Neuro-Immune Interactions and IFN-γ in Post-Infectious Cough

Cough is a key symptom of respiratory infections.¹,² In addition to being highly prevalent in patients with acute infectious conditions, cough may be associated with severe physical distress and pain.³ Moreover, due to the risk of airborne transmission, cough can have a negative social impact on patients, sometimes leading to social withdrawal or isolation. This negative social influence is increased due to the coronavirus-19 pandemic.¹,⁴ Following recovery from acute infections, cough may persist in some individuals for weeks or months, a phenomenon termed post-infectious cough.²

The mechanisms underlying cough in patients with respiratory infections may vary according to pathogens.¹ Cough has been associated with neuroinflammation and neuro-immune interactions, with the common effect being the triggering and sensitization of cough reflex pathways.¹ Sensory neurons may be directly infected by viruses, and the activation of antiviral signaling in neurons can lead to the production of interferons (IFNs), cytokines, neuropeptides, and/or adenosine triphosphate (ATP), which can subsequently stimulate immune systems.¹,⁵ Neurons can also be affected by inflammatory mediators released by infected epithelial and activated immune cells (neuro-immune interactions). Importantly, sensory neurons and immune cells share danger recognition pathways, including several cytokine receptors such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α receptors; Toll-like receptors (TLRs), such as TLRs 3, 4, 7, and 9; transient receptor potential (TRP) channels; and P2X receptors.⁶ These shared danger systems are the key to neuro-immune interactions in host defenses.

Neuronal hypersensitivity is a key mechanism underlying cough in patients with acute infections. Human rhinovirus (HRV)-16 was shown to infect sensory neurons in vitro, replicate in these cells, and actively upregulate neuronal receptors involved in cough hypersensitivity, such as TRPV1 and A1 channels.⁷ HRV-16 infection of A549 cells was found to significantly increase intracellular levels of ATP, a key mediator in chronic refractory cough,⁸,⁹ leading to the extracellular release of ATP in response to secondary stimulation with both hypotonic and isotonic solutions.¹⁰ Parainfluenza virus type 3 infection in guinea pigs led to a phenotypic switch to express de novo TRPV1 in nodose and jugular ganglia.¹¹ Certain pathogens, such as Mycobacterium tuberculosis, produce microbial products, such as sulfolipid-1, that can directly activate nociceptive neurons and induce cough in guinea pigs.¹² However, the mechanisms responsible for persistent coughing, particularly in post-acute infectious conditions, are poorly understood.

The biological relevance of cough reflex hypersensitivity in acute infections can be bimodal. Enhanced cough sensitivity can reduce the risk of further infection or inhalation, but can also increase the risk of viral transmission, as suggested by the in vitro infection of sensory neurons with HRV.⁷ Persistent cough under post-infectious conditions, however, may be an adaptive host response for better protection. Thus, the post-infectious cough may be driven by certain protective neuro-immune interactions, such as IFN-γ pathways. IFN-γ is produced during various infections and has been considered essential in host defenses against tuberculosis and viral infections.¹³,¹⁴ Neurons may express functional IFN-γ receptors.¹⁵,¹⁶

A paper published in the current issue of Allergy, Asthma & Immunology Research reported that intratracheal IFN-γ treatment in animal models could lead to a state of cough reflex hypersensitivity and pulmonary lymphocytic infiltration, particularly by IFN-γ-secreting T cells.¹⁷ These findings were an extension of previous studies, which demonstrated (1) the effects of IFN-γ on vagal sensory neurons,¹⁶ (2) the effects of IFN-γ on cough reflex sensitivity in guinea pigs and humans,¹⁶,¹⁸ and (3) higher levels of IFN-γ (+) T cells in the sputum of patients with chronic refractory cough than in controls.¹⁸ An attempt to identify the potential molecular mechanisms linking post-infectious cough and IFN-γ pathways found that intratracheal administration of high physiological levels of IFN-γ in mice induced airway epithelial damage with lymphocytic inflammation. IFN-γ may link innate immune responses, as shown by IFN-γ-induced epithelial cell activation, with adaptive immune responses, as shown by T cell infiltration and amplified responses to IFN-γ. The persistence of IFN-γ (+) T cells in the lungs after the post-acute phase of infections suggests that IFN-γ pathways could form positive loop feedback between the nervous and immune systems, leading to a persistent cough.

These findings, however, warrant further investigation and clinical validation. Although the dose of instilled IFN-γ in mice may represent a high physiological level, these concentrations may differ from those in post-infectious lungs in vivo. The actual contribution of IFN-γ to post-infectious cough requires further studies with different chronic animal models of post-viral infection. It is even more important to clinically validate the roles of IFN-γ in humans. Although a few studies have measured IFN-γ levels in patients with respiratory influenza virus infections or chronic cough,¹⁴,¹⁸,¹⁹,²⁰ the sizes of these samples were small. In addition, microglial cells are likely to be relevant to neuro-immune interactions driven by IFN-γ,²¹,²² and studies determining the roles of these cells are needed to better understand the mechanisms underlying chronic and post-infectious cough.

Prolonged inflammation following increased T-cell migration to the airways may be caused by CXCR3-mediated T-lymphocyte activation.¹⁷ The CXCR3 receptor is a seven-transmembrane G protein-coupled receptor expressed primarily on activated T cells, and to some extent, on other cells, including dendritic cells, natural killer cells, epithelial cells, and fibroblasts.²³ The CXCR3 receptor is activated by various chemokines, including the ligands CXCL9, CXCL10, and CXCL11, produced in response to IFN-γ activation under pro-inflammatory conditions. Accordingly, the role of CXCR3 signaling activation has been studied in several pathologic conditions, including cancer, inflammatory disorders, and infection. Either blocking CXCR3 ligands or CXCR3 receptor signaling may provide an attractive therapeutic target for patients with chronic or post-infectious cough. For example, the anti-CXCL10 antibody BMS-936557 has been tested in several in vivo mouse models,²⁴ as well as in phase II clinical trials in patients with ulcerative colitis and rheumatoid arthritis.²⁵,²⁶ Because of the essential roles of IFN-γ in host defenses, further investigations of its downstream pathways, including CXCR3, may provide clues for the development of new therapeutic options for post-infectious cough.

Targeting both neural and immune pathways may result in more effective control and resolution of chronic cough. The infection with respiratory viruses is one of the most frequent triggers of cough hypersensitivity and chronic cough, but the mechanisms underlying the persistence of cough in specific individuals remain unclear.² The present study by Deng and colleagues¹⁷ expands knowledge of the involvement of IFN-γ in the neuro-immune interactions of cough and may lead to further investigations.