Unraveling the Complex Pathogenesis of Mycoplasma pneumoniae Pneumonia: Insights into Immune Responses, Traditional Medicine, and Molecular Mechanisms


Mycoplasma pneumoniae pneumonia (MPP) is a prevalent respiratory illness in pediatric patients, primarily caused by the infection of Mycoplasma pneumoniae (M. pneumoniae).

This article delves into the multifaceted aspects of MPP, exploring its prevalence, clinical features, immune responses, treatment modalities, and molecular mechanisms, with a focus on the role of Qingfei Tongluo formula (QTF) and the active ingredient Kukoamine A (KuA).

Prevalence and Clinical Features

M. pneumoniae accounts for a significant proportion of community-acquired pneumonia, with approximately 40% of cases attributed to this pathogen. While MPP typically presents clinical features akin to other atypical pathogens, including Chlamydia pneumoniae and various respiratory viruses and bacteria, the etiology and pathogenesis of MPP remain largely unknown [1–6]. Notably, about 18% of MPP cases require hospitalization, highlighting the severity of this respiratory condition [1–3].

Immune Responses and Treatment Modalities

Studies suggest that excessive host immune reactions contribute to MPP development, activating lymphocytes, particularly T helper (Th)1 and Th17 cells. This immune activation is regulated by costimulatory molecules on antigen-presenting cells, leading to elevated levels of proinflammatory cytokines such as IL-6 and TNF-α [7–10].

Although MPP can be self-limiting, clinicians often employ antibiotics for treatment. Interestingly, the traditional Chinese medicine formula, Qingfei Tongluo (QTF), has demonstrated efficacy in MPP treatment. Molecular investigations revealed that QTF inhibits key signaling pathways, including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and nuclear factor-κB (NF-κB) [11,12].

Role of Kukoamine A (KuA)

Kukoamine A (KuA), a major active ingredient in QTF derived from Cortex Lycii radices, possesses diverse pharmacological properties. Despite its known benefits, there is a lack of research on KuA’s role in MPP. Further studies are warranted to elucidate the potential therapeutic effects of KuA in managing MPP.

Molecular Mechanisms and Virulence Factors

M. pneumoniae deploys metabolites, exotoxins, and exotoxin-like toxic substances, causing toxin-like effects. The pathogen infiltrates bronchial mucous membranes, releasing hydrogen peroxide, leading to bronchial epithelial cell damage. Virulence factors such as Superoxide dismutase 2 (SOD2) and catalases are implicated in controlling reactive oxygen species (ROS) production. Excessive ROS damages cellular components, affecting cell metabolism, aging, and death. M. pneumoniae-produced ions impede antioxidant enzymes, rendering host cells susceptible to toxic oxygen, resulting in mitochondrial enlargement and impaired cilia movement in lung epithelium [14–18].

TABLE 1 – Qingfei Tongluo Formula (QTF): An In-Depth Exploration of a Traditional Chinese Medicine Approach to Respiratory Health

Qingfei Tongluo Formula (QTF) stands as a testament to the rich heritage of Traditional Chinese Medicine (TCM), offering a holistic approach to addressing respiratory ailments, particularly Mycoplasma pneumoniae pneumonia (MPP). Rooted in centuries-old wisdom and refined through generations, QTF has garnered attention for its efficacy in treating respiratory conditions. This chapter delves into the intricate components, historical context, pharmacological properties, and contemporary research surrounding QTF.

Historical Background

QTF traces its roots to the extensive pharmacopoeia of TCM, where herbal formulations are curated based on principles of balancing Yin and Yang, promoting Qi flow, and harmonizing bodily functions. The formula has evolved over time, integrating the insights of ancient Chinese physicians with contemporary scientific knowledge.

Ingredients of Qingfei Tongluo Formula

QTF is a composite formula, combining multiple herbs synergistically selected to address the multifaceted nature of respiratory disorders. Notable components include Cortex Lycii Radices, the traditional source of Kukoamine A (KuA), a prominent active ingredient within the formula. Other herbs such as Forsythiae Fructus and Houttuyniae Herba contribute to the formula’s anti-inflammatory and antiviral properties.

Kukoamine A (KuA): A Keystone Ingredient

KuA, derived from Cortex Lycii Radices, plays a pivotal role in the therapeutic efficacy of QTF. This spermine alkaloid exhibits diverse pharmacological properties, including anti-inflammatory and antioxidant effects. Recent studies have spotlighted KuA’s potential in alleviating Mycoplasma pneumoniae-induced pneumonia, hinting at its role in modulating oxidative stress and inflammatory pathways.

Pharmacological Properties

The pharmacological properties of QTF are multifaceted, encompassing anti-inflammatory, antiviral, antioxidant, and immunomodulatory effects. The formula’s ability to regulate key signaling pathways, such as c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and nuclear factor-κB (NF-κB), highlights its potential in modulating immune responses and mitigating inflammation.

