PULMONARY INFECTIONS CAUSE BIDIRECTIONAL COMMUNICATION OF THE LUNG-BRAIN AXIS

Metodiev K. Pulmonary infections cause bidirectional communication of the lung-brain axis.  International Journal of Infection. 2026;10(2):41-45.

K. Metodiev^*

Medical University, Department of Preclinical and Clinical Sciences, Varna, Bulgaria.

*Correspondence to:
Prof. Krassimir Metodiev,
Medical University of Varna,
Varna, Bulgaria.
e-mail: kr.metod@yahoo.com

Received: 28 May, 2026 Accepted: 06 July, 2026

ISSN 3103-6678 [online] Copyright 2026 © by Biolife Publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Pulmonary infections are caused by viruses, bacteria, fungi, or parasites that reach the airways and bind to lung epithelial cells. The innate immune response is activated when alveolar epithelial cells and macrophages recognize pattern-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) via receptors such as Toll-like receptors (TLRs), nod-like receptors (NLRs), and retinoic acid-inducible gene I (RIG-I). Activation of these receptors induces the production of cytokines, interferons, and chemokines, which cause inflammation, fever, and the recruitment of immune cells. Inflammation increases capillary permeability, causing accumulation of exudate in the alveoli, reduced gas exchange, hypoxemia, and tissue damage. The adaptive response eliminates the pathogen through T and B lymphocytes and is followed by an anti-inflammatory phase mediated by M2 macrophages, while the lung-brain axis allows a bidirectional communication that influences both brain function and the respiratory and immune response. The innate response is followed by the adaptive response, with CD4⁺ lymphocytes coordinating the immune response and CD8⁺ lymphocytes eliminating infected cells. B lymphocytes produce IgA and IgG antibodies that neutralize the pathogen, promote opsonization, and activate complement. Subsequently, M2 macrophages release anti-inflammatory cytokines such as IL-10 and TGF-β to promote resolution of inflammation. The lung-brain axis represents a two-way communication system linking respiratory function, the lung microbiota, the immune system, and the brain. In conclusion, lung infections result from the interaction between the pathogen and the immune system, in which the correct balance between inflammatory response, elimination of the microorganism and subsequent resolution of inflammation, together with communication between the lung-brain axis, is essential to limit tissue damage and promote the organism’s recovery.

KEYWORDS: Lung, pulmonary infection, lung-brain axis, bidirectional communication, immune system

INTRODUCTION

Pulmonary and alveolar infections can be caused by various pathogenic microorganisms and are characterized by the interaction between the microorganism and the host’s immune defences (1). They begin with the entry and colonization of the microbe, which may be a virus, bacterium, fungus, or parasite (2).  Microorganisms reach the respiratory tract through aerosols or micro aspiration. Pathogens bind to respiratory epithelial cells through adhesins (as with bacteria), glycoproteins in the case of viruses, for example, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the angiotensin-converting enzyme 2 (ACE2) receptor present on type II pneumocytes, or ligand-receptor interactions (3).

The first immune defensive intervention is the innate response, where lung epithelial cells and alveolar macrophages recognize microbial proteins called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) (4). PAMPs and DAMPs are recognized by Toll-like receptors (TLRs), NOD-like receptors (NLRs), and retinoic acid-inducible gene I (RIG-I) receptors (5). TLRs recognize lipopolysaccharide (LPS) from Gram-negative bacteria, and TLR3 recognizes double-stranded viral RNA (6). Activation of these receptors induces an intracellular cascade that activates NF-κB, MAPK, and IRF3/IRF7, culminating in the production of cytokines IL-1β, IL-6, TNF, and interferons (IFNs), as well as chemokines, including CXCL8 (also called IL-8) (7).  These proteins are highly inflammatory because they induce a systemic response characterized by fever, increased vascular permeability, and recruitment of immune cells such as natural killer (NK) cells, neutrophils, and monocytes (8). This severe inflammatory response increases capillary permeability, forming an inflammatory exudate, and protein-rich fluid enters the alveoli, leading to reduced gas exchange, hypoxemia, and tissue damage (9). Other inflammatory molecules that are released in this process include vascular endothelial growth factor (VEGF), complement proteins C3a and C5a, and free radicals (10).

The innate response is followed by the adaptive response, with the involvement of CD4⁺ lymphocytes, which coordinate the immune response, and CD8⁺ lymphocytes, which destroy virus-infected cells (11).  B lymphocytes produce mucosal IgA and systemic IgG antibodies that neutralize the pathogen, promote opsonization, and activate complement (12). A few days after infection, M2 macrophages produce anti-inflammatory cytokines such as IL-10 and TGF-β (13).

