Viral Respiratory Pathogens and Lung Injury

Abstract

Several viruses target the human respiratory tract, causing different clinical manifestations spanning from mild upper airway involvement to life-threatening acute respiratory distress syndrome (ARDS). As dramatically evident in the ongoing SARS-CoV-2 pandemic, the clinical picture is not always easily predictable due to the combined effect of direct viral and indirect patient-specific immune-mediated damage. In this review, we discuss the main RNA (orthomyxoviruses, paramyxoviruses, and coronaviruses) and DNA (adenoviruses, herpesviruses, and bocaviruses) viruses with respiratory tropism and their mechanisms of direct and indirect cell damage. We analyze the thin line existing between a protective immune response, capable of limiting viral replication, and an unbalanced, dysregulated immune activation often leading to the most severe complication. Our comprehension of the molecular mechanisms involved is increasing and this should pave the way for the development and clinical use of new tailored immune-based antiviral strategies.

Keywords: COVID-19; SARS-CoV-2; respiratory tract; viral infections.

FIG 1

Respiratory viruses and their direct mechanisms of tissue damage. (A) Targets of virus infection. Viral infections by orthomyxoviruses (influenza A virus [IAV], for example) herpesviruses (HHV), adenoviruses (AdV), paramyxoviruses (respiratory syncytial virus [RSV], for example), and coronaviruses (CoV) commonly affect the upper and lower respiratory tract. Thus, all of them might cause of pneumonia, and infection might result in bronchiolitis. RSV is the most common cause of bronchiolitis and pneumonia in children younger than 1 year of age. Focusing on the pulmonary alveolus, CoV and IAV infect directly type II pneumocytes, and RSV, AdV, and HHV infect both type I and II cells. Endothelial cells are targeted by RSV and HHV. On the other hand, immune cells recruited to the site of infection, such as macrophages, neutrophils, T cells, NK cells, B cells, and antigen-presenting cells (APCs), can be infected by AdV, CoV, IAV, and HHV. (B) Direct mechanisms of tissue damage. After infection, viruses alter cellular homeostasis causing different types of damage or alterations. AdV are responsible for the direct lysis of the infected cells, while IAV, CoV, and HHV induce apoptosis of their target cells. Inclusion bodies are a consequence of AdV, RSV, and HHV infection, and syncytium formation has been described for cells infected by RSV, CoV, and HHV.

FIG 2

Immune cell activation in the lungs during viral infections. In healthy lungs, the resident immune cells include primarily alveolar macrophages, conventional and plasmacytoid dendritic cells, and tissue-resident lymphocytes and eosinophils, which patrol the tissue for foreign threats. In addition, respiratory epithelial cells (e.g., club cells and goblet cells) secrete mucins, surfactants, and other molecules that preserve homeostasis, as well as maintain immune cells in their quiescent states. During viral infections, viruses are sensed by innate immune receptors (or pattern recognition receptors) which activate immune responses. Secretion of chemokines and growth factors by respiratory epithelium and resident immune cells leads to the phased recruitment and activation of neutrophils, monocytes, NK cells, and T cells. Type I (IFN-α/β) and type III (IFN-λ) IFNs are the primary cytokines produced upon viral detection, followed by other inflammatory cytokines, as well as ISGs. Other antiviral effectors produced by epithelial, endothelial, and immune cells include lactoferrins, β-defensins, ROS, and RNS. Innate immune cells (neutrophils, macrophages, and DCs) mediate the activation of the adaptive responses (NK cells, B cells, and T cells) that involve IFN-γ secretion, antibody production, and cytotoxic killing of infected cells. Persistence of a viral infection, as well as the accompanying antiviral immune responses, often leads to widespread lung damage and secondary complications such as systemic inflammation (due to dysregulated immune responses) and bacterial coinfections. A prolonged infection can result in oxygen deprivation, ARDS, asthma, remodeled lung structure (e.g., excess collagen deposition, thickening of basal membrane, and scar tissue formation), organ failure, and even death in extreme cases. Resolution of a respiratory viral infection by a kinetically controlled, successful immune activation and a reversal to homeostasis is facilitated by anti-inflammatory cytokines, immunosuppressive molecules, the removal of active, cytotoxic immune cells by efferocytosis, and extensive tissue repair. This image was created using BioRender (BioRender.com). DC, dendritic cells; CoV, coronavirus; RSV, respiratory syncytial virus; AdV, adenovirus; IAV, influenza virus; TLR, Toll-like receptor; RIG-I, retinoic-acid inducible gene I; MDA5, melanoma differentiation-associated protein 5; NLRP3, NOD-like receptor protein 3; RNA Pol III, RNA polymerase III; AIM2, absent in melanoma 2; IFI16, IFN-inducible protein 16; cGAS, cyclic GMP-AMP synthase; CXCL, C-X-C motif chemokine ligand; CCL, C-C motif chemokine ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; NK cells, natural killer cells; IFN, interferon; ISG, interferon-stimulated genes; IL, interleukin; TNF, tumor necrosis factor; TGFβ, transforming growth factor β; ROS, reactive oxygen species; RNS, reactive nitrogen species; MPO, myeloperoxidase; NET, neutrophil extracellular traps.

