Song Zhijun, Wu Hong, Ciofu Oana, Kong Kok-Fai, Høiby Niels, Rygaard Jørgen, Kharazmi Arsalan, Mathee Kalai
Department of Biological Sciences, Florida International University, Miami, FL 33199, USA 2Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark 3Bartholin Institute, Kommunehospitalet, Copenhagen, Denmark.
J Med Microbiol. 2003 Sep;52(Pt 9):731-740. doi: 10.1099/jmm.0.05122-0.
Pseudomonas aeruginosa is an opportunistic respiratory pathogen that accounts for most of the morbidity and mortality in cystic fibrosis (CF) patients. In CF-affected lungs, the bacteria undergo conversion from a non-mucoid to a non-tractable mucoid phenotype, due to overproduction of alginate. The effect of alginate production on pathogenicity was investigated by using an acute lung infection mouse model that compared a non-mucoid P. aeruginosa strain, PAO1, to its constitutive alginate-overproducing derivative, Alg(+) PAOmucA22, and an alginate-defective strain, Alg(-) PAOalgD. Bacterial suspensions were instilled into the left bronchus and examined 24 and 48 h post-infection. The highest bacterial loads and the most severe lung pathology were observed with strain Alg(-) PAOalgD at 24 h post-infection, which may have been due to an increase in expression of bacterial elastase by the mutant. Significantly lower lung and spleen bacterial loads were found in the two non-mucoid (PAO1 and Alg(-) PAOalgD) groups, compared to the mucoid Alg(+) PAOmucA22 group, between 24 and 48 h post-infection. The positive correlation between lung bacteriology and lung macroscopic pathology in the Alg(+) PAOmucA22 group suggests that alginate production not only impedes pulmonary clearing, but also results in severe lung damage. Positive correlations between IL12 levels and lung macroscopic pathology, and between IL12 and IFN-gamma levels in the Alg(+) PAOmucA22 group, suggested a possible contribution of these pro-inflammatory cytokines to tissue damage. No significant differences were found between the three groups in lung cytokine responses at 24 or 48 h post-infection. However, on comparison within each group at 24 and 48 h post-infection, a significant increase in the pro-inflammatory cytokine IFN-gamma was observed. Higher ratios of IFN-gamma/IL4 and IFN-gamma/IL10, but lower IL10 levels, were also found in all three groups. These results indicate a Th1-predominated immune response in these animals. Such cytokine responses could have aided the clearance of non-mucoid P. aeruginosa, but were not sufficient to alleviate infection by the mucoid variants. Alginate production may promote survival and persistence of this pathogenic micro-organism in the lung.
铜绿假单胞菌是一种机会性呼吸道病原体，在囊性纤维化（CF）患者的发病和死亡中占大多数。在受CF影响的肺部，由于藻酸盐的过量产生，细菌会从非黏液型转变为难以处理的黏液型表型。通过使用急性肺部感染小鼠模型研究了藻酸盐产生对致病性的影响，该模型将非黏液型铜绿假单胞菌菌株PAO1与其组成型藻酸盐过量产生衍生物Alg(+) PAOmucA22以及藻酸盐缺陷型菌株Alg(-) PAOalgD进行了比较。将细菌悬液滴入左支气管，并在感染后24小时和48小时进行检查。在感染后24小时，Alg(-) PAOalgD菌株观察到最高的细菌载量和最严重的肺部病理，这可能是由于突变体细菌弹性蛋白酶表达增加所致。在感染后24至48小时之间，与黏液型Alg(+) PAOmucA22组相比，两个非黏液型（PAO1和Alg(-) PAOalgD）组的肺和脾细菌载量明显更低。Alg(+) PAOmucA22组中肺部细菌学与肺部宏观病理之间的正相关表明，藻酸盐的产生不仅阻碍肺部清除，还会导致严重的肺损伤。Alg(+) PAOmucA22组中IL12水平与肺部宏观病理之间以及IL12与IFN-γ水平之间的正相关表明，这些促炎细胞因子可能对组织损伤有贡献。在感染后24或48小时，三组之间的肺细胞因子反应未发现显着差异。然而，在感染后24小时和48小时对每组进行比较时，观察到促炎细胞因子IFN-γ有显着增加。在所有三组中还发现IFN-γ/IL4和IFN-γ/IL10的比例更高，但IL10水平更低。这些结果表明这些动物中以Th1为主的免疫反应。这种细胞因子反应可能有助于清除非黏液型铜绿假单胞菌，但不足以减轻黏液型变体的感染。藻酸盐的产生可能促进这种致病微生物在肺部的存活和持续存在。
