ABSTRACT
Global Zika virus (ZIKV) outbreaks and their link to microcephaly have raised major public health concerns. However, the mechanism of maternal-fetal transmission remains largely unknown. In this study, we determined the role of yolk sac (YS) microglial progenitors in a mouse model of ZIKV vertical transmission. We found that embryonic (E) days 6.5-E8.5 were a critical window for ZIKV infection that resulted in fetal demise and microcephaly, and YS microglial progenitors were susceptible to ZIKV infection. Ablation of YS microglial progenitors significantly reduced the viral load in both the YS and the embryonic brain. Taken together, these results support the hypothesis that YS microglial progenitors serve as "Trojan horses," contributing to ZIKV fetal brain dissemination and congenital brain defects.
Subject(s)
Fetus/pathology , Microcephaly/pathology , Microglia/virology , Pregnancy Complications, Infectious/pathology , Zika Virus Infection/pathology , Zika Virus/isolation & purification , Animals , Brain/virology , Disease Models, Animal , Female , Fetus/virology , Humans , Infectious Disease Transmission, Vertical , Male , Mice , Mice, Inbred C57BL , Microcephaly/embryology , Microcephaly/virology , Microglia/metabolism , Pregnancy , Pregnancy Complications, Infectious/virology , Viral Load , Zika Virus/physiology , Zika Virus Infection/transmission , Zika Virus Infection/virologyABSTRACT
BACKGROUND: Iron deficiency is common in obese subjects. This may be due to an increase in serum hepcidin and a decrease in iron absorption from adiposity-related inflammation. OBJECTIVE: We evaluated whether weight and fat loss in obese subjects would decrease inflammation and serum hepcidin and thereby improve iron absorption. DESIGN: We performed a 6-mo prospective study in obese [body mass index (in kg/m2) ≥35 and <45] adults who had recently undergone laparoscopic sleeve gastrectomy. At 2 and 8 mo postsurgery, subjects consumed a test drink with 6 mg 57Fe as ferrous sulfate and were intravenously infused with 100 µg 58Fe as iron citrate. We then compared erythrocyte incorporation of iron isotopic labels, changes in body composition, iron status, hepcidin, and inflammation at each time point. RESULTS: Forty-three subjects were studied at baseline, and 38 completed the protocol (32 women and 6 men). After 6 mo, total body fat, interleukin IL-6, and hepcidin were significantly lower (all P < 0.005). In iron-deficient subjects (n = 17), geometric mean (95% CI) iron absorption increased by 28% [from 9.7% (6.5%, 14.6%) to 12.4% (7.7%, 20.1%); P = 0.03], whereas in iron-sufficient subjects (n = 21), absorption did not change [5.9% (4.0%, 8.6%) and 5.6% (3.9%, 8.2%); P = 0.81]. CONCLUSION: Adiposity-related inflammation is associated with a reduction in the normal upregulation of iron absorption in iron-deficient obese subjects, and this adverse effect may be ameliorated by fat loss. This protocol was approved by the ethics committees of Wageningen University, ETH Zurich, the University of Monterrey, and the Federal Commission for the Protection against Sanitary Risks, and registered at clinicaltrials.gov as NCT01347905.
