Immune dysfunction and bacterial coinfections following influenza

Abstract

Secondary pulmonary infections by encapsulated bacteria including Streptococcus pneumoniae and Staphylococcus aureus following influenza represent a common and challenging clinical problem. The reasons for this polymicrobial synergy are still not completely understood, hampering development of effective prophylactic and therapeutic interventions. Although it has been commonly thought that viral-induced epithelial cell damage allows bacterial invasiveness, recent studies by several groups have now implicated dysfunctional innate immune defenses following influenza as the primary culprit for enhanced susceptibility to secondary bacterial infections. Understanding the immunological imbalances that are responsible for virus/bacteria synergy will ultimately allow the design of effective, broad-spectrum therapeutic approaches for prevention of enhanced susceptibility to these pathogens.

Figure 1

Kinetics of influenza virus infection and susceptibility to bacterial co-infection.

Figure 2

A model for the influence of influenza infection on innate antibacterial immunity. (A), In the normal, uninfected lung, resident alveolar macrophages provide the first line of defense against encapsulated bacteria such as pneumococci. If macrophage defenses are overwhelmed, neutrophils are recruited to the airways through the action of IL-17 and related cytokines, likely produced by γδ T cells. (B) During influenza infection, CD4 and CD8 T cells are recruited into the lung to help resolve viral infection. These T cells secrete copious amounts of IFN-γ that binds to alveolar macrophages and modifies their properties, including inhibition of scavenger receptor expression, such as MARCO, and upregulation of MHC class II. In addition, IFN-αβ produced by virally-infected epithelial cells inhibits IL-17 production and thus, neutrophil recruitment is diminished. Not shown is the infiltration of other inflammatory myeloid cells into the lung following influenza. The result is that while adaptive immunity designed to establish anti-viral immune memory is enhanced, innate antibacterial defenses are suppressed. By approximately Day 14 following influenza infection, levels of type I and type II IFN are decreased and innate defenses against bacterial invasion are restored.