Department of Microbiology & Immunology, University of Nevada, Reno School of Medicine, Reno, Nevada, USA.
J Bacteriol. 2022 Nov 15;204(11):e0025122. doi: 10.1128/jb.00251-22. Epub 2022 Oct 26.
The group A Streptococcus (GAS; Streptococcus pyogenes) causes an elaborate array of human diseases. In part, such variability in disease potential is a consequence of GAS manipulating the expression of a catalogue of virulence factors, with regulation occurring at both the transcriptional and posttranscriptional levels. The GAS small regulatory RNA (sRNA) FasX contributes to this regulatory activity, enhancing expression of the thrombolytic agent streptokinase, and reducing expression of collagen (pili) and fibronectin (PrtF1 and PrtF2) -binding adhesins. Here, we expand insight into the regulatory targets of FasX by identifying the M-related protein (Mrp), a fibrinogen-binding adhesin with anti-phagocytic activity, as a negatively-regulated target of FasX. Importantly, investigation of the consequences of FasX-mediated regulation led to the discovery that FasX is a major positive regulator of GAS survival and proliferation in non-immune whole human blood, with a 30-fold difference in GAS cell numbers between a mutant strain and isogenic parental and complemented mutant strains. No difference in cell numbers were observed when these strains were grown in human serum, consistent with the protective phenotype associated with FasX occurring due to the inhibition of cell (e.g., neutrophil) - mediated GAS killing. The FasX-regulated factor/s responsible for the blood survival phenotype remain to be defined. In summary, we expand the known FasX regulon and identify a new phenotype associated with the regulatory activity of this key GAS sRNA. Small regulatory RNAs (sRNAs) represent a major class of regulatory molecule that promotes the ability of the group A Streptococcus (GAS) and other pathogens to regulate virulence factor expression. Despite FasX being the best-described sRNA in GAS, there remains much to be learned. Here, we highlight the importance of FasX, identifying for the first time that the loss of this sRNA results in a major reduction in the ability of GAS to survive in human blood, a phenotype critical to the ability of this human-specific pathogen to cause severe invasive infections. We also identified a novel regulatory target of FasX, thereby expanding the known regulon of this key sRNA.
A 组链球菌（GAS；酿脓链球菌）可引起多种人类疾病。部分原因是 GAS 通过操纵一系列毒力因子的表达来改变疾病的潜在表现，其调控发生在转录和转录后水平。GAS 小调控 RNA（sRNA）FasX 有助于这种调控活性，增强了纤溶酶原激活剂链激酶的表达，降低了胶原蛋白（菌毛）和纤维连接蛋白（PrtF1 和 PrtF2）结合黏附素的表达。在这里，我们通过鉴定与纤维蛋白原结合的黏附蛋白 M 相关蛋白（Mrp）作为 FasX 的负调控靶标，扩展了 FasX 调控靶标的见解。重要的是，对 FasX 介导的调控的后果进行的研究导致发现 FasX 是 GAS 在非免疫全人血中存活和增殖的主要正调控因子，突变株与同源亲本和互补突变株之间 GAS 细胞数量相差 30 倍。当这些菌株在人血清中生长时，没有观察到细胞数量的差异，这与 FasX 相关的保护性表型一致，因为 FasX 的抑制作用是由于细胞（例如中性粒细胞）介导的 GAS 杀伤。负责血液存活表型的 FasX 调节因子/因素仍有待确定。总之，我们扩展了已知的 FasX 调控基因，并确定了与这种关键 GAS sRNA 调控活性相关的新表型。小调控 RNA（sRNA）是一类主要的调控分子，可增强 A 组链球菌（GAS）和其他病原体调节毒力因子表达的能力。尽管 FasX 是 GAS 中描述最好的 sRNA，但仍有许多未知之处。在这里，我们强调了 FasX 的重要性，首次发现缺失这种 sRNA 会导致 GAS 在人血中存活能力大幅下降，这种表型对于这种人类特异性病原体引起严重侵袭性感染的能力至关重要。我们还鉴定了 FasX 的一个新的调控靶标，从而扩展了这种关键 sRNA 的已知调控基因。
