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

有充分的证据表明，最近有急性疟疾感染史的儿童患严重威胁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联系的生物学机制。疟疾会破坏红细胞(溶血)，将血红蛋白释放到血液中。血红蛋白被降解成亚铁血红素，亚铁血红素被一种名为亚铁血红素合酶-1(HO-1)的酶解毒。我们发现，HO-1会导致白细胞(中性粒细胞)的异常分化和功能丧失，而中性粒细胞是杀菌所必需的。因此，疟疾感染引起的贫血导致中性粒细胞功能障碍，从而容易发生严重的细菌感染。与没有疟疾的国家相比，疟疾流行地区的严重细菌感染要普遍得多，随着疟疾开始得到控制，严重细菌疾病的发病率也有所下降。然而，大多数患上严重细菌感染的儿童没有最近一次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，并被认为是导致慢性疟疾贫血的原因)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，这些病例的数量远远超过具有典型疟疾症状的病例。因此，无症状的感染者可能代表了一大群迄今未被认识到的人群，由于持续的中性粒细胞功能障碍，他们患严重细菌感染的风险很高。因此，支持这项研究的中心假设是，慢性“无症状”疟疾会导致持续性溶血和中性粒细胞功能障碍，从而降低控制继发性细菌感染的能力。此外，我们假设慢性“无症状”疟疾的治疗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、低度“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、中性粒细胞功能与细菌疾病易感性之间的关系，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相关的程度。最后，我们将开展一项小型原则验证研究，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。如果是这样的话，这可能为未来的临床试验提供理由，以确定治疗“无症状”疟疾的公共卫生计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.