Pathogenicity and virulence of malaria: Sticky problems and tricky solutions

Abstract

Infections with Plasmodium falciparum and Plasmodium vivax cause over 600,000 deaths each year, concentrated in Africa and in young children, but much of the world’s population remain at risk of infection. In this article, we review the latest developments in the immunogenicity and pathogenesis of malaria, with a particular focus on P. falciparum , the leading malaria killer. Pathogenic factors include parasite-derived toxins and variant surface antigens on infected erythrocytes that mediate sequestration in the deep vasculature. Host response to parasite toxins and to variant antigens is an important determinant of disease severity. Understanding how parasites sequester, and how antibody to variant antigens could prevent sequestration, may lead to new approaches to treat and prevent disease. Difficulties in malaria diagnosis, drug resistance, and specific challenges of treating P. vivax pose challenges to malaria elimination, but vaccines and other preventive strategies may offer improved disease control.

A paradoxical population structure ofvarDBLα types in Africa

“…The 62,168 representative DBLα types from the seven combined MRS surveys were classified into upsA (5.4%), upsB (56.6%), and upsC (37.9%) groups (Table I in Data S1). This points to a highest DBLα richness for the upsB group (35,215 types), followed by the upsC group (23,583 types) and upsA group (3,370 types) in combined surveys, and this hierarchy of richness is similarly observed for individual surveys (Figure 1A). The differences in proportions of ups groups at the isolate versus population levels is attributed to the negative relationship between PTS and richness, as a higher level of upsA type sharing will result in lower proportion of unique representative DBLα types in the population.…”

“…The prevailing understanding is that var genes and DBLα variants (i.e., DBLα types) in the upsA group are generally more conserved compared to those in upsB or upsC groups (i.e., non-upsA) (15,16,19,22). This has largely been attributed to the association of upsA genes to severe malaria, including cerebral malaria, due to their host receptor binding phenotypes (23). Expression of upsA var genes encoding the DBLα+CIDRα1 head structure mediate endothelial protein C receptor (EPCR)-binding and/or intercellular adhesion molecule-1 (ICAM-1)-binding has been associated with severe malaria and/or cerebral malaria (24)(25)(26).…”

SKSR1 identified as key virulence factor inCryptosporidiumby genetic crossing

“…secreted into the parasite-host interface during invasion and early development. 28,29 The SKSR1 family is one of a small number of multigene families in Cryptosporidium spp. They are secreted proteins encoded by 8-11 subtelomeric genes.…”

Enhanced Antimalarial and Antisequestration Activity of Methoxybenzenesulfonate-Modified Biopolymers and Nanoparticles for Tackling Severe Malaria

“…Another hallmark of severe P. falciparum infection in humans is the phenomenon called sequestration, i.e., binding of iRBCs to specific receptors on the blood vessel endothelium. 6 Hence, interfering with both invasion and sequestration might be a suitable strategy to avoid potentially fatal multiplication and blood flow obstruction in severe malaria cases.…”

“…falciparum erythrocyte membrane protein 1 ( Pf EMP1). This protein is translocated to the iRBC surface to mediate specific interactions with endothelial receptors including heparan sulfate, , chondroitin sulfate A (CSA), and intercellular adhesion molecule 1 (ICAM-1), among others . The CSA interaction can cause placental malaria, while the ICAM-1 interaction is associated with cerebral malaria; both represent severe health risks for the unborn child and mother and cerebral malaria patient, respectively.…”