We still cannot address the slippery problem of whether this order reflects the circulation of genotypes with different transmissibility; under this scenario, high fitness genotypes lead to high prevalence and therefore low age of first infection and coincidentally cause more disease in relatively nonimmune children compared with low fitness genotypes as a result. FUNDING Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. Keywords: Immunology, Infectious disease Keywords: Adaptive immunity, Immunoglobulins, Malaria A prospective study in Mali revealed early acquisition of IgG to PfEMP1 CIDR1.7 and CIDR1.8 and an association of IgG to CIDR3 with malaria protection. Introduction Malaria due to causes more than 400,000 deaths per year (1). Severe clinical manifestations of malaria are precipitated by widespread sequestration of infected erythrocytes (IEs) in host microvasculature, including in the brain and placenta, which can lead to cerebral malaria and placental malaria, respectively (2). Cytoadherence of IEs occurs via specific interactions between host endothelial receptors and erythrocyte membrane protein (PfEMP1), a parasite-derived protein expressed on the surface of IEs that is a major target of naturally acquired immunity to malaria (3C5). The PfEMP1 adhesins are encoded by approximately 60 gene variants that differ within and between parasite genomes and that are expressed in a mutually exclusive manner within each IE (6C8). Switching between genes aids in parasite immune evasion and functional diversification of the PfEMP1 family has resulted in mutually exclusive receptor-binding phenotypes correlated with differences in clinical severity (9, 10). Members of the PfEMP1 family vary in the size and number of extracellular Duffy-binding-like (DBL) and cysteine-rich interdomain region (CIDR) domains (11). DBL and CIDR domains are classified based on sequence similarity into 6 (, , , , , ) and 4 (, , , ) main classes, respectively, of which some can be further divided into subclasses (e.g., CIDR1.1) (12, 13). PfEMP1 generally has a semiconserved head structure near the N-terminus consisting of a tandem DBL-CIDR domain. This can be followed by a second DBL-CIDR tandem domain or additional other types of DBL domains in larger proteins. Notably, however, the VAR2CSA PfEMP1 variants do not contain typical CIDR domains and bind placental chondroitin sulfate A via specialized DBL domains (14, 15). PfEMP1 has diversified to bind the endothelial protein C receptor (EPCR) (10), the scavenger receptor CD36 (16), or yet undermined receptors via head structure CIDR domains. These phenotypes are maintained by the chromosomal organization of the genes (17). Among the subtelomeric genes, group A genes transcribed toward the telomere encode DBL1-CIDR1 head structures binding to EPCR or DBL1-CIDR// head structures, with unknown endothelial receptor specificities. Subtelomeric group B genes transcribed toward the centromere as well as centromeric group C genes encode DBL0-CIDR2-6 head structures binding to CD36. Rabbit polyclonal to AATK In addition to this, chimeric group B/A genes encode EPCR-binding DBL0-CIDR1 head structures. The EPCR-binding phenotype has been implicated in severe malaria (18C21), whereas CD36 binding has been associated with uncomplicated malaria (22, 23). Severe malaria has been associated with rosetting, a phenomenon with unclear clinical significance that involves binding between 10-Oxo Docetaxel an IEs and several uninfected erythrocytes. A set of group A PfEMP1 with DBL1-CIDR// domains has been shown to mediate rosettes. Immunity to severe malaria is generally acquired after only 1 1 or 2 2 severe episodes (24), with naturally acquired antibodies specific for PfEMP1 variants likely playing an important role in clinical protection (25). 10-Oxo Docetaxel Antibodies against group A PfEMP1 variants tend to be acquired before antibodies against group B and C variants (26) and are associated with protection from severe 10-Oxo Docetaxel malaria (27). Similarly, antibodies against EPCR-binding CIDR1 domains are acquired more rapidly than antibodies against other CIDR domains in areas of high malaria transmission intensity and 10-Oxo Docetaxel are boosted by severe malaria but not uncomplicated malaria (28, 29). However, a recent study showed that antibodies against both rosetting-associated DBL variants and CD36-binding CIDR domains predicted reduced risk of severe malaria to a similar extent as antibodies against EPCR-binding CIDR domains (30). The same study also showed that antibodies against group 2 DBL variants, which are associated with rosetting (31), also predicted protection from uncomplicated malaria. To gain further insight into the role of PfEMP1-variant specific antibodies, we assessed IgG responses against a repertoire of PfEMP1 CIDR domains to determine the rate and order of variant-specific antibody acquisition and their association with protection against uncomplicated febrile malaria in a prospective cohort study conducted in a Malian village with intense and seasonal malaria transmission. Results IgG antibodies specific for CIDR1, CIDR, and CIDR domain variants are acquired rapidly. Naturally acquired IgG antibody responses to.