Gravidity-dependent associations between interferon response and birth weight in placental malaria

Abstract

Background: Maternal malarial infection leads to poor perinatal outcomes, including low birth weight from preterm delivery and/or fetal growth restriction, particularly in primigravidas. In placental malaria, Plasmodium falciparuminfected red blood cells cause an inflammatory response that can interfere with maternal-fetal exchange, leading to poor growth. The type I interferon (IFN-I) pathway plays an immunomodulatory role in viral and bacterial infections, usually by suppressing inflammatory responses. However, its role in placental malaria is unknown. This study examines the cytokine responses in placental tissue from subsets of malaria-infected and uninfected women, and attempts to correlate them with particular birth outcomes. Methods: 40 whole placental biopsy samples were obtained from pregnant women at least 16 years of age recruited to a larger prospective chemoprevention trial against malaria. These were patients at Tororo District Hospital in Uganda, an area of high malaria endemicity where approximately 40% of women have evidence of malaria infection at delivery. They were regularly followed at a local clinic and monitored for fever, with blood smears performed then and at time of delivery to diagnose malaria infection. Placenta biopsies were taken for histological diagnosis of placental malaria, as well as quantitative PCR analysis of genes in the IFN-I pathway (IFN-β, IL-10 and MX-1). Parameters such as infant birth weight and gestational age were also recorded. Results: Histological analysis revealed placental malaria in 18 samples, while 22 were found to be uninfected. RT-PCR analysis showed a four-fold increase in IFN-β and IL-10 expression in multigravidas with placental malaria when compared to gravidity-matched, uninfected controls. This effect was not observed in primigravidas. Interestingly, linear regression analysis showed a positive association between IFN-β levels and higher birth weights (β = 101.2 g per log2-fold increase in IFN-β expression, p = 0.042). This association was strongest in primigravidas with placental malaria (β = 339.0, p = 0.006). Conclusions: These results demonstrate differential regulation of the IFN-I pathway in placental malaria according to gravidity, with the greatest anti-inflammatory response seen in multigravidas. The association between IFN-β levels and higher birth weight also suggests a protective role for IFN-I against fetal growth restriction in placental malaria.

Pathogenicity and virulence of malaria: Sticky problems and tricky solutions

“…Malaria also disrupts the balance of pro-inflammatory and anti-inflammatory cytokines required for a healthy pregnancy and several maternal cytokines have been associated with poor pregnancy outcomes including preterm birth, small for gestational age babies, and pregnancy loss [ 274–276 ]. Placental inflammation is strongly linked to poor pregnancy outcomes, due to impaired placental development or function (see section 9.4 ), and the local placental cytokine environment can differ significantly from the maternal periphery [ 277 ], adding a layer of complexity to finding prognostic markers.…”

The Innate Immune Response in DENV- and CHIKV-Infected Placentas and the Consequences for the Fetuses: A Minireview

“…It is noteworthy that IFN-I is an essential molecule for the proper development of a pregnancy since these cytokines act in the placenta by regulating inflammation, protecting against viral infections, and contributing to fetal immunity [ 193 , 194 ]. Loss of an IFN-I-mediated response in the placenta can lead to a number of events, including exacerbated viral replication, fetal infection, and other factors that contribute to pregnancy complications [ 194 , 195 , 196 ]. Thus, the need for and urgency of carrying out studies evaluating the role of IFN-I in placental infection by DENV and CHIKV is evident.…”

The Innate Defense in the Zika-Infected Placenta

“…Some studies have pointed out the importance of IFN-I as a protective factor at the maternal-fetal interface in situations of viral infection, directly impacting viral replication in the placenta as well as vertical transmission, especially of flaviviruses such as zika virus [144]. In immunocompetent mice, the response via IFN-I is essential for preventing infection, and the loss of signaling via IFN beta in the placenta can lead to exacerbated viral replication, fetal infection, hypersensitivity to bacterial products and even maternal mortality [128,143,[145][146][147][148].…”