Metkar Shalaka, Awasthi Shanjana, Denamur Erick, Kim Kwang Sik, Gangloff Sophie C, Teichberg Saul, Haziot Alain, Silver Jack, Goyert Sanna M
Department of Microbiology and Immunology, CUNY Medical School, and Sophie Davis School for Biomedical Sciences, City College of New York, New York, New York, USA.
Infect Immun. 2007 Nov;75(11):5415-24. doi: 10.1128/IAI.00601-07. Epub 2007 Aug 20.
Severe bacterial infections leading to sepsis or septic shock can be induced by bacteria that utilize different factors to drive pathogenicity and/or virulence, leading to disease in the host. One major factor expressed by all clinical isolates of gram-negative bacteria is lipopolysaccharide (LPS); a second factor expressed by some Escherichia coli strains is a K1 polysaccharide capsule. To determine the role of the CD14 LPS receptor in the pathogenic effects of naturally occurring E. coli, the responses of CD14-/- and CD14+/+ mice to three different isolates of E. coli obtained from sepsis patients were compared; two isolates express both smooth LPS and the K1 antigen, while the third isolate expresses only LPS and is negative for K1. An additional K1-positive isolate obtained from a newborn with meningitis and a K1-negative isogenic mutant of this strain were also used for these studies. CD14-/- mice were resistant to the lethal effects of the K1-negative isolates. This resistance was accompanied by significantly lower levels of systemic tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in these mice than in CD14+/+ mice, enhanced clearance of the bacteria, and significantly fewer additional gross symptoms. In contrast, CD14-/- mice were as sensitive as CD14+/+ mice to the lethal effects of the K1-positive isolates, even though they had significantly lower levels of TNF-alpha and IL-6 than CD14+/+ mice. These studies show that different bacterial isolates can use distinctly different mechanisms to cause disease and suggest that new, nonantibiotic therapeutics need to be directed against multiple targets.
导致败血症或脓毒性休克的严重细菌感染可由利用不同因素驱动致病性和/或毒力从而在宿主体内引发疾病的细菌引起。革兰氏阴性菌的所有临床分离株表达的一个主要因素是脂多糖（LPS）；一些大肠杆菌菌株表达的另一个因素是K1多糖荚膜。为了确定CD14 LPS受体在天然存在的大肠杆菌致病作用中的作用，比较了CD14 -/- 和CD14 +/+ 小鼠对从败血症患者获得的三种不同大肠杆菌分离株的反应；两种分离株同时表达光滑型LPS和K1抗原，而第三种分离株仅表达LPS且K1呈阴性。从一名患有脑膜炎的新生儿获得的另一种K1阳性分离株及其K1阴性同基因突变体也用于这些研究。CD14 -/- 小鼠对K1阴性分离株的致死作用具有抗性。这种抗性伴随着这些小鼠体内全身肿瘤坏死因子α（TNF-α）和白细胞介素-6（IL-6）水平明显低于CD14 +/+ 小鼠，细菌清除增强，以及明显更少的其他总体症状。相比之下，CD14 -/- 小鼠对K1阳性分离株的致死作用与CD14 +/+ 小鼠一样敏感，尽管它们的TNF-α和IL-6水平明显低于CD14 +/+ 小鼠。这些研究表明，不同的细菌分离株可使用截然不同的机制来引发疾病，并表明需要针对多个靶点开发新的非抗生素疗法。
