Influenza A Virus Infection Causes Chronic Lung Disease Linked to Sites of Active Viral RNA Remnants

Abstract

Clinical and experimental observations suggest that chronic lung disease is linked to respiratory viral infection. However, the long-term aspect of this relationship is not yet defined using a virus that replicates at properly high levels in humans and a corresponding animal model. In this study, we show that influenza A virus infection achieves 1 × 10-fold increases in viral load in the lung and dose-dependent severity of acute illness in mice. Moreover, these events are followed by persistence of negative- and positive-strand viral RNA remnants for 15 wk and chronic lung disease for at least 26 wk postinfection. The disease is manifested by focal areas of bronchiolization and mucus production that contain increased levels of viral RNA remnants along with mucin Muc5ac and Il13 mRNA compared with uninvolved areas of the lung. Excess mucus production and associated airway hyperreactivity (but not fibrosis or emphysema) are partially attenuated with loss of IL-13 production or signaling (using mice with IL-13 or STAT6 deficiency). These deficiencies cause reciprocal increases in l17a mRNA and neutrophils in the lung; however, none of these disease endpoints are changed with IL-13/IL-17a compared with IL-13 deficiency or STAT6/IL-17a compared with STAT6 deficiency. The results establish the capacity of a potent human respiratory virus to produce chronic lung disease focally at sites of active viral RNA remnants, likely reflecting locations of viral replication that reprogram the region. Viral dose dependency of disease also implicates high-level viral replication and severity of acute infection as determinants of chronic lung diseases such as asthma and COPD with IL-13-dependent and IL-13/IL-17-independent mechanisms.

Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost

“…The clearance of infectious virus also raises the issue of persistent viral-RNA remnants that are likely noninfectious but might still have a role in postviral disease. In that context, we reported (and confirm in this study) that viral-RNA remnants are found long after clearance of infectious virus in the case of SeV (28), and we found the same persistence more recently for IAV (31). In addition, our report for IAV includes data for active viral-RNA replication with detection of both positive-and negative-strand viral RNA and for localization of these viral-RNA remnants to sites of chronic lung disease.…”

“…9A). We detected no significant increase in baseline R RS at 8 or 49 d after viral infection in wild-type, Stat1 2/2 , or Foxj1-Scgb1a1-Cre-Stat1 f/f mice (data not shown), consistent with our studies of SeV and IAV infections (28,29,31). To further address the comparison between the post-EV-D68 mouse model with chronic lung disease in humans, we also assessed the development of fibrosis as a feature of airway disease.…”

“…Further studies will be needed to determine whether the same mechanism drives chronic disease after EV-D68 infection. Nonetheless, the present finding for induction of Clca1 gene expression, which is highly dependent on IL-13 stimulation (29,31,64,65), suggests that the type 2 immune response might also drive chronic mucus production and airway hyperreactivity after EV-D68 similar to SeV and IAV infections (28)(29)(30)(31). The same mechanism is also proposed to mediate short-term airway disease after human RV infections in mice (66).…”

“…This transient effect was slightly suppressed with anti-IL-17A-blocking Ab, consistent with neutrophil-linked hyperreactivity found after short-term airway injury even in response to noninfectious agents (62), but the immune basis for subsequent longer-term disease after EV-D68 infection still needs to be defined. In contrast to the case for EV-D68, there is considerable evidence for SeV and IAV infections that the immune mechanism for postviral disease is based on a prolonged type 2 immune response (and not an IL-17 response) that proceeds from epithelial stem cell expansion to innate immune cell activation and feed forward to APEC differentiation toward mucous cells (28)(29)(30)(31)63). Further studies will be needed to determine whether the same mechanism drives chronic disease after EV-D68 infection.…”

Pathogenesis and prevention of risk of cardiovascular events in patients with pneumococcal community‐acquired pneumonia

“…This is supported by substantial evidence, much of it derived from animal models of experimental infection, that influenza virus infection is associated with alterations in the host respiratory tract that predispose to adherence, invasion and induction of disease by the pneumococcus [46]. These result in increased adhesion of the pneumococcus to virus-activated respiratory epithelium, together with alterations in pulmonary innate and adaptive immune responses that result in impaired clearance of the bacteria, as well as a chronic inflammatory response lasting for up to 26 weeks due to persistent viral antigenaemia, specifically RNA, in the lower airways [47][48][49]. Pneumococcal replication in the airways may be further enhanced by an increased availability of free sialic acids derived from cleavage of host mucin by viral neuraminidase [50].…”