Table 3.
Variables that can potentially confound systems studies of malaria immunity
| Variable | Comments | Suggested References |
|---|---|---|
| age | In long-term residents of endemic areas, age is inextricably linked to malaria exposure. Additionally, there are age-related differences in immune cell composition and immunity that are independent of malaria exposure. | 112,113 |
| previous malaria exposure | Prior malaria episodes can generate immunity that is protective against clinical malaria but can also shape the quality of the immune response. | 113,114 |
| erythrocyte polymorphisms | Erythrocyte variants such as sickle hemoglobin (HbS) and thalassemias can adversely affect parasite growth and protect against malaria. | 115,116 |
| spatial factors | Microgeography including residence near mosquito-breeding sites, near health clinics, and within clusters of asymptomatic carriers can influence malaria exposure. | 117,118 |
| helminth co-infections | Co-infection with helminths can affect malaria risk and the quality of the immune response. | 119,120 |
| parasite biomass | Parasite biomass, which includes the amount of sequestered parasite, can influence the host response to P. falciparum malaria. This is typically measured using plasma histidine-rich protein 2 (HRP2) levels. | 9,51 |
| nutrition status | Although evidence on the effect of malnutrition of malaria risk remains inconclusive, primary childhood malnutrition impairs host defense mechanisms, potentially increasing the risk and severity of infection. | 121,122 |
| microbiota | Gut microbiota composition has been shown to affect risk of P. falciparum infection in humans and malaria severity in a mouse malaria model. | 123–125 |
| timing of blood sampling | Duration of parasitemia is generally not known at time of blood sampling in naturally infected individuals. Thus, there can be significant variability in immunological responses between subjects based on the natural history of acute malaria. | 126–128 |
| parasite genetics | The parasite employs antigenic diversity and variation as immune evasion mechanisms. For example, certain parasite variants, such as those expressing PfEMP-1 variants with EPCR-binding phenotype, have been associated with cerebral malaria. | 129–131 |
| host genetics | In addition to erythrocyte variants, other unknown host genetic determinants can potentially affect malaria severity. | 132,133 |