Defining upper respiratory colonisation and microbiome evolution in mother-infant pairs following Neisseria lactamica inoculation in late pregnancy

背景：研究新的策略来预防由生活在鼻子和喉咙中的细菌引起的婴儿严重感染是很重要的。这些细菌通常是无害的，但在某些情况下会引起肺部感染（肺炎）和脑部感染（脑膜炎），这是全世界幼儿死亡的最常见原因之一。虽然疫苗可以预防某些形式的肺炎和脑膜炎，但它们不能保护最年幼的婴儿（他们面临的风险最大），而且世界上20%以上的儿童没有接种所有推荐的疫苗。治疗感染变得越来越困难，因为细菌对抗生素的耐药性越来越强，而这些耐药性感染每年在全世界造成21.4万多名新生儿死亡。给婴儿喂“好”细菌可能是减少潜在危险“坏”细菌风险的一种方法。出生后，婴儿迅速被来自母亲、其他人和环境的细菌覆盖（定植）。所有在特定身体部位定居的细菌都被称为微生物群。其中许多是“好”细菌，可以防止“坏”细菌的滋生，鼻子和喉咙里有某些“好”细菌的婴儿胸部和耳朵感染较少。科学家们已经尝试给孕妇、新妈妈和婴儿服用益生菌（“好”细菌）。这些研究表明，益生菌是安全的，但给予的细菌数量往往是未知的，也不清楚它们是否有效，或者它们如何影响婴儿的微生物群。一个更精确的选择是使用受控的人类感染研究，在这种研究中，细菌的数量是已知的。我们的研究小组以前曾利用受控的人类感染将内酰胺奈瑟菌（“有益”细菌）引入成人鼻子。这种方法安全可靠地减少了脑膜炎奈瑟菌（“坏”细菌）的数量，但尚未在孕妇或婴儿中进行试验。内酰胺奈瑟菌（“有益”细菌）自然存在于超过40%的1-2岁儿童体内，但在成人和新生儿中并不常见。它不会引起感染：事实上，它可以自然地防止脑膜炎奈瑟菌（“坏”细菌）。拟议的研究：我将通过将内酰胺奈瑟菌（“好”细菌）引入孕妇的鼻子来进行一项对照人类感染研究，以确定它是否会在出生后转移给她们的婴儿。这模仿了新生婴儿从母亲那里获得细菌的自然方式。然后，我将研究婴儿及其母亲的鼻子和喉咙微生物群。如果在婴儿身上检测到“有益”细菌，我将调查婴儿出生后第一个月与母亲相比细菌数量的变化情况。然而，如果在婴儿身上没有发现这种“好”细菌，我将调查其他类型的“好”细菌是否已经从母亲自然转移到婴儿身上。在设计这项研究时，我采访了孕妇，发现她们支持这一建议。应用和益处：这项研究将提高我们对细菌如何从母亲转移到婴儿的理解，以及孕期控制的人类感染是否会改变新生儿微生物群的发育。从长远来看，最终目标是使用“好”细菌来改变婴儿的微生物群，以防止“坏”细菌定植并引起疾病，特别是在风险最高的出生后的第一个月。

Background:It is important to research new strategies to prevent serious infections in babies caused by bacteria living in the nose and throat. These bacteria are generally harmless, but in some circumstances cause infections of the lungs (pneumonia) and brain (meningitis), which are among the commonest causes of death in young children worldwide. Although vaccines protect against some forms of pneumonia and meningitis, they do not protect the very youngest babies (who are most at risk), and over 20% of the world's children do not receive all recommended vaccines. It is becoming harder to treat infections, because bacteria are becoming more resistant to antibiotics, and these resistant infections cause over 214,000 newborn deaths worldwide per year.Giving 'good' bacteria may be one way to reduce the risk of potentially dangerous 'bad' bacteria to babies. After birth, babies rapidly become covered (colonised) with bacteria from their mothers, other people and the environment. All the bacteria colonising a particular body site are called the microbiome. Many of these are 'good' bacteria, which can prevent 'bad' bacteria from colonising, and babies with certain 'good' bacteria in the nose and throat have fewer chest and ear infections. Scientists have tried giving probiotics ('good' bacteria swallowed or sprayed into the nose) to pregnant women, new mothers and babies. These studies show that probiotics are safe, but the amount of bacteria given is often unknown, and it is unclear if they work or how they affect the baby's microbiome. A more precise option is to use a controlled human infection study, where the amount of bacteria given is known. Our team has previously used controlled human infection to introduce Neisseria lactamica ('good' bacteria) into adult noses. This method safely and reliably decreases the amount of Neisseria meningitids ('bad' bacteria), but has not been tried in pregnant women or babies. Neisseria lactamica ('good' bacteria) is naturally found in over 40% of children aged 1-2 years, but is uncommon in adults and newborns. It does not cause infections: in fact, it may naturally protect against Neisseria meningitidis ('bad' bacteria).Proposed research:I will perform a controlled human infection study by introducing Neisseria lactamica ('good' bacteria) into pregnant women's noses, to find out if it is transferred to their babies after birth. This mimics the natural way that newborn babies become colonised with bacteria from their mothers. I will then study the nose and throat microbiome of the babies and their mothers. If the 'good' bacteria is detected in the babies, I will investigate how the population of bacteria changes over the first month of life in babies compared with their mothers. However, if this 'good' bacteria is not found in the babies, I will investigate if other types of 'good' bacteria have transferred naturally from the mothers to their babies. I have interviewed pregnant women when designing this study, and found that they support this proposal.Applications and benefits: This study will improve our understanding of how bacteria transfer from mothers to their babies, and whether controlled human infection in pregnancy can alter a newborn's developing microbiome. In the long term, the ultimate goal is to use 'good' bacteria to alter a baby's microbiome to prevent 'bad' bacteria from colonising and causing disease, especially in the highest-risk first month of life.