Clinical Efficacy in Mycoplasma pneumoniae Pneumonia

Clinical observations and research studies have explored the efficacy of QTF in the context of Mycoplasma pneumoniae pneumonia. Research findings suggest that QTF administration leads to the effective inhibition of the phosphorylation of JNK, ERK, and NF-κB signaling pathways in a Mycoplasma pneumoniae-induced pneumonia mouse model. This inhibition correlates with a reduction in proinflammatory cytokine levels, providing a mechanistic insight into QTF’s therapeutic action.

Safety Profile and Side Effects

Traditional Chinese Medicine often emphasizes the importance of balancing therapeutic effects with safety. QTF, with its natural plant-based composition, is generally well-tolerated. However, individual reactions may vary, and consulting with a qualified healthcare professional is recommended before initiating any herbal treatment.

Contemporary Research and Future Directions

As the global interest in integrative medicine grows, so does the attention on TCM formulations like QTF. Contemporary research efforts aim to elucidate the molecular mechanisms underlying QTF’s efficacy, explore potential synergies with conventional treatments, and identify specific patient populations that may benefit the most.

MicroRNAs (miRNAs) and Exosomes

Noncoding RNAs, especially microRNAs (miRNAs), play pivotal roles in physiological processes. In pediatric MPP patients, 26 differentially regulated miRNAs, including miR-222-3p, were identified, suggesting their potential as diagnostic and prognostic indicators [19,20]. Exosomes, extracellular vesicles containing proteins, DNA, and RNA, have emerged as key regulators of cellular function. In MPP patients, peripheral blood serum exosomes may contribute to the pathogenesis, as evidenced by miRNA-sequencing findings distinguishing pneumonia patients from healthy controls [21–23].

In Vitro Model and Future Directions

The study presented here employs human alveolar basal epithelial cells (HABECs) as an in vitro model to investigate changes in SOD2 and proinflammatory cytokines in response to exosomes isolated from peripheral blood serum of MPP patients. Future research should further explore the intricate interplay between exosomes, immune responses, and molecular mechanisms in MPP pathogenesis.


Mycoplasma pneumoniae (M. pneumoniae) is a significant contributor to community-acquired pneumonia, characterized by excessive inflammation that intensifies the severity of the disease. Despite its prevalence, the mechanistic underpinnings of this inflammation remain elusive.

Our investigation focused on miR-222-3p, a microRNA upregulated in the peripheral blood serum exosomes of Mycoplasma pneumoniae pneumonia (MPP) patients compared to healthy individuals.

The study uncovered a potential link between elevated miR-222-3p expression and the dysregulation of key cellular processes. Specifically, upregulation of miR-222-3p in MPP was associated with a decrease in Superoxide dismutase 2 (SOD2) activity, an increase in nuclear factor-κB (NF-κB) expression, heightened proinflammatory cytokine levels (IL-6 and TNF-α), and the induction of reactive oxygen species (ROS) in human alveolar basal epithelial cells and A549 cells. Notably, treatment with Kukoamine A (KuA), a major active ingredient in the Qingfei Tongluo formula (QTF), partially reversed the effects of miR-222-3p mimic, suggesting a potential therapeutic avenue for MPP [12, 28].

Our findings align with recent research demonstrating the alleviating effects of KuA-containing QTF in a mouse model of MPP, emphasizing the potential role of KuA in regulating oxidative stress [29, 30]. This study establishes a novel molecular pathway, linking peripheral blood serum exosomes, inflammation, and oxidative stress in the lung tissues of MPP patients.

Importantly, we elucidated the role of miR-222-3p in human alveolar basal epithelial cells, uncovering its negative regulation of SOD2 and positive regulation of proinflammatory cytokines. While previous studies on miR-222-3p primarily focused on its role in cancer and viral infections, our study expands its relevance to MPP.

Intriguingly, our results are in line with reports of increased miR-222-3p abundance but reduced CD4 mRNA levels in peripheral blood monocytes of MPP patients [20]. This study emphasizes the efficient delivery of miR-222-3p via serum exosomes into human alveolar basal epithelial cells, suppressing SOD2 activity and providing novel insights into MPP pathogenesis.

The study underscores the significant role of serum exosomes in initiating inflammation and contributing to MPP pathogenesis. Exosomes, known for their role in intercellular communication, particularly in response to stress conditions, serve as carriers of RNA and proteins. Our findings suggest that the increased release of exosomes and their contents in peripheral blood, triggered by M. pneumoniae infection, profoundly modulates the functions of genes involved in inflammation. This supports the notion that exosomes may play a crucial role in the complex pathophysiological conditions of human lung tissues during MPP. Future research may delve into identifying the cellular origin of miR-222-3p-containing exosomes to further enrich our understanding of MPP.

In conclusion, this study establishes the pivotal role of serum exosomal miR-222-3p in disrupting SOD2 activity and promoting proinflammatory cytokines in human alveolar basal epithelial cells. Targeting exosome access to these cells emerges as a promising therapeutic strategy for MPP, offering potential avenues for further exploration and development of targeted interventions in the management of this respiratory ailment.

reference link : https://www.hindawi.com/journals/bmri/2022/2064013/


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