Status: Funded - Open
Placental malaria and maternal-fetal microchimerism
Whitney Harrington, M.D., Ph.D.
BACKGROUND: 125 million pregnant women are at risk of malaria each year, resulting in poor
outcomes for the fetus, neonate, and infant, and an estimated 1,300 children less than five die
of malaria each day. The determinants of malaria susceptibility in pregnancy and infancy are
largely unknown but may include maternal microchimerism (MMc), a form of non-Mendelian
maternal heritability. Maternal-fetal exchange during pregnancy leads to MMc, induction of fetal
regulatory T-cells to maternal antigens, and durable maternal-specific tolerance.
GAP: The effect of maternal malaria infection during pregnancy on MMc has not yet been
explored. In addition, MMc may be a potential mechanism for the association between placental
malaria (PM) and malaria susceptibility during infancy via an MMc-associated induction of fetal
tolerance to malaria antigens.
HYPOTHESIS: We hypothesized that PM, with its associated damage to the trophoblast barrier,
increases the prevalence and level of MMc and that MMc alters malaria susceptibility during
METHODS: We utilized samples from women with and without PM and their children, matched
for demographic factors and derived from a larger, pre-established birth cohort from Muheza,
Tanzania. Women and their infants were genotyped at polymorphic loci to determine a
discordant marker, and MMc was investigated in cord blood samples using a validated panel of
quantitative PCR assays. Presence and level of MMc were compared across PM groups. In
addition, we investigated the ability of cord blood MMc to predict malaria outcomes during early
RESULTS: We found that inflammatory PM significantly increased detection of MMc among
offspring of primi- and secundigravidae and that both non-inflammatory PM and inflammatory
PM significantly increased the level of MMc among all offspring. Detection and level of MMc
were associated with sFlt-1, a biomarker of placental dysfunction. Detectable MMc at birth
predicted an increased risk of positive blood smear but, surprisingly, a decreased risk of
symptomatic malaria or malaria hospitalization during early childhood. In addition, MMc was
protective against non-malarial fever. Such a phenotype may confer a survival benefit, allowing
experience of infection but protection from disease.
IMPACT: We provide evidence supporting the hypothesis that the fetus acquires more MMc in
the setting of PM, a state characterized by a high degree of placental pathology. This is the first
demonstration that placental pathology, in this case secondary to infection, directly leads to an
increased maternal graft. In addition, our data suggest that maternal cells acquired in utero have
the potential to directly or indirectly alter infectious disease susceptibility in the child, a novel
paradigm with broad implications for perinatal infections, other postnatal infections, and
response to vaccination. In particular, modulation of MMc may represent a new target for
malaria prevention strategies.
Fred Hutchinson Cancer Research Center