Exploring Plasmodium falciparum Var Gene Expression to Assess Host Selection Pressure on Parasites During Infancy

Abstract

In sub-Saharan Africa, children below 5 years bear the greatest burden of severe malaria because they lack naturally acquired immunity that develops following repeated exposure to infections by Plasmodium falciparum. Antibodies to the surface of P. falciparum infected erythrocytes (IE) play an important role in this immunity. In children under the age of 6 months, relative protection from severe malaria is observed and this is thought to be partly due to trans-placental acquired protective maternal antibodies. However, the protective effect of maternal antibodies has not been fully established, especially the role of antibodies to variant surface antigens (VSA) expressed on IE. Here, we assessed the immune pressure on parasites infecting infants using markers associated with the acquisition of naturally acquired immunity to surface antigens. We hypothesized that, if maternal antibodies to VSA imposed a selection pressure on parasites, then the expression of a relatively conserved subset of var genes called group A var genes in infants should change with waning maternal antibodies. To test this, we compared their expression in parasites from children between 0 and 12 months and above 12 months of age. The transcript quantity and the proportional expression of group A var subgroup, including those containing domain cassette 13, were positively associated with age during the first year of life, which contrasts with above 12 months. This was accompanied by a decline in infected erythrocyte surface antibodies and an increase in parasitemia during this period. The observed increase in group A var gene expression with age in the first year of life, when the maternal antibodies are waning and before acquisition of naturally acquired antibodies with repeated exposure, is consistent with the idea that maternally acquired antibodies impose a selection pressure on parasites that infect infants and may play a role in protecting these infants against severe malaria.

Gene expression profiling of malaria parasites reveals common virulence gene expression in adult first-time infected patients and severe cases

“…However, a recent study explored the var gene expression during infancy in Kenyan children and could correlate the waning of maternal antibodies with increasing transcription of DC8, DC13 and A-type var genes in general. After the first year of life the amount of these transcripts decreases with age and acquired immunity (Kivisi et al, 2019). A high expression of A-type var genes in naïve malaria cases imported to France and an association of DC4, 8 and 13 with disease severity has also been reported (Argy et al, 2017).…”

Analysis of var Gene Transcription Pattern Using DBLα Tags

“…Colonies formed by nonrecombinant cells appear blue, while those formed by recombinant cells appear white. Either 100 or 32 colonies can be picked for sequencing [7,20]. However, deeper sequencing provides better estimates of diversity in expression.…”

“…var genes containing DBLα-tag sequence with a reduced number of cysteine residues have been shown to predominantly fall under group A and to be preferentially transcribed by isolates from children with severe malaria and low host immunity [7,8,[20][21][22]. Here, we describe an approach that we have used to determine var gene transcription using the DBLα tag.…”