The impact of genetic susceptibility to systemic lupus erythematosus on placental malaria in mice

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 (SLE(s)) mice were similar as were the number and viability of fetuses in pregnant WT and SLE(s) 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 SLE(s) 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 SLE(s) 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.

Figure 1. Effects of SLE susceptibility and malaria on parasitemia, hemoglobin and body weight.

(A–B) Peripheral parasitemia were determined at days 6, 7 and 8 post-conception. (C–D) Blood hemoglobin concentrations were determined at day 6, 7 and 8 post-inoculation. Data are stratified according to pregnancy and infection status. (E–F) Body weight was determined at days 6, 7 and 8 post-conception. Data was stratified according to pregnancy and infection status. n = 15 (WT) and n = 18 (SLE^s) for parasitemia; n = 30 (WT) and 34 (SLE) for hemoglobin and body weight.

Figure 2. Effects of SLE susceptibility and malaria on reproductive fitness.

(A) Conception rates (i.e. percentage of plugged animals that were determined to be pregnant) were determined at day 8 post-copula. (B) The total number of fetuses was determined at day 8 post-conception. (C) Graph shows the percentage of non-necrotic fetuses determined by analyzing H&E sections of uteri collected at day 8 post-conception. Samples marked as ‘All’ represented the pooled data for SLE^s or all WT, independent of infection status. WT (n = 36) and SLEs mice (N = 36).

Figure 3. Malaria caused massive decidual necrosis in SLE^s and control animals.

Uterine section of an infected SLE mouse (A) or infected WT mouse (D) showing massive decidual necrosis at day 8 post-conception at low-magnification (1.25×). High-magnification views (4× and 10×) of uteri from an infected SLE (B–C) and infected WT mouse (E–F). Uterine section of an uninfected SLE (G) or uninfected WT mouse (J) showing normal morphology of an 8 day old fetus at low-magnification (1.25×). High-magnification views (4× and 10×) of uteri from a non-infected SLE (H–I) or uninfected WT mouse (K–L). Uteri from all mice were analyzed by a pathologist (n = 72).