Influenza virus-induced lung injury: pathogenesis and implications for treatment

Abstract

The influenza viruses are some of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. In humans, infection of the lower respiratory tract of can result in flooding of the alveolar compartment, development of acute respiratory distress syndrome and death from respiratory failure. Influenza-mediated damage of the airway, alveolar epithelium and alveolar endothelium results from a combination of: 1) intrinsic viral pathogenicity, attributable to its tropism for host airway and alveolar epithelial cells; and 2) a robust host innate immune response, which, while contributing to viral clearance, can worsen the severity of lung injury. In this review, we summarise the molecular events at the virus-host interface during influenza virus infection, highlighting some of the important cellular responses. We discuss immune-mediated viral clearance, the mechanisms promoting or perpetuating lung injury, lung regeneration after influenza-induced injury, and recent advances in influenza prevention and therapy. @ERSpublications We discuss novel aspects of virus-and immune-mediated lung injury and repair after influenza infection

Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection

“…Tissue resident AM play key roles in sensing viral infection and activating the initial innate and later adaptive immune responses to IAV infection (46). In concert with the macrophage populations recruited upon infection, they establish a proinflammatory environment by production and release of mediators such as IFN, leading to enhanced viral clearance and better disease outcomes (43,47).…”

Inflammatory damage on respiratory and nervous systems due to hRSV infection

“…Both, bronchiolitis and pneumonia are due to an excessive inflammation of the airways that induces lung damage and changes in the AEC morphology of bronchioles and alveolus affecting the gas exchange. While these pathologic changes are commonly induced by Flu, hADV, among others, they differ with the hRSVcaused immunopathology [7][8][9]. The host immune response elicited by hRSV is characterized by a predominant Th2 differentiation, which is not appropriate for an effective viral clearance and induces lung injury and disease.…”

“…Airway obstruction alters the exhalation capacity leading to lung hyperexpansion, increased respiratory rates, reduced lung function, upregulated mucus production, atelectasis and wheezing [5 ,6 ]. Most of these symptoms have been considered as common with infections caused by other respiratory viruses, such as Influenza (Flu), Adenovirus (hADV) and Human Metapneumovirus (hMPV) [7][8][9]. Two events can cause viral pneumonia: direct infection of the alveolar epithelium and distal airway inflammation induced by the viral infection.…”

Human Alveolar Macrophages May Not Be Susceptible to Direct Infection by a Human Influenza Virus

“…Alveolar macrophages (AMs) generally have been considered to be the first leukocyte-based line of defense against respiratory pathogens such as influenza virus [3][4][5][6]. AMs must protect the lungs not only from pathogens but also from constant immunopathological processes due to all types of inhaled material [6], and elimination of AMs in immunized mice can enhance inflammatory responses to antigen [7], suggesting that AMs play a predominantly suppressive role during inflammatory responses in vivo. Our early studies showed that human AMs from healthy volunteer donors differed substantially from autologous peripheral blood blood-derived monocytes-macrophages (PBMs) in support of lymphocyte proliferative responses to both mitogens and antigens, including inactivated IAV [3].…”

“…However, isolated ferret alveolar tissues seem to be as susceptible to infection as the airways, suggesting that host defenses prevent viral infection at the alveolar level [2]. Alveolar macrophages (AMs) generally have been considered to be the first leukocyte-based line of defense against respiratory pathogens such as influenza virus [3][4][5][6]. AMs must protect the lungs not only from pathogens but also from constant immunopathological processes due to all types of inhaled material [6], and elimination of AMs in immunized mice can enhance inflammatory responses to antigen [7], suggesting that AMs play a predominantly suppressive role during inflammatory responses in vivo.…”