Abstract
Severe malaria, including cerebral malaria (CM) and placental malaria (PM), have been recognized to have many of the features of uncontrolled inflammation. We recently showed that in mice genetic susceptibility to the lethal inflammatory autoimmune disease, systemic lupus erythematosus (SLE), conferred resistance to CM. Protection appeared to be mediated by immune mechanisms that allowed SLE-prone mice, prior to the onset of overt SLE symptoms, to better control their inflammatory response to Plasmodium infection. Here we extend these findings to ask does SLE susceptibility have 1) a cost to reproductive fitness and/or 2) an effect on PM in mice? The rates of conception for WT and SLE susceptible (SLEs) mice were similar as were the number and viability of fetuses in pregnant WT and SLEs mice indicating that SLE susceptibility does not have a reproductive cost. We found that Plasmodium chabaudi AS (Pc) infection disrupted early stages of pregnancy before the placenta was completely formed resulting in massive decidual necrosis 8 days after conception. Pc-infected pregnant SLEs mice had significantly more fetuses (∼1.8 fold) but SLE did not significantly affect fetal viability in infected animals. This was despite the fact that Pc-infected pregnant SLEs mice had more severe symptoms of malaria as compared to Pc-infected pregnant WT mice. Thus, although SLE susceptibility was not protective in PM in mice it also did not have a negative impact on reproductive fitness.
Highlights
It is estimated that in Africa more than 125 million pregnant women are at risk for Plasmodium falciparum infections leading to placental malaria (PM)
We evaluated systemic lupus erythematosus (SLE) mice infected with non-lethal parasite Plasmodium chabaudi chabaudi AS (Pc) that induces a disease which is similar to PM, involving sequestration of infected red blood cells in the placenta and local inflammation that leads to fetal loss [13]
The generalized estimating equation (GEE) analysis showed that pregnant, Pc-infected SLEs mice had significantly lower hemoglobin levels as compared to pregnant infected WT mice at day 6 (2.6 g/dL [95% CI, 0.6–4.5] lower; P = 0.01), day 7 (2.9 g/dL [95% CI, 1.0–4.8] lower; P = 0.003) and day 8 (3.5 g/ dL [95% CI, 1.6–5.4] lower; P,0.001) post Pc infection (Figure 1C)
Summary
It is estimated that in Africa more than 125 million pregnant women are at risk for Plasmodium falciparum infections leading to placental malaria (PM). Protection appeared to be mediated by mechanisms that allowed the SLEs mice to better control inflammation possibly through the heightened production of the anti-inflammatory cytokine IL-10 Consistent with this conclusion, Pb ANKA-infected SLEs and WT mice were susceptible to death caused by severe anemia that did not involve inflammation. Relevant to these observations in mice, a human FccRIIB allele that encodes a polymorphism in the transmembrane domain of the receptor that results in loss of function and is associated with SLE (OR = 1.73), is significantly more common in Africans and is associated with protection from severe malaria in African children [12]
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