The role of influenza in the severity and transmission of respiratory bacterial disease

Abstract

Infections with influenza viruses and respiratory bacteria each contribute substantially to the global burden of morbidity and mortality. Simultaneous or sequential infection with these pathogens manifests in complex and difficult-to-treat disease processes that need extensive antimicrobial therapy and cause substantial excess mortality, particularly during annual influenza seasons and pandemics. At the host level, influenza viruses prime respiratory mucosal surfaces for excess bacterial acquisition and this supports increased carriage density and dissemination to the lower respiratory tract, while greatly constraining innate and adaptive antibacterial defences. Driven by virus-mediated structural modifications, aberrant immunological responses to sequential infection, and excessive immunopathological responses, co-infections are noted by short-term and long-term departures from immune homoeostasis, inhibition of appropriate pathogen recognition, loss of tolerance to tissue damage, and general increases in susceptibility to severe bacterial disease. At the population level, these effects translate into increased horizontal bacterial transmission and excess use of antimicrobial therapies. With increasing concerns about future possible influenza pandemics, the past decade has seen rapid advances in our understanding of these interactions. In this Review, we discuss the epidemiological and clinical importance of influenza and respiratory bacterial co-infections, including the foundational efforts that laid the groundwork for today's investigations, and detail the most important and current advances in our understanding of the structural and immunological mechanisms underlying the pathogenesis of co-infection. We describe and interpret what is known in sequence, from transmission and phenotypic shifts in bacterial dynamics to the immunological, cellular, and molecular modifications that underlie these processes, and propose avenues of further research that might be most valuable for prevention and treatment strategies to best mitigate excess disease during future influenza pandemics.

Figure 1. Timing of synergism between influenza and pneumococcal infection

Groups of mice were challenged with Pneumococcus at different times relative to influenza infection at day zero of infection. Bars=percentage survival after pneumococcal inoculation. Line with black squares=mean duration of survival (only for mice that died). Adapted with permission from McCullers and Rehg.

Figure 2. Mechanisms of influenza–bacterial co-infection

Influenza viruses and respiratory bacteria enter into, infect, or colonise the cells of the upper respiratory tract. Increased bacterial adherence after influenza infection results from an increased number of PAFr and plgR receptors, viral neuraminidase cleavage of sialic acids, and epithelial denudation that exposes basement membrane components; each enables enhanced binding by bacterial adherence factors (eg, ChoP, cbpA, and PspA) with increased bacterial replