How MicroRNAs Influence Klebsiella pneumoniae Infections

Klebsiella pneumoniae is gaining attention in the scientific and medical community for all the wrong reasons. Known as a leading cause of hospital-acquired infections, this Gram-negative bacterium has evolved into a major public health concern, especially with the emergence of multidrug-resistant and hypervirulent strains. A new review published in Biomolecules and Biomedicine examines the roles of microRNAs (miRNAs) during K. pneumoniae infection, revealing potential directions for diagnosis and therapy.

Understanding Klebsiella pneumoniae and Its Clinical Impact

1. K. pneumoniae was first identified in the lungs of patients who had died from pneumonia. Since then, it has been found colonizing the mucosal surfaces of the upper respiratory and gastrointestinal tracts. It can cause a wide range of diseases, including:

• Pneumonia
• Sepsis
• Urinary tract infections
• Peritonitis
• Lung injury

The bacterium’s virulence is driven by several factors such as capsules, lipopolysaccharides, membrane proteins, and iron-acquisition systems. These allow it to adhere to, invade, and colonize host tissues.

Two main types of K. pneumoniae exist: classical (cKp) and hypervirulent (hvKp). Through the acquisition of mobile genetic elements, classical strains have become increasingly aggressive. Compounding the threat, the spread of carbapenem-resistant K. pneumoniae (CR-Kp) limits treatment options, often leading to high mortality rates.

To respond to this growing crisis, researchers are focusing on understanding how the host immune system interacts with the pathogen. One area of interest is the role of miRNAs, which regulate gene expression and are involved in immune responses and inflammation.

miRNAs: The Body’s Molecular Regulators

miRNAs are small, non-coding RNA molecules about 22 nucleotides long. They bind to complementary regions of mRNA, resulting in translation inhibition or degradation. miRNAs can modulate entire signaling pathways and restore cellular functions altered by infections.

They are involved in several biological processes including:

• Inflammation
• Immune cell development
• Host-pathogen interactions
• Cell differentiation and proliferation

In the context of K. pneumoniae infection, miRNAs influence inflammation, regulate cytokine secretion, and even play roles in epigenetic modifications such as SUMOylation.

Key Findings: miRNAs in K. pneumoniae-Induced Diseases

The review outlines miRNA activity in three major disease scenarios caused by K. pneumoniae: lung injury, sepsis, and peritonitis.

1. Lung Injury: A Focus on Inflammation and Adhesion

• miR-155 and miR-23a are downregulated in lung epithelial cells infected with K. pneumoniae. They regulate adhesion through the integrin α5β1/Rac1 pathway by targeting HMGN2 and nuclear factor I (NFI).
• miR-124-3p has an anti-inflammatory effect by inhibiting the p38MAPK pathway, reducing lung damage.
• Exosomal miR-155-5p, derived from macrophages, promotes acute lung injury by activating the MSK1/DUSP1/p38MAPK pathway and M1 macrophage polarization.
• MVs-miR-223/142, encapsulated in extracellular vesicles, suppress the activation of the NLRP3 inflammasome and reduce lung inflammation.
• Exosomal miR-181a-5p, derived from adipose-derived mesenchymal stem cells, targets STAT3 and alleviates inflammation and lung damage.

2. Sepsis: miRNAs as Mediators and Biomarkers

• A K. pneumoniae-associated gene, ygiM, has been linked to miRNAs such as miR-7108-5p, miR-4433b-3p, and miR-342-3p, which may influence bacterial resistance to macrophage phagocytosis.
• miR-155 has been implicated in neutrophil extracellular trap formation but may also contribute to tissue damage and worse outcomes in sepsis.
• Differentially expressed miRNAs in sepsis may serve as potential biomarkers for disease severity and prognosis.

3. Peritonitis: Modulating Cytokine Responses

• In a mouse model of peritonitis, several miRNAs showed altered expression. Notably, miR-21, miR-132, miR-301a, and miR-652 were upregulated, while miR-375 was downregulated.
• miR-146a and miR-155 modulate the TLR/IL-1 signaling pathways by targeting IRAK1/2 and TRAF6 or by suppressing SOCS1 and SHIP1, influencing TNF-α levels.
• These miRNAs collectively regulate inflammatory cytokines such as IL-1β, IL-6, and TNF-α, helping shape host tolerance and immune responses.

4. SUMOylation: A New Dimension in Infection Biology

• SUMOylation is a post-translational modification that enhances host cell defense.
• Let-7 miRNA, induced by IFN-I signaling, reduces SUMOylation and thereby promotes K. pneumoniae infection.
• This finding suggests a pathogen-driven mechanism to suppress host inflammation via miRNA modulation.

Implications and Future Directions

The findings presented in this review emphasize the crucial regulatory role of miRNAs in K. pneumoniae infections. They not only modulate immune responses but also provide insight into new avenues for clinical diagnostics and therapy development.

Potential applications include:

• miRNA-based diagnostics to detect severe infection or treatment response.
• Therapeutic targeting of specific miRNAs (e.g., miR-155 or miR-181a-5p) to reduce inflammation or enhance bacterial clearance.
• Combination therapies using miRNA modulators and antibiotics to overcome resistance.

Conclusion

This article underscores the growing importance of miRNAs in infectious diseases, particularly in the context of K. pneumoniae, a pathogen of increasing concern due to its virulence and resistance profile. As researchers continue to explore the molecular pathways of host-pathogen interactions, miRNAs stand out as both key regulators and promising targets for intervention.

Understanding how these small RNAs influence inflammation, immunity, and bacterial survival may pave the way for new strategies to combat multidrug-resistant infections in clinical settings.

