Abstract:
Background: Plasmodium falciparum malaria remains one of the biggest health problems in tropical regions. Current preventive and therapeutic measures are only partially effective given the parasite’s complicated life cycle and its ability to develop resistance to antimalarial drugs over relatively short times. Therefore, the search for more potent vaccines and stable drugs has become a high priority over the past years. Immunologic data collection is an important tool within current malaria research and can provide insight in the pathologic mechanisms during a plasmodium infection.
Objective: The severity of a malaria infection strongly depends on a patient’s immunologic state. Even among patients in malaria endemic regions changes within their immune defense against P. falciparum over time can be observed. It is known that malaria infections during pregnancy, as well as the number of pregnancies, affect the immunologic state of the placenta, and therefore the unborn child, and increase the risk of infections with malaria during the neonatal period and infancy. This work focuses on the modulation of the cellular (T-helper cell) and humoral (cytokines IL-10, IL-12, INF-gamma) immune defense of newborns. By analyzing cytokine patterns after in vitro stimulation of neonatal immune cells it was possible to gain insight in the development of the prenatal immune system during a malaria infection of the maternal placenta.
Methods: Neonatal cord blood cells were collected from newborns of primigravid mothers at the Hôpital Albert Schweitzer in Lambaréné, Gabon, a year-round P. falciparum endemic region. Cord blood was obtained shortly after delivery of the placenta. Mononuclear cells were isolated and then cultivated under exposure to certain stimulants: PHA (Mitogen), PPD (recall antigen), schizont antigens (endemic isolates). After cultivation, cytokine concentrations of IL-10, IL-12, and INF-gamma were measured in the supernatants by ELISA. Cytokine patterns were compared among cells from newborns born to mothers without malaria infection (KI), infection during pregnancy (IS), or infection at time of delivery (IG).
Results: High IL-10 concentrations could be measured in the KI- and IG- group after stimulation with schizont antigen. PPD triggered only small IL-10 responses in any of the groups. IL-12 concentrations were low in the IG-group for each of the stimulants, however, reached high concentrations in the IS-group. Similarly, high INF-gamma concentrations could be observed in the KI- and IG- group after stimulation with schizont antigen. Additionally, cells of the IG-group also showed an increased INF-gamma production after PPD stimulation. After correlation of the obtained cytokine levels a combined response of IL-10 and INF-gamma could be observed among cells of the SI- and KI-group after schizont antigen stimulation. In addition, a strong correlation of increased production of IL-10 and IL-12 was found in cells of the KI-group after exposure to schizont antigen.
Conclusion: There was a strong impact on neonatal immune cells through in utero exposure to plasmodium placenta infection. Exposed neonatal cells showed a stronger IL-12 mediated immune response and gained the ability to form a plasmodium specific immune memory that could be activated later. In contrast, plasmodium infection at the end of pregnancy seemed to inhibit the formation of a specific immune memory through suppression of an IL-12 mediated response, instead favoring a less specific IL-10 mediated proinflammatory response. This modulation of the immune memory in these newborns towards a more plasmodium susceptible immune milieu seems to contribute to the observed increased malaria infection risk of these children during infancy.