Nhu Nguyen T Q, Lin Huaiying, Pigli Ying, Sia Jonathan K, Kuhn Pola, Snitkin Evan S, Young Vincent, Kamboj Mini, Pamer Eric G, Rice Phoebe A, Shen Aimee, Dong Qiwen
Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Duchossois Family Institute, University of Chicago, Chicago, Illinois, USA.
bioRxiv. 2024 Sep 24:2023.06.22.546185. doi: 10.1101/2023.06.22.546185.
RT027 strains cause infections that vary in severity from asymptomatic to lethal, but the molecular basis for this variability is poorly understood. Through comparative analyses of RT027 clinical isolates, we determined that isolates that exhibit greater variability in their flagellar gene expression exhibit greater virulence . flagellar genes are phase-variably expressed due to the site-specific inversion of the 5'UTR region, which reversibly generates ON vs. OFF orientations for the flagellar switch. We found that longer inverted repeat (IR) sequences in this switch region correlate with greater disease severity, with RT027 strains carrying 6A/6T IR sequences exhibiting greater phenotypic heterogeneity in flagellar gene expression (60%-75% ON) and causing more severe disease than those with shorter IRs (> 99% ON or OFF). Taken together, our results reveal that phenotypic heterogeneity in flagellar gene expression may contribute to the variable disease severity observed in patients.
RT027菌株引起的感染严重程度各不相同，从无症状到致命，但这种变异性的分子基础却知之甚少。通过对RT027临床分离株的比较分析，我们确定，在鞭毛基因表达上表现出更大变异性的分离株具有更强的毒力。鞭毛基因由于5'UTR区域的位点特异性倒位而发生相变表达，这会可逆地产生鞭毛开关的“开”与“关”方向。我们发现，该开关区域中较长的反向重复（IR）序列与更严重的疾病相关，携带6A/6T IR序列的RT027菌株在鞭毛基因表达上表现出更大的表型异质性（60%-75%为“开”），并且比那些具有较短IR序列的菌株（>99%为“开”或“关”）引起更严重的疾病。综上所述，我们的结果表明，鞭毛基因表达的表型异质性可能是导致患者疾病严重程度不同的原因。
