Iron and Infection: Neonatal Nutritional Immunity

The epicentres of neonatal death worldwide are West and Central Africa, with an estimated 35 deaths per 1000 births. Neonatal infection is the third largest cause of death in children under five worldwide and is an ongoing major global public health challenge (WHO Millennium Development Goal 4). Intrauterine and neonatal infections have a high risk of causing substantial long-term neurological morbidity, affecting not just the individual but the local community and national productivity. Current research on neonatal sepsis in low-resource settings is focused on the use of mass perinatal antibiotic therapy for both mothers and babies. However, antibiotic resistance in the developing world is dramatically increasing and ablation of the neonatal microbiome has been linked with long-term health consequences. Novel therapeutic solutions are urgently required.

Nutritional immunity is the process by which the host innate immune system limits nutrient availability to invading organisms. Iron is an essential micronutrient for both microbial pathogens and their mammalian hosts. Changes in iron availability and distribution have significant effects on pathogen virulence and on the immune response to infection. Commonly found in blood, iron and its moieties (heme) are sequestered mainly in chaperone molecules (transferrin, lactoferrin, haptoglobin, hemopexin). The long-term goal of our research is to develop an anti-virulence therapeutic strategy that will augment nutritional immunity in the at-risk newborn, in order to improve neonatal survival, while avoiding the use of traditional empirical antibiotics.

During the dynamic neonatal period there are significant changes in circulation, oxygenation and iron homeostasis, the foetus maintains a high haematocrit to facilitate perfusion in utero. Within the first week of life, the neonate's haematocrit decreases as the RBCs containing foetal haemoglobin are broken down. Our preliminary data shows that during the first 24 hours of life full-term neonates will actively reduce the overall serum iron concentration and transferrin saturation decreases rapidly from 45% in cord blood to \~20% by six hours post-delivery.

Currently, little is known about nutritional immunity in the neonates or about its impact on bacterial pathogens. In the aims below, the investigators will investigate the hypothesis that nutritional immunity may be an evolutionary mechanism designed to protect neonates from infection during the first critical days of life, by limiting the pathogenicity and virulence of these organisms by reducing the availability of iron. The investigators hypothesize that this protective mechanism may not be activated in preterm and low birth weight neonates, putting these babies at an enhanced risk of neonatal infection.

Host chaperoned or unchaperoned iron, hemoglobin and heme in the blood can provide a growth-limiting nutrient to bacterial pathogens depending on the specific bacterial species and their iron-uptake mechanisms. Bacterial co-evolution with the host has resulted in two main strategies to combat host nutritional immunity: (1) chelation of iron away from chaperone proteins with siderophores, and (2) direct uptake of hemoglobin and heme moieties. Previous research and preliminary experiments conducted by our group, using ex-vivo growth assays in adult serum, has shown that growth of a panel of neonatal pathogenic bacteria each decreases in response to decreasing transferrin saturation and increases in response to increasing hemoglobin concentration. In addition, the investigators have shown that the in vitro growth of standard laboratory strains of four important causes of early neonatal sepsis in the developing world (Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, and Streptococcus agalactiae) is decreased in hypoferremic serum collected from full term neonates between 6-24 hours after birth compared to serum from the umbilical cord at birth.

In an effort to study neonatal nutritional immunity and its role in neonatal susceptibility to infection, the investigators will conduct an observational study in full-term (FT), preterm (PTB) and low birth weight (LBW) vaginally-delivered neonates born at Serrekunda Hospital in The Gambia. The investigators will fully characterize and quantify nutritional immunity during the early neonatal period (Research Question 1, Research Question 2 and Research Question 3) and the investigators will assess how it impacts bacterial growth using in vitro assays (Research Question 4). Mothers will be consented and enrolled at delivery. Blood samples will be collected once from the umbilical cord and at serial time points from the neonates (see sampling schema).