Page 42 - MI-2-4

Microbes & Immunity Pulmonary immunity: Pathogens versus protectors

The non-structural protein 1 of influenza A inhibits type I MCC is impaired – due to chronic respiratory diseases
IFN production, while the open reading frame 6 protein (e.g., COPD), cystic fibrosis, or primary ciliary dyskinesia –
of SARS-CoV-2 blocks the nuclear translocation of signal the lung microenvironment undergoes significant changes
transducer and activator of transcription 1, a critical that disrupt the balance of the pulmonary microbiome
transcription factor for IFN-stimulated genes. 25-27 Fungal and facilitate the persistence of harmful pathogens. Under
pathogens such as Aspergillus fumigatus also employ normal conditions, MCC helps maintain a dynamic
immune evasion strategies. They produce secondary equilibrium in the lung microbiome by continuously
metabolites like gliotoxin, which inhibits nuclear factor eliminating microbes before they can colonize. However,
kappa B activation and induces apoptosis in immune cells. impaired MCC leads to mucus accumulation, creating
These pathogen-mediated disruptions of immune signaling stagnant niches where bacteria can thrive. 32,33 Impaired
not only facilitate microbial survival but also contribute to MCC is not only unable to eliminate pathogens but also
the progression of chronic pulmonary infections. 28 exacerbates inflammation. The resulting immune response
further damages the airway epithelium, worsening MCC
6.2.2. Host-mediated inhibition of immune signaling: dysfunction in a vicious cycle. Prolonged inflammation
A protective mechanism? alters the lung microenvironment, favoring pathogen
While pathogen-mediated modulation of immune adaptation and resistance.
signaling is often detrimental, the host also downregulates
immune responses to prevent excessive inflammation. 6.3. Resistance to AMPs and phagocytosis
Treg cells and anti-inflammatory cytokines – such as The pulmonary immune system relies heavily on
IL-10 and transforming growth factor β – play crucial AMPs and phagocytic cells such as macrophages and
roles in maintaining immune homeostasis. However, in neutrophils to eliminate pathogens. However, pathogens
chronic pulmonary diseases – such as asthma, COPD, such as S. pneumoniae and Haemophilus influenzae have
and idiopathic pulmonary fibrosis – dysregulated developed resistance mechanisms to AMPs by modifying
immune signaling can lead to persistent inflammation their cell membranes or secreting proteases that degrade
and tissue remodeling. Therefore, targeted inhibition these peptides. Furthermore, Legionella pneumophila and
of specific immune signaling pathways has emerged as M. tuberculosis manipulate phagocytic cells, enabling them
a promising therapeutic approach. For example, Janus to survive and replicate within macrophages by inhibiting
kinase inhibitors have shown efficacy in suppressing phagosome–lysosome fusion or resisting oxidative burst
cytokine storms in severe COVID-19 and autoimmune mechanisms. 31
lung diseases. 29,30 Similarly, monoclonal antibodies
targeting IL-4, IL-5, and IL-13 have transformed the 6.4. Biofilm formation
treatment of eosinophilic asthma by selectively inhibiting Biofilms are structured communities of microorganisms
Th2-mediated inflammation. However, the key challenge encased in a self-produced protective extracellular matrix.
remains: suppressing harmful immune responses without In the respiratory tract, pathogens such as P. aeruginosa
compromising protective immunity. and S. aureus form biofilms to shield themselves from
a. Innovative therapeutic approaches immune cells and antibiotics. The biofilm matrix not only
Recent advances in immunomodulatory therapies have acts as a physical barrier but also modulates immune
introduced new strategies for targeting immune signaling responses by trapping and neutralizing antimicrobial
in pulmonary diseases. Approaches such as small molecule agents, thereby complicating treatment and contributing
inhibitors, biologics, and gene-editing technologies like to chronic infections. 34,35 Biofilm formation begins
CRISPR-Cas9 offer precise tools to modulate immune with the attachment of planktonic (free-floating)
pathways. For instance, inhaled nanoparticles delivering microorganisms to the pulmonary epithelium or medical
small interfering RNA against pro-inflammatory cytokines devices, such as endotracheal tubes. This attachment is
can suppress inflammation locally, reducing the risk of facilitated by adhesins and other surface proteins that
systemic side effects. In addition, microbiome-based recognize host cell receptors or synthetic materials.
therapies are being explored to restore immune homeostasis Following attachment, the pathogens proliferate and
in the lungs by modulating the gut–lung axis. 31 secrete extracellular polymeric substances – including
b. The role of impaired mucociliary clearance (MCC) on polysaccharides, proteins, and extracellular DNA –
the pulmonary microbiome and pathogen persistence forming the biofilm matrix. This matrix not only provides
The MCC system is a critical defense mechanism in the structural integrity but also acts as a barrier against
respiratory tract, responsible for trapping and removing the host immune system – such as phagocytosis – and
inhaled pathogens, pollutants, and cellular debris. When reduces the penetration of antibiotics. 36

Volume 2 Issue 4 (2025) 34 doi: 10.36922/MI025100019