characterise malaria infections and depends on the synchronisation of variant expression so as to avoid exhausting the available repertoire. Although this synchronisation, at least in the later stages of infection, might be provided by the host’s own immune responses , analyses of in vitro var gene transcription profiles of cloned parasites have revealed highly structured and non-random patterns of transcriptional switching between individual var genes . By developing new analytical tools for inferring genetic switching pathways from in vitro transcription data  we are investigating these ‘hardwired’ switch patterns, especially in relation to in vivo infection dynamics, which we hope will help to understand the molecular mechanisms underlying antigenic variation and further elucidate the evolutionary forces that have shaped the antigenic repertoire of P. falciparum.
- Gupta S, Snow RW, Donnelly CA, Marsh K, Newbold C (1999) Immunity to non-cerebral severe malaria is acquired after one or two infections. Nat Med 5: 340-343. PDF
- Gupta S, Trenholme K, Anderson RM & Day KP (1994) Antigenic diversity and the transmission dynamics of Plasmodium falciparum. Science 263, 961-963. PDF
- Gupta S & Day KP (1994) A theoretical framework for the immunoepidemiology of Plasmodium falciparum malaria. Parasite Immunology 16 : 361-370. PDF
- Gupta S, Ferguson N, Anderson R (1998) Chaos, persistence, and evolution of strain structure in antigenically diverse infectious agents. Science 280: 912-915. PDF
- Buckee CO, Bull PC, Gupta S (2009) Inferring malaria parasite population structure from serological networks. Proc Biol Sci 276: 477-485. PDF
- Recker M, Arinaminpathy N, Buckee CO (2008) The effects of a partitioned var gene repertoire of Plasmodium falciparum on antigenic diversity and the acquisition of clinical immunity. Malar J 7: 18. PDF
- Buckee CO, Recker M (2012) Evolution of the Multi-Domain Structures of Virulence Genes in the Human Malaria Parasite, Plasmodium falciparum. PLoS Comput Biol 8: e1002451. PDF
- Recker M, Buckee CO, Serazin A, Kyes S, Pinches R, et al. (2011) Antigenic variation in Plasmodium falciparum malaria involves a highly structured switching pattern. PLoS Pathog 7: e1001306. PDF
- Noble R, Recker M (2012) A statistically rigorous method for determining antigenic switching networks. PLoS ONE (under review / accepted).
- Recker M, Nee S, Bull PC, Kinyanjui S, Marsh K, et al. (2004) Transient cross-reactive immune responses can orchestrate antigenic variation in malaria. Nature 429: 555-558. PDF