Compromised respiratory function in lethal influenza infection is characterized by the depletion of type I alveolar epithelial cells beyond threshold levels

Abstract

During influenza virus infection, it is unclear how much alveolar cell loss can be tolerated before the host succumbs to the disease. We sought to define relevant correlates of disease severity in the mouse influenza model, hypothesizing that a susceptibility threshold exists for alveolar epithelial cell loss. We compared lung pathology, virus spread, alveolar epithelial cell depletion, arterial blood oxygenation, physiological responses measured by unrestrained plethysmography, and oxygen consumption and carbon dioxide production by gas analysis in mice at intervals after infection with virus strains and doses that cause mild (x31) or severe (PR/8) influenza. Both mild and severe infections showed similar degrees of lung damage and virus dissemination until day 6 after inoculation but diverged in survival outcomes from day 9. Day 6 PR/8-infected mice had normal respiratory and gas exchange functions with 10% type I cell loss. However, day 10 PR/8-infected mice had 40% type I cell loss with a concomitant drastic decreases in tidal and minute volumes, Vo(2), Vco(2), and arterial blood oxygenation, compared with a maximum 3% type I cell loss for x31 on day 10 when they recovered body weight and respiratory functions. Alterations in breaths per minute, expiratory time, and metabolic rate were observed in both infections. A threshold for maintenance of proper respiratory function appears to be crossed once 10% of alveolar type I cells are lost. These data indicate that lethality in influenza virus infection is a matter of degree rather than quality.

Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection

“…The direct cytopathicity model posits that although the innate immune system reaches a high level of activation (51)(52)(53)(54), it nevertheless is incapable of containing the pathogen before viral cytopathicity causes loss of lung homeostasis (55,56). In this view, the inflammatory response is a correlate of the damaging infection and not directly immunopathologic.…”

Novel Ranking System for Identifying Efficacious Anti-Influenza Virus PB2 Inhibitors

“…After centrifugation, the supernatant was injected into an Agilent 1100 HPLC system coupled with a tandem mass spectrometer in atmospheric pressure chemical ionization (APCI) positive-ion mode. Chromatography was performed using an Xterra MS C 18 analytical column (5 m, 2.1 by 50 mm) and a mobile phase consisting of a mixture of 10 mM ammonium acetate and acetonitrile running in a 3.0-min linear gradient. Compounds of interest were analyzed using an AB Sciex API 4000 mass spectrometer.…”

“…Loss of 10% of type I alveolar pneumocytes is a threshold for the initiation of loss of lung function, as measured by whole-body plethysmography (WBP); with a 40% reduction in type I alveolar pneumocytes, there are dramatic decreases in tidal and minute volumes that correlate with reduced oxygen consumption (VO 2 ) and arterial blood oxygenation. This has led to the overall conclusion that morbidity and death in the mouse model correlate with loss of type I alveolar pneumocytes (18).…”

“…This technique has proven useful in understanding lung dysfunction and host responses in the mouse and cotton rat models of respiratory syncytial virus (RSV) and influenza virus (4,(17)(18)(19)(20)(21)(22)(23). While multiple parameters of lung function can be measured by WBP, the enhanced pause (Penh), a unitless calculated value that reflects pulmonary resistance, has been used in the majority of respiratory virus infection models (18,20,24,25). Penh is derived from changes in the holding container pressure, which fluctuates as a consequence of changes in the animal's breathing pattern.…”

Influenza A matrix protein M2 downregulates CFTR: inhibition of chloride transport by a proton channel of the viral envelope

“…The epithelial cells of the airway are the first targets for the influenza virus, eliciting an immune response leading to activation of a myriad of signaling pathways, ultimately resulting in apoptosis of the host cell (27). The majority of influenza infections are caused by influenza virus A, which consists of three transmembrane proteins: hemagglutinin, neuraminidase, and matrix protein 2 (M2).…”