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Microbes & Immunity Pulmonary immunity: Pathogens versus protectors

Within the biofilm, microorganisms undergo immunity. For instance, during chronic viral infections
significant phenotypic changes, including altered or tuberculosis, the constant antigen exposure induces
metabolic activity and gene expression, which contribute T-cell exhaustion, characterized by the upregulation of
to their increased resistance to antimicrobial agents. This PD-1 on T cells and PD-L1 on infected cells or antigen-
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phenotypic shift is further exacerbated by the presence of presenting cells. This interaction effectively dampens the
persister cells – dormant subpopulations exhibiting high immune response, allowing pathogens to establish chronic
tolerance to antibiotics. In addition, biofilms facilitate infections. 39
horizontal gene transfer, promoting the spread of The exploitation of immune checkpoints extends
antibiotic resistance genes among microbial communities. beyond infectious diseases. In lung cancer, tumor cells
The host immune system faces significant challenges in frequently manipulate these pathways to establish an
combating biofilm-associated infections. Neutrophils – immunosuppressive microenvironment. By expressing high
the primary immune cells recruited to infection sites – levels of PD-L1, tumor cells engage PD-1 on cytotoxic T
often struggle to penetrate the biofilm matrix and instead cells, leading to their functional exhaustion and impairing
release reactive oxygen species and proteolytic enzymes the anti-tumor immune response. This immune suppression
that can damage surrounding host tissues, contributing to has been a major focus of cancer immunotherapy, with
chronic inflammation and tissue remodeling. Moreover, checkpoint inhibitors such as anti-PD-1 and anti-cytotoxic
biofilms can modulate the host immune response by T lymphocyte-associated protein 4 antibodies showing
releasing virulence factors that disrupt signaling pathways remarkable success in restoring T cell activity and improving
and promote immune evasion.
patient outcomes. However, therapeutic targeting of
6.5. Exploitation of immune checkpoints immune checkpoints poses significant challenges. In the
context of pulmonary infections, checkpoint inhibitors
Some pathogens exploit the host’s immune regulatory can trigger immune-mediated tissue damage, as seen
mechanisms for their own advantage. For instance, in immune-related adverse events such as pneumonitis.
M. tuberculosis upregulates immune checkpoint molecules Achieving a balance between restoring immune function
such as programmed cell death protein 1 (PD-1) on T cells, and preventing immune hyperactivation remains a critical
thereby inducing T cell exhaustion and impairing adaptive consideration in the development of immunotherapies
immunity. By exploiting these regulatory pathways, for pulmonary diseases. Moreover, the interplay between
pathogens effectively suppress immune responses, allowing immune checkpoints and the lung microbiome introduces
them to persist in the host.
additional complexity. Although it harbors a lower microbial
6.6. Exploitation of immune checkpoints in density than the gut microbiome, the lung microbiome
pulmonary immune responses plays a crucial role in modulating local immune responses.
Dysbiosis, or microbial imbalance, may influence checkpoint
The immune checkpoint pathway, a critical regulator expression and function, potentially enhancing pathogen
of immune homeostasis, plays both protective and immune evasion or contributing to chronic inflammatory
detrimental roles in pulmonary immunity. While these conditions such as asthma and COPD.
checkpoints are essential for maintaining self-tolerance
and preventing excessive immune activation, pathogens 6.7. Modulation of host cell death pathways in
and tumors have developed sophisticated strategies to pulmonary immune responses
exploit them, enabling evasion of immune surveillance. In Pathogens often manipulate host cell death pathways to
the lungs – a site of continuous exposure to environmental evade recognition and elimination. For example, influenza
and microbial stimuli – this exploitation poses a major
barrier to effective immunity and carries significant viruses inhibit apoptosis in infected cells to prolong viral
implications for respiratory health. Immune checkpoints replication. Conversely, M. tuberculosis induces necrosis
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– such as PD-1/programmed death-ligand 1 (PD-L1) and in macrophages, promoting bacterial dissemination
cytotoxic T lymphocyte-associated protein 4 – are pivotal while evading immune surveillance. By modulating cell
death mechanisms, pathogens ensure their survival and
in modulating T-cell responses. Under normal conditions,
these pathways ensure that immune reactions remain propagation within the host.
proportionate and targeted, thereby preventing collateral The interplay between pathogens and the host’s
damage to delicate lung tissues. However, pathogens – pulmonary immune system represents a complex and
including viruses such as influenza and SARS-CoV-2, as dynamic battle, in which modulation of host cell death
well as bacteria such as M. tuberculosis – have been shown pathways plays a pivotal role. Cell death mechanisms –
to upregulate checkpoint molecules to suppress host including apoptosis, necrosis, pyroptosis, and necroptosis

Volume 2 Issue 4 (2025) 35 doi: 10.36922/MI025100019