The lung–brain axis is a bidirectional communication system between the two organs that involves alterations in the lung microbiota that can influence brain function. In turn, the brain can modulate the respiratory and immune response (14).

DISCUSSION

In pulmonary infections caused by pathogenic microorganisms, inflammation is triggered by the activation of innate immune cells such as alveolar macrophages, neutrophils, lymphocytes, epithelial cells, and endothelial cells (15). Activation of these cells leads to the production of pro-inflammatory cytokines such as IL-1β, TNF, IL-6, and IFNg (16). Pro-inflammatory cytokines travel through the bloodstream and can reach the central nervous system (CNS) and activate microglia and astrocytes (17). The activation and release of inflammatory cytokines induces neuroinflammation, which can influence cognitive impairment, depression, and anxiety (18).

Cytokines produced by lung cells bind to their receptors on microglia, neurons, and astrocytes, activating a cascade of intracellular pathways through NF-κB, MAPK, and JAK/STAT (19). This cascade leads to the release of additional pro-inflammatory cytokines, and the production of reactive oxygen species (ROS) and nitric oxide (NO), creating a circuit of inflammatory amplification in the brain (20). The lung is innervated by the vagus nerve, which controls the inflammatory response through the anti-inflammatory reflex, while it can also communicate lung inflammation with the central nervous system (21). The vagus nerve is a component of the parasympathetic nervous system that modulates systemic and pulmonary inflammation through the release of acetylcholine, a neurotransmitter that inhibits the production of pro-inflammatory cytokines, reducing tissue damage (22).

Pulmonary inflammation communicates with the CNS, which in turn regulates inflammation. Conversely, on the pathway from inflammation to the brain, vagal branches in the lungs control bronchial diameter and glandular secretions (21). In pulmonary inflammation, the vagus nerve communicates with the brain; this axis can also be used by pathogenic microorganisms to cause neuroinflammation, resulting in chronic fatigue and mental fog (23). Some typical effects of vagus nerve inflammation may include nausea, vomiting, dizziness, and headache (24). Pulmonary inflammation activates vagal sensory receptors and generates afferent impulses to the brainstem, hypothalamus, and the solitary tract (25).  These reactions lead to behavioral changes, fever, lethargy, fatigue, social withdrawal, and decreased appetite (Fig.1).

Fig. 1. Lung infection by microorganisms causes an inflammatory cascade mediated by alveolar macrophages, with the participation of the vagus nerve and microglia, that can cause neuroinflammation.

Systemic inflammation can lead to alterations in the blood-brain barrier (BBB) and increased levels of metalloproteinases (MMP-2, MMP-9), VEGF, and free radicals (26). This can damage tight junctions, resulting in the passage of immune cells, cytokines, and other pathological mediators. Pathogenic effects of pulmonary infection on the lung lead to hypoxia with activation of hypoxia-inducible factor 1α (HIF-1α), which induces pro-inflammatory genes, anaerobic glycolysis, and VEGF (27). The induction of these factors can cause mitochondrial damage, neuronal dysfunction, and cognitive deficits. The lung microbiota can influence the CNS, generating a true lung microbiota-brain axis (28).  In the lung, microorganisms and their metabolites produce butyrate, acetate, and propionate, all short-chain fatty acids that can modulate Treg cell activity, alter the BBB, and affect microglial cells (29).

Neuroinflammation can be caused by neurotransmitters as well as pulmonary dysbiosis, with activation of the hypothalamic neuroendocrine axis (30). This activates the pituitary gland, which in turn activates the adrenal gland, inducing the release of cortisol, corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH) (31). Cortisol release produces an initial anti-inflammatory effect, but if the increase is chronic, it can lead to impaired memory, hippocampal neurogenesis, and synaptic plasticity (32) (Table I).

Table I. Key molecules involved in inflammation of the lung-brain axis.

CONCLUSIONS

Pulmonary and alveolar infections result from a complex interplay between invading pathogens and the host immune system, in which a balanced innate and adaptive immune response is essential for pathogen clearance while limiting tissue damage. Pulmonary inflammation extends beyond the respiratory system by activating systemic immune pathways that can profoundly affect CNS function through cytokine signalling, vagal nerve communication, BBB disruption, hypoxia, neuroendocrine activation, and alterations of the lung microbiota. The lung-brain axis highlights the bidirectional communication between the respiratory and nervous systems, emphasizing its potential role in modulating immune responses and disease outcomes. Understanding the mechanisms underlying the lung-brain axis may provide new therapeutic strategies to reduce neuroinflammation, preserve neurological function, and improve clinical outcomes in patients with pulmonary infections.

Conflict of interest

The author declares that they have no conflict of interest.

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