Linking Virulence and Iron Limitation Response in Staphylococcus aureus: The sRNA IsrR Is Involved in SaeRS Activation

The Gram-positive opportunistic pathogen Staphylococcus
aureus colonizes ∼30% of the human population
but also causes various diseases. Precise regulation of genes involved
in virulence and metabolic functions is required to adapt to changing
host conditions, such as severe restriction of iron availability.
In addition to the global regulator Fur (ferric uptake regulator),
the iron limitation response of S. aureus is shaped by the recently identified sRNA IsrR (iron sparing response
regulator). IsrR mediates an iron sparing response by inhibiting the
synthesis of nonessential iron-containing proteins, which are in particular
involved in the central metabolism. In addition, we demonstrate that isrR expression is positively associated with α-hemolysin
levels and the hemolysis activity of S. aureus HG001. To investigate the influence of IsrR on virulence factor
production, we performed a mass spectrometry-based secretome analysis
of isrR-expressing and nonexpressing strains under
iron-limited and iron-sufficient conditions. The SaeR regulon was
positively influenced by the presence of IsrR, and IsrR is likely
involved in the activation of the Sae system. Additionally, IsrR also
positively affected the protein levels of the isdABCDEFGH-encoded heme uptake system (e.g., IsdB). Taken together, IsrR establishes
a link between the iron limitation response and the virulence in S. aureus.

革兰氏阳性条件致病菌金黄色葡萄球菌（Staphylococcus aureus）约定植于30%的人群中，同时可引发多种疾病。为适应宿主环境的动态变化，例如铁可用性的严格限制，该菌需精准调控毒力与代谢功能相关基因的表达。除全局调控因子铁吸收调控蛋白Fur（ferric uptake regulator）外，金黄色葡萄球菌的铁限制响应还受新近发现的小RNA（small RNA, sRNA）IsrR（iron sparing response regulator）调控。IsrR通过抑制非必需含铁蛋白的合成介导铁节约响应，这类蛋白尤其参与中心代谢过程。此外，本研究证实isrR的表达与α-溶血素（α-hemolysin）水平及金黄色葡萄球菌HG001菌株的溶血活性呈正相关。为探究IsrR对毒力因子产生的影响，本研究在铁限制与铁充足培养条件下，对表达与不表达isrR的菌株开展了基于质谱（mass spectrometry）的分泌组（secretome）分析。结果显示，SaeR调控子（SaeR regulon）的表达受IsrR的正向调控，且IsrR大概率参与Sae系统的激活过程。此外，IsrR还正向影响由isdABCDEFGH编码的血红素摄取系统（如IsdB）的蛋白水平。综上，IsrR在金黄色葡萄球菌的铁限制响应与毒力之间建立了关联。