 

The translation of the preceding English text in Chinese:

 

肺炎克雷伯菌（Klebsiella pneumoniae）因不良原因而受到科学与医学界的关注。 作为医院获得性感染的主要病因之一，这种革兰氏阴性菌现已演变成一个严重的公共卫生问题，尤其是由于多重耐药株与高毒力株的出现。一篇新发表在《Biomolecules and Biomedicine》期刊的综述文章探讨了肺炎克雷伯菌感染过程中微小RNA（miRNA）的作用，揭示了在诊断与治疗方面的潜在方向。

认识肺炎克雷伯菌及其临床影响

肺炎克雷伯菌最早是在死于肺炎的患者肺部发现的。此后，人们发现在人体上呼吸道与胃肠道的黏膜表面也存在其定植现象。它可引起多种疾病，包括：

• 肺炎

• 败血症

• 尿路感染

• 腹膜炎

• 肺损伤

该菌的毒力来源于多个因素，例如荚膜、多糖体、膜蛋白及铁摄取系统，这些因素使其能粘附、侵入并定植于宿主组织。

肺炎克雷伯菌分为两种主要类型：经典型（cKp）和高毒力型（hvKp）。经典型通过获得可移动遗传元件变得越来越具攻击性。更糟的是，碳青霉烯耐药肺炎克雷伯菌（CR-Kp）的传播限制了治疗手段，常导致高死亡率。

为应对这一日益严重的危机，研究人员正在聚焦宿主免疫系统与病原体之间的相互作用。其中一个研究热点是miRNA的作用，它们调控基因表达，并参与免疫反应和炎症过程。

miRNA：身体的分子调控器

miRNA是一类长度约22个核苷酸的小型非编码RNA分子。它们可与mRNA的互补区域结合，抑制翻译或促进mRNA降解。miRNA能够调节整个信号通路并恢复因感染而受损的细胞功能。

miRNA参与多个生物过程，包括：

• 炎症反应

• 免疫细胞发育

• 宿主与病原体互作

• 细胞分化与增殖

在肺炎克雷伯菌感染中，miRNA可调控炎症、细胞因子分泌，甚至参与如SUMO化这类表观遗传修饰过程。

关键发现：miRNA在肺炎克雷伯菌相关疾病中的作用

综述文章总结了miRNA在三种由肺炎克雷伯菌引起的主要疾病情境中的活性：肺损伤、败血症与腹膜炎。

肺损伤：聚焦炎症与细胞黏附

• miR-155 和 miR-23a 在感染肺上皮细胞中表达下调，参与通过整合素α5β1/Rac1通路调控黏附，靶向HMGN2和核因子I（NFI）。

• miR-124-3p通过抑制p38MAPK通路具有抗炎作用，可减少肺部损伤。

• 巨噬细胞来源的外泌体miR-155-5p通过激活MSK1/DUSP1/p38MAPK通路及M1型巨噬细胞极化加重急性肺损伤。

• 封装于细胞外囊泡中的MVs-miR-223/142可抑制NLRP3炎症小体的激活，减轻肺部炎症。

• 脂肪来源间充质干细胞外泌体中的miR-181a-5p靶向STAT3，缓解炎症与肺损伤。

败血症：miRNA作为调控因子与生物标志物

• 肺炎克雷伯菌相关基因ygiM与miR-7108-5p、miR-4433b-3p和miR-342-3p有关，这些miRNA可能影响细菌对巨噬细胞吞噬的抵抗。

• miR-155参与中性粒细胞胞外诱捕网形成（NETosis），但也可能促进组织损伤，加重败血症结局。

• 差异表达的miRNA有潜力作为败血症严重程度与预后判断的生物标志物。

腹膜炎：调节细胞因子反应

• 小鼠腹膜炎模型中，多种miRNA表达发生变化。miR-21、miR-132、miR-301a与miR-652上调，miR-375下调。

• miR-146a与miR-155通过靶向IRAK1/2与TRAF6，或抑制SOCS1和SHIP1来调节TLR/IL-1信号通路，影响TNF-α水平。

• 这些miRNA共同调控IL-1β、IL-6与TNF-α等炎性细胞因子，影响宿主耐受性与免疫应答。

SUMO化：感染生物学的新维度

SUMO化是一种翻译后修饰，可增强宿主细胞的防御功能。
Let-7 miRNA在I型干扰素信号激活下表达升高，可减少SUMO化，从而促进肺炎克雷伯菌感染。
这一发现提示病原体可能通过miRNA调控机制来抑制宿主炎症反应。

启示与未来方向

综述强调miRNA在肺炎克雷伯菌感染中具有关键调控作用。它们不仅调节免疫反应，还为临床诊断与治疗策略提供了新思路。

潜在应用包括：

• 基于miRNA的诊断方法，用于检测严重感染或治疗反应

• 靶向特定miRNA（如miR-155或miR-181a-5p）的治疗策略，以减轻炎症或增强病菌清除

• 将miRNA调节剂与抗生素联合应用，以克服耐药性

结语

本文强调了miRNA在传染病，特别是肺炎克雷伯菌感染中的重要作用。该菌因其高毒力和耐药性而日益受到关注。在研究者继续探索宿主与病原体相互作用的分子通路过程中，miRNA作为核心调节因子和潜在干预靶点显得尤为重要。

理解这些小RNA如何影响炎症、免疫与细菌存活，有望为临床上应对多重耐药感染提供新的治疗策略。

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Reference:

Chuhan Zhang, Ge Li, Safi Ullah, Liang Liu, Huajie Zhao, Fan Yang, Liwei Guo, Duan Li

Function and mechanism of miRNAs during the process of Klebsiella pneumoniae infection.

Biomol Biomed [Internet]. 2025 Feb. 28 [cited 2025 Apr. 15];

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/11421

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