Evolutionary Parasitology Genetic and genomic analyses of host-pathogen interactions in malaria Silayuv E. Bongfen 1 , Aure ´ lie Laroque 1 , Joanne Berghout 1 and Philippe Gros Department of Biochemistry, and Complex Traits Program, McGill University, Montreal, Canada The Plasmodium parasite successfully infects and repli- cates in both human and insect vectors. Population studies in humans have long detected the enormous selective pressure placed by the parasite on its human host, revealing the footprints of co-evolution. Available complete genomic sequences for the human and insect hosts, and additional sequences from multiple field iso- lates of Plasmodium falciparum have identified a wide array of protein and gene families that play a crucial role at the interface of host–parasite interaction. Selected examples of such interactions will be reviewed herein. Malaria Five members of the apicomplexan family of Plasmodium parasites cause malaria in humans. In 2006, the WHO estimated 247 million clinical cases of malaria with close to a million associated deaths occurring mostly in children under the age of five (http://www.who.int/malaria/ wmr2008/). Furthermore, adults living in endemic and hyper-endemic areas can be chronically infected with the parasite throughout their lifetime, with occasional bouts of clinical symptoms. In these areas, the malaria problem has been exacerbated by the emergence of widespread resist- ance to anti-malarial drugs, the absence of an efficacious vaccine, and the risk of co-infection in immunologically weakened chronic Plasmodium carriers [1]. During their life cycle (Box 1), Plasmodium parasites must penetrate several protective physical barriers and defeat the host(s) defenses. Some of these challenges in- clude (i) penetrating and replicating inside hepatocytes and erythrocytes, (ii) avoiding recognition and destruction by the immune system of the human host, (iii) establishing long-term parasitism in humans to survive the long, rela- tively mosquito-free dry season, and (iv) penetrating sev- eral epithelial layers and avoiding elimination by the insect’s innate immune defenses. In humans, the ability of Plasmodium species to cause either acute or chronic infections is due in part to their capacity to evade immune detection. Nevertheless, most infected humans do not develop severe disease, and repeated cycles of infection cause a slow build-up of protective immunity, reached by adulthood. The rate of acquisition of protection against malaria has been shown to be dependent on the intensity of transmission [2], and this protection is mainly antibody- dependent [3]. Any inherited genetic variant affecting replication of the parasite in humans (erythrocyte, hep- atocytes) and mosquito (gut), and/or modulating recog- nition of the parasite by the innate immune system of the host(s) is expected to have a profound effect on the type of disease developed and on the ultimate outcome of infection. The genetic analysis of differential resistance to infection in human and insect hosts has shed light on the proteins and pathways that play a critical role at the interface of host-pathogen interactions, and that could fail during acute infection. The available complete genome sequences of (i) the human host, (ii) several insect genomes and (iii) multiple laboratory and field isolates of P. falci- parum have together enabled the systematic cataloging of protein families playing a key role at this interface. The current review will focus on these interactions in all three protagonists. The reader is referred to excellent recent reviews that deal with other important aspects of Plasmo- dium infection [4–9] not covered herein. The human host Malaria constitutes one of the best-studied examples of host genetic factors affecting disease incidence and sever- ity, including strong evidence of selective pressure by the parasite on the human gene pool [7]. In malaria-endemic areas of disease, two major factors contribute to this unique situation: (i) the very high incidence of infection in these populations (with exposure to infected insects assumed to be constant), and (ii) the fact that most malaria-associated deaths occur in young children. These combined effects favor selection and retention of infection- resistant genetic variants, although in some instances homozygosity for these same variants can cause other diseases that might have otherwise disfavored their reten- tion (reviewed in [10]). Additional genetic epidemiology data supporting an important but complex genetic com- ponent to quantitative (level of parasitemia, fever) and qualitative (cerebral malaria, severe malarial anemia, death) measures of disease severity include differences in susceptibility among distinct ethnic groups living in the same area, family studies showing increased sibling risk, heritability of certain responses to infection, and studies in twins [7]. Several major gene effects have been characterized at the molecular level, whereas others have only been detected in association and linkage studies. The erythrocyte is a major site of parasite replication. The parasite binds to specific receptors on these cells, initiates intracellular replication and expresses certain Review Corresponding author: Gros, P. (philippe.gros@mcgill.ca) 1 These authors have contributed equally to the preparation of this review.. 1471-4922/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2009.05.012 417