FIG 3

Clinical interventions impacting immune responses and viral replication during respiratory viral infections. Several preventive and therapeutic interventions targeting immune responses are approved or currently being tested to combat virus-dependent immunopathology. After initial exposure to a respiratory virus, symptoms begin manifesting within a few days, depending on the virus replication kinetics. The clinical severity of disease can range from mild to moderate, severe, or critical (that define the early, pulmonary, or hyperinflammatory stages) and is often dictated by a persisting infection and/or an aberrant, uncontrolled antiviral immune response. Severe cases of viral infections frequently require hospitalization that can lead to intensive care and ventilation in patients with deteriorating lung functions or other associated systemic complications. In a healthy, uninfected individual, the administration of vaccines is the most effective route to prevent respiratory viral illnesses. Examples include annual vaccinations against the predicted evolving strains of influenza. Currently, several vaccines against COVID-19 have received emergency authorization around the world. Recent authorized SARS-CoV-2 vaccines (with published data from phase 3 clinical trials) include mRNA vaccines from Pfizer-BioNTech and Moderna, as well as an adenovirus-based vaccine from Oxford-AstraZeneca. Prophylaxis with antiviral drugs is another preventive measure for unimmunized children or immunocompromised individuals, or against viruses for which there are no vaccines (e.g., RSV). Prophylactics include oral oseltamivir phosphate for influenza and palivizumab for RSV, and there are considerations for developing nasally administered IFNs for prophylaxis against SARS-CoV-2. In asymptomatic patients or presymptomatic patients with early detection or with mild disease, early complementary type I or type III IFN administration can be beneficial. In severe cases of lung infection, multiple anti-inflammatory immunomodulators such as neutralizing antibodies or inhibitors are used to supplement the antiviral therapies to prevent and mitigate cytokine storm. While mild respiratory illnesses can be relieved with over-the-counter fever-reducing drugs, pathogen-specific antiviral drugs are used in cases of moderate to critical disease, either singularly or in combination with other therapeutic interventions. In COVID-19, patients have also benefited from treatment with antiviral monoclonal antibody cocktails (e.g., bamlanivimab by Eli Lilly or casirivimab and imdevimab by Regeneron) and with convalescent plasma from recovered individuals with high antibody titers. Early administration of the antivirals displays better efficiency in viral clearance. In critical patients with hyperimmune responses and ARDS, treatment with corticosteroids (e.g., dexamethasone) relieves respiratory distress. The effectiveness of steroids in the first phases of a viral infection is controversial, since they may hamper the establishment of a properly effective antiviral response. The image was created using BioRender.