The relationship between malarial anaemia, neutrophil function and susceptibility to invasive bacterial disease.

有充分证据表明，近期有急性疟疾感染史的儿童发生严重、危及生命的细菌感染的风险增加，我们最近描述了一种解释这种关联的生物学机制。疟疾导致红细胞破坏（溶血），将血红蛋白释放到血液中。血红蛋白被降解为血红素，血红素被血红素氧化酶-1 （HO-1）解毒。我们发现HO-1导致白细胞群（中性粒细胞）的异常分化和功能丧失，而白细胞群是杀死细菌所必需的。因此，疟疾感染引起的贫血会导致中性粒细胞功能障碍，从而导致严重的细菌感染。严重的细菌感染在疟疾流行地区比在没有疟疾的国家更为常见，由于疟疾已开始得到控制，严重细菌疾病的发病率也有所下降。然而，大多数发生严重细菌感染的儿童并没有最近急性疟疾感染的病史。这导致我们假设慢性、低级别疟疾感染（通常被错误地描述为“无症状”感染，并且已知会导致慢性疟疾贫血）也可能增加严重细菌感染的风险。在大多数疟疾流行环境中，疟疾感染的主要负担是由这些“无症状”病例造成的，这些病例的数量大大超过有典型疟疾症状的病例。因此，“无症状”感染的个体可能代表了一个庞大的、迄今未被认识的人群，由于持续的中性粒细胞功能障碍，他们处于发展为严重细菌感染的高风险中。因此，支持本研究的中心假设是，慢性“无症状”疟疾导致持续溶血和中性粒细胞功能障碍，导致控制继发性细菌感染的能力下降。此外，我们假设治疗慢性“无症状”疟疾将恢复中性粒细胞功能。为了验证这一假设，我们将确定慢性、低级别“无症状”疟疾感染对中性粒细胞功能和控制细菌感染能力的影响程度。我们将首先在小鼠模型系统中探索疟疾贫血的严重程度和持续时间、中性粒细胞功能和对细菌疾病的易感性之间的关联，然后通过对患有慢性亚临床疟疾感染和贫血的冈比亚儿童进行横断面研究，确定这些发现与人类的相关性程度。最后，我们将进行一项小型的原理验证研究，以确定用抗疟疾药物治疗儿童是否会恢复中性粒细胞功能。如果是这样，这可能为未来的临床试验提供理由，以确定治疗“无症状”疟疾的公共卫生规划是否会减少疟疾流行人群中严重细菌感染的发生率。

It is well documented that children with a recent history of acute malaria infection are at increased risk of developing severe, life threatening bacterial infections and we have recently described a biological mechanism that explains this association. Malaria causes destruction of red blood cells (haemolysis), releasing haemoglobin into the blood stream. Haemoglobin is degraded to heme and the heme is detoxified by an enzyme, heme-ozygenase-1 (HO-1). We found that HO-1 causes abnormal differentiation and loss of function of a white blood cell population (neutrophils) that are essential for killing bacteria. Thus, the anaemia caused by malaria infection causes the neutrophil dysfunction which predisposes to severe bacterial infections. Severe bacterial infections are much more common in areas where malaria is endemic than in countries where malaria is absent, and as malaria has begun to be controlled, the incidence of severe bacterial disease has also fallen. However, most children who develop severe bacterial infections do not have the history of a very recent episode of acute malaria infection. This has led us to hypothesise that chronic, low grade malaria infections (which are often, erroneously, described as "asymptomatic" infections and which are known to contribute to chronic malarial anaemia) may also increase the risk of severe bacterial infection. In most malaria endemic settings, the major burden of malaria infection is due to these "asymptomatic" cases, which greatly outnumber those with classical malaria symptoms. "Asymptomatically" infected individuals may thus represent a large, hitherto unrecognized, population that is at high risk of developing severe bacterial infection due to persistent neutrophil dysfunction. Thus, the central hypothesis underpinning this study is that chronic "asymptomatic" malaria leads to persistent haemolysis and neutrophil dysfunction, resulting in a decreased ability to control secondary bacterial infections. In addition, we hypothesise that treatment of chronic "asymptomatic" malaria will restore neutrophil function. To test this hypothesis we will determine the extent to which chronic, low grade "asymptomatic" malaria infection affects neutrophil function and the ability to control bacterial infections. We will begin by exploring the association between severity and duration of malarial anaemia, neutrophil function and susceptibility to bacterial disease in a mouse model system and then determine the extent to which these findings are relevant in humans by carrying out a cross-sectional study of Gambian children with chronic, subclinical malaria infection and anaemia. Finally, we will carry out a small proof-of-principle study to determine whether treating children with anti-malarial drugs will restore neutrophil function. If so, this may provide the justification for future clinical trials to determine whether public health programmes to treat "asymptomatic" malaria would reduce the incidence of severe bacterial infections in malaria endemic populations.