Gilchrist James J, Heath Jennifer N, Msefula Chisomo L, Gondwe Esther N, Naranbhai Vivek, Mandala Wilson, MacLennan Jenny M, Molyneux Elizabeth M, Graham Stephen M, Drayson Mark T, Molyneux Malcolm E, MacLennan Calman A
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Clin Vaccine Immunol. 2016 Jul 5;23(7):601-9. doi: 10.1128/CVI.00128-16. Print 2016 Jul.
Nontyphoidal Salmonella is a leading cause of sepsis in African children. Cytokine responses are central to the pathophysiology of sepsis and predict sepsis outcome in other settings. In this study, we investigated cytokine responses to invasive nontyphoidal Salmonella (iNTS) disease in Malawian children. We determined serum concentrations of 48 cytokines with multiplexed immunoassays in Malawian children during acute iNTS disease (n = 111) and in convalescence (n = 77). Principal component analysis and logistic regression were used to identify cytokine signatures of acute iNTS disease. We further investigated whether these responses are altered by HIV coinfection or severe malnutrition and whether cytokine responses predict inpatient mortality. Cytokine changes in acute iNTS disease were associated with two distinct cytokine signatures. The first is characterized by increased concentrations of mediators known to be associated with macrophage function, and the second is characterized by raised pro- and anti-inflammatory cytokines typical of responses reported in sepsis secondary to diverse pathogens. These cytokine responses were largely unaltered by either severe malnutrition or HIV coinfection. Children with fatal disease had a distinctive cytokine profile, characterized by raised mediators known to be associated with neutrophil function. In conclusion, cytokine responses to acute iNTS infection in Malawian children are reflective of both the cytokine storm typical of sepsis secondary to diverse pathogens and the intramacrophage replicative niche of NTS. The cytokine profile predictive of fatal disease supports a key role of neutrophils in the pathogenesis of NTS sepsis.
非伤寒沙门氏菌是非洲儿童败血症的主要病因。细胞因子反应在败血症的病理生理学中至关重要，并可预测其他情况下败血症的转归。在本研究中，我们调查了马拉维儿童对侵袭性非伤寒沙门氏菌（iNTS）疾病的细胞因子反应。我们采用多重免疫测定法测定了马拉维儿童在急性iNTS疾病期间（n = 111）和恢复期（n = 77）48种细胞因子的血清浓度。使用主成分分析和逻辑回归来确定急性iNTS疾病的细胞因子特征。我们进一步研究了这些反应是否因合并感染HIV或严重营养不良而改变，以及细胞因子反应是否可预测住院死亡率。急性iNTS疾病中的细胞因子变化与两种不同的细胞因子特征相关。第一种特征是已知与巨噬细胞功能相关的介质浓度增加，第二种特征是在多种病原体引起的败血症中典型反应的促炎和抗炎细胞因子升高。这些细胞因子反应在很大程度上不受严重营养不良或合并感染HIV的影响。患有致命疾病的儿童具有独特的细胞因子谱，其特征是已知与中性粒细胞功能相关的介质升高。总之，马拉维儿童对急性iNTS感染的细胞因子反应既反映了多种病原体引起的败血症典型的细胞因子风暴，也反映了NTS在巨噬细胞内的复制生态位。预测致命疾病的细胞因子谱支持中性粒细胞在NTS败血症发病机制中的关键作用。
