Compromised Defenses: Exploitation of Epithelial Responses During Viral-Bacterial Co-Infection of the Respiratory Tract

Respiratory infections are the greatest single contributor to the overall burden of disease worldwide [1]. Polymicrobial infections are becoming increasingly recognized in terms of both prevalence and their effect on disease severity, causing many common diseases such as oral infections, otitis media, chronic wound infections, and implanted medical device infections, as well as chronic pulmonary disease in cystic fibrosis patients [2,3]. There is a large body of literature demonstrating synergy between viral and bacterial infections at mucosal surfaces; for example, (i) the intestinal microbiota promotes enteric viral infection via direct interactions and modulation of the immune system [4]; (ii) sexually transmitted viruses exploit the altered environment, including altered pH, inflammatory, and oxidative settings, during bacterial vaginosis or aerobic vaginitis to increase infection of the vaginal and cervical epithelium [5]; and (iii) bacteria take advantage of the altered innate and adaptive immune responses of the respiratory tract during viral infection of the respiratory epithelium to increase infectivity and virulence [6]. Many studies have focused on the consequences of influenza infection on secondary bacterial infection in the respiratory tract, where altered lung physiology and immune status increases susceptibility to severe secondary bacterial infections with common commensal organisms of the upper respiratory tract, such as Streptococcus pneumoniae and Staphylococcus aureus [7]. Here, we focus on the role of the respiratory epithelium in defending against microbial pathogens as well as in facilitating synergistic pathogenic interactions (Fig 1). Fig 1 Model of increased susceptibility to secondary bacterial infection after primary viral infection of the respiratory epithelium. Role of the Respiratory Epithelium in Innate and Adaptive Immunity The respiratory epithelium is the primary site of host–pathogen encounter in the respiratory tract and the first line of defense against infection (extensively reviewed [8–10]). The epithelium employs a wide array of tools to inhibit colonization as well as dictate innate and adaptive immune responses to pathogens that overcome these initial barriers. First and foremost, the epithelium is a physical barrier to pathogen invasion, forming cell–cell junctions to exclude pathogens from the underlying tissues and actively restrict nutrient availability. Respiratory epithelial cells maintain an airway surface liquid into which they secrete mucins that form a mucus layer to trap and propel pathogens out of the respiratory tract via mucociliary beat. The epithelium also secretes many additional effectors in the airway surface liquid, including antimicrobial peptides and proteins, such as degradative enzymes, iron sequestration proteins, protease inhibitors, collectin surfactant proteins, chemokines, and various forms of palate-lung-nasal-clone protein (PLUNC). The airway epithelium also produces toxic reactive nitrogen species and reactive oxygen species. These direct antimicrobial effectors are upregulated in response to pathogen or pro-inflammatory signals. Airway epithelial cells also produce cytokines and chemokines in response to pathogens, via pattern recognition receptor (PRR) activation, or to pro-inflammatory signals to shape the innate and adaptive immune responses, leading to an influx of neutrophils and monocytes, differentiation of monocytes into dendritic cells and macrophages, influx and activation of Th cells, and differentiation of B cells. B cell differentiation leads to immunoglobulin (Ig) class switching, and epithelial cells transcytose polymeric IgM and IgA into the airway surface liquid. Despite this array of defense functions, synergistic interactions between viral and bacterial respiratory pathogens can arise when one pathogen is able to suppress the antimicrobial activities of the epithelium or when an epithelial response that is protective against one pathogen makes the airway more permissive for infection by the other pathogen.