Fitzpatrick Elizabeth A, You Dahui, Shrestha Bishwas, Siefker David, Patel Vivek S, Yadav Nikki, Jaligama Sridhar, Cormier Stephania A
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, United States of America.
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, United States of America.
PLoS One. 2017 Jan 6;12(1):e0169273. doi: 10.1371/journal.pone.0169273. eCollection 2017.
Pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of morbidity and mortality in infants particularly following lower respiratory tract viral infections such as Respiratory Syncytial Virus (RSV). However, the mechanisms by which co-infection of infants by MRSA and RSV cause increased lung pathology are unknown. Because the infant immune system is qualitatively and quantitatively different from adults we developed a model of infant MRSA pneumonia which will allow us to investigate the effects of RSV co-infection on disease severity. We infected neonatal and adult mice with increasing doses of MRSA and demonstrate that neonatal mice have delayed kinetics in clearing the bacteria in comparison to adult mice. There were differences in recruitment of immune cells into the lung following infection. Adult mice exhibited an increase in neutrophil recruitment that coincided with reduced bacterial titers followed by an increase in macrophages. Neonatal mice, however, exhibited an early increase in neutrophils that did not persist despite continued presence of the bacteria. Unlike the adult mice, neonatal mice failed to exhibit an increase in macrophages. Neonates exhibited a decrease in phagocytosis of MRSA suggesting that the decrease in clearance was partially due to deficient phagocytosis of the bacteria. Both neonates and adults responded with an increase in pro-inflammatory cytokines following infection. However, in contrast to the adult mice, neonates did not express constitutive levels of the anti-microbial peptide Reg3γ in the lung. Infection of neonates did not stimulate expression of the co-stimulatory molecule CD86 by dendritic cells and neonates exhibited a diminished T cell response compared to adult mice. Overall, we have developed a neonatal model of MRSA pneumonia that displays a similar delay in bacterial clearance as is observed in the neonatal intensive care unit and will be useful for performing co-infection studies.
耐甲氧西林金黄色葡萄球菌（MRSA）引起的肺炎是婴儿发病和死亡的重要原因，尤其是在呼吸道合胞病毒（RSV）等下呼吸道病毒感染之后。然而，MRSA和RSV共同感染婴儿导致肺部病理加重的机制尚不清楚。由于婴儿免疫系统在质和量上都与成人不同，我们建立了婴儿MRSA肺炎模型，这将使我们能够研究RSV共同感染对疾病严重程度的影响。我们用递增剂量的MRSA感染新生小鼠和成年小鼠，结果表明与成年小鼠相比，新生小鼠清除细菌的动力学延迟。感染后肺部免疫细胞的募集存在差异。成年小鼠中性粒细胞募集增加，这与细菌滴度降低同时发生，随后巨噬细胞增加。然而，新生小鼠中性粒细胞早期增加，尽管细菌持续存在，但这种增加并未持续。与成年小鼠不同，新生小鼠巨噬细胞未增加。新生小鼠对MRSA的吞噬作用降低，这表明清除率降低部分是由于细菌吞噬不足。新生小鼠和成年小鼠在感染后促炎细胞因子均增加。然而，与成年小鼠相比，新生小鼠肺部未表达组成水平的抗菌肽Reg3γ。新生小鼠感染未刺激树突状细胞表达共刺激分子CD86，与成年小鼠相比，新生小鼠的T细胞反应减弱。总体而言，我们建立了一个MRSA肺炎新生模型，该模型显示出与新生儿重症监护病房中观察到的类似的细菌清除延迟，将有助于进行共同感染研究。
