P. falciparum and Its Molecular Markers of Resistance to Antimalarial Drugs

The use of molecular markers of resistance to monitor the emergence, and the spread of parasite resistance to antimalarial drugs is a very effective way of monitoring antimalarial drug resistance. The identification and validation of molecular markers have boosted our confidence in using these tools to monitor resistance. For example, P. falciparum chloroquine resistance transporter (PfCRT), P. falciparum multidrug resistance protein 1 (PfMDR1), P. falciparum multidrug kelch 13 (pfk13), have been identified as molecular markers of resistance to chloroquine, lumefantrine, and artemisinin respectively. The mechanism of resistance to antimalarial drugs is mostly by; (1) undergoing mutations in the parasite genome, leading to expelling the drug from the digestive vacuole, or (2) loss of binding affinity between the drug and its target. Increased copy number in the pfmdr1 gene also leads to resistance to antimalarial drugs. The major cause of the widespread chloroquine and sulfadoxine-pyrimethamine resistance globally is the spread of parasites resistant to these drugs from Southeast Asia to Africa, the Pacific, and South America. Only a few mutations in the parasite genome lead to resistance to chloroquine and sulfadoxine-pyrimethamine arising from indigenous parasites in Africa, Pacific, and South America.

The protective effect of sickle cell haemoglobin against severe malaria depends on parasite genotype

Host genetic factors can confer resistance against malaria, raising the question of whether this has led to evolutionary adaptation of parasite populations. In this study we investigated the correlation between host and parasite genetic variation in 4,171 Gambian and Kenya children ascertained with severe malaria due to Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and variation in three regions of the parasite genome, including nonsynonymous variants in the acyl-CoA synthetase family member PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The HbS-associated parasite alleles are in strong linkage disequilibrium and have frequencies which covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome, and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.

Estimating the overlap between two malaria parasites’ var repertoires

Measuring the overlap between the var gene repertoires of two P. falciparum parasites is, in principle, easy. Each parasite genome contains a repertoire of approximately 60 var genes, so upon fully sequencing both parasites’ genomes, the number of shared var sequences can be directly counted. In practice, however, only a fraction of each parasite’s var repertoire is likely to be sampled due to the difficulties of whole-genome sequencing for var genes and the stochastic sample provided by PCR techniques. Although a method exists for quantifying repertoire overlap under these subsampled conditions, its bias is well documented and the uncertainty of its estimates cannot be quantified. Here we derive and validate a method to rigorously estimate the repertoire overlap between two parasites from the overlap of their subsampled repertoires. By solving a Bayesian inference problem, this method takes into account the rates of subsampling and produces unbiased and Bayes-optimal estimates of overlap. In addition, it provides a natural framework for computing the uncertainty of its estimates, and can be used in laboratory planning by quantifying the tradeoff between sequencing effort and uncertainty.

Schistosoma Tegument Proteins in Vaccine and Diagnosis Development: An Update

The development of a vaccine against schistosomiasis and also the availability of a more sensitive diagnosis test are important tools to help chemotherapy in controlling disease transmission. Bioinformatics tools, together with the access to parasite genome, published recently, should help generate new knowledge on parasite biology and search for new vaccines or therapeutic targets and antigens to be used in the disease diagnosis. Parasite surface proteins, especially those expressed in schistosomula tegument, represent interesting targets to be used in vaccine formulations and in the diagnosis of early infections, since the tegument represents the interface between host and parasite and its molecules are responsible for essential functions to parasite survival. In this paper we will present the advances in the development of vaccines and diagnosis tests achieved with the use of the information from schistosome genome focused on parasite tegument as a source for antigens.