Figure provided by Dr. Whitney Harrington.
Plasmodium falciparum (P. falciparum) is the etiologic agent of malaria. The parasite can be carried from one individual to the other by female Anopheles mosquitoes. Once in the human host, P. falciparum infects liver cells, and eventually red blood cells. When the latter rupture they release more parasites, propagating the infection. Sub-Saharan countries are the most affected by the disease and do not have sufficient access to effective anti-malarial drugs. Pregnant women and children are even more at risk in these areas. In pregnant women infected red blood cells can traffic to the placenta and are associated with increased inflammatory response and infiltration of mononuclear cells, a phenomenon known as placental malaria. This can result in miscarriage or intrauterine growth restriction. Intriguingly, the offspring is more at risk for malaria if the mother had placental malaria. Little research has been done to explain this phenomenon.
Dr. Whitney Harrington, a research fellow in the lab of Dr. Lee Nelson (Clinical Research Division) has been interested in maternal microchimerism (MMc) - the transfer of maternal cells to the fetus- and how placental malaria affects this phenomenon (see Fred Hutch News articles). Maternal cells can persist for years in the offspring but the implications of such exchange are not well understood (1). In a recent study published in the Journal of Infectious Diseases, Dr. Harrington and the rest of Dr. Nelson’s group have established a link between placental malaria and increased MMc, which may help to explain increased susceptibility of babies born to women infected during the pregnancy.
The authors quantified MMc in cord blood samples from maternal-infant pairs that were divided into three groups: mothers without placental malaria, mothers with non-inflammatory placental malaria, and mothers with inflammatory placental malaria. Samples were collected at several time points and children were followed for up to four years. MMc was quantified by analyzing single nucleotide polymorphisms in maternal-specific markers in genomic DNA.
Among first and second time mothers, MMc detection was higher in cord blood of babies born to women with inflammatory placental malaria (71%) relative to those with non-inflammatory placental malaria (27%) or uninfected women (9%). On average, babies born to women with placental malaria had 1% maternal DNA in the cord blood, and three babies had more than 5%, a strikingly high level. According to Dr. Harrington “There is limited data on the mechanism by which the fetus acquires MMc, but it may be related to a VEGF gradient across the placenta. We are planning to investigate whether the amount of VEGF and / or its soluble receptor sFlt-1 (a marker of placental dysfunction) predict the amount of MMc acquired by the fetus in our African cohorts to further explore this question”.
Further analysis of P. falciparum in the offspring to understand the role of maternal cells revealed that MMc positive infants were more at risk for malaria infection, but less likely to be sick or hospitalized when infected. This suggests that maternal cells may protect from disease development.
How can MMc be responsible for a different response to infection and malaria disease development? Dr. Harrington explained, “we think the babies may have acquired a graft of malaria-specific regulatory maternal cells which allow experience of infection but protection from disease. We know that in healthy pregnancies, maternal cells are enriched among antigen experienced T cells. In addition, during malaria, regulatory cells (classical Tregs, Tr1 cells) may protect from immune-mediated pathology. We hypothesize that these maternal cells influence or educate the fetal immune system in utero, or alternatively, they become directly activated during malaria infection in the infant”.
When asked about future directions, Dr. Harrington outlined: “First, we want to understand the cellular phenotype of the maternal cells, for example, are they T cells, B cells, antigen presenting cells, or some other type of cell? Then we want to know whether the fetus acquires maternal malarial antigen-specific cells (i.e. a maternal graft with "memory"). In addition, we want to know whether these maternal cells are able to educate or shape the fetal and infant immune response against malaria, as well as other perinatal infections (e.g. HIV, CMV) and childhood immunizations. The influence of these intergenerational immune interactions on infectious diseases susceptibility in the offspring is thus far unexplored, and may represent an opportunity to develop entirely novel therapeutics”.
This work was funded by the Thrasher Research Fund, the National Institutes of Health (T32 and R01) and the Intramural Research Program of National Institute of Allergy and Infectious Diseases (NIAID-NIH).
Harrington WE,Kanaan SB,Muehlenbachs A,Morrison R,Stevenson P,Fried M,Duffy PE,Nelson JL. 2017. Maternal microchimerism predicts increased infection but decreased disease due to P. falciparum during early childhood. The Journal of Infectious Diseases.
1- Maloney S, Smith A, Furst DE, MyersonD, Rupert K, Evans PC, Nelson JL. 1999. Microchimerism of maternal origin persists into adult life. The Journal in Clinical Investigation. 104(1):41-7.
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