Airway Epithelial versus Immune Cell Stat1 Function for Innate Defense against Respiratory Viral Infection

Abstract

The epithelial surface is often proposed to actively participate in host defense, but the evidence remains circumstantial. Here we use a mouse paramyxovirus (Sendai virus; SeV) to show that a prominent early event in respiratory infection is activation of Stat1 in airway epithelial cells. Stat1−/– mice developed illness that resembled severe paramyxoviral respiratory infection in humans and was characterized by increased viral replication and neutrophilic inflammation in concert with overproduction of TNF‐α and MIP‐2. Poor control of viral replication as well as TNF‐α and MIP‐2 overproduction were mimicked by infection of Stat1−/– airway epithelial cells in vitro. TNF‐α drives the MIP‐2 response, since it can be reversed by TNF‐α blockade both in vitro and in vivo. These findings pointed to an epithelial defect in Stat1−/– mice. Indeed, Stat1−/– mice reconstituted with wild‐type bone marrow were still susceptible to infection with SeV whereas wild‐type mice that received Stat1−/– bone marrow retained resistance to infection. The susceptible epithelial Stat1−/– chimeric mice also exhibited increased viral replication as well as excessive neutrophils, MIP‐2, and TNF‐α in the airspace. These findings provide some of the most definitive evidence for the role of barrier epithelial cells in innate immunity to common pathogens, particularly in controlling viral replication. Funding: NIH & Parker B. Francis Foundation

Chlorinated lipid species in activated human neutrophils: lipid metabolites of 2-chlorohexadecanal

“…It has been previously shown that neutrophils infi ltrate the lungs of SeV-infected mice. Neutrophils are the predominant cell present in the BALF until day 5, when macrophages and lymphocytes increase in number ( 24 ). The involvement of neutrophil activation and MPO-derived products in this model was verifi ed by showing that 2-ClHA accumulated in BALF collected from SeV-infected mice compared with control-treated mice.…”

“…Thus, experiments were performed to assess the accumulation of these lipids in a mouse model of respiratory viral infection that results in the recruitment and activation of neutrophils to the lung ( 24 ). SeVspecifi c RNA was present only in the lungs of SeV-infected mice, demonstrating virus replication.…”

“…SeV is a natural mouse pathogen that causes a neutrophilic bronchiolitis. During SeV infection, neutrophil infi ltration in the lung peaks on day 3 postinfection, prior to the peak of both macrophage and lymphocyte infl ux ( 24 ). Therefore, experiments were terminated on day 3 when both BALF and serum were collected.…”

“…Mice were infected with parainfl uenza 1 virus strain Sendai/52 (SeV), which causes a neutrophilic bronchiolitis ( 24 ). Adult C57BL/6 mice 8-12 weeks of age were anesthetized by intraperitoneal injection of ketamine HCl (86.98 mg/kg) plus xylazine HCl (13.04 mg/kg).…”

Local Blockade of Epithelial PDL-1 in the Airways Enhances T Cell Function and Viral Clearance during Influenza Virus Infection

“…The airway epithelium lining the respiratory tract not only represents the first barrier of defense against respiratory pathogens but is often the primary target of infection (1). Consequently, apart from a critical role in gas exchange function, airway epithelial cells additionally participate in host defense mechanisms by producing cytokines and chemokines (2)(3)(4)(5)(6)(7)(8). Since exacerbated responses by airway epithelial cells in response to innocuous antigens or pathogens can prove detrimental to lung function, airway epithelial cells have also evolved to regulate pulmonary homeostasis by multiple mechanisms, including, among others, expression of CD200 (9), MUC-1 (10), and surfactant proteins (11) and reduced expression of adaptor molecules (12)(13)(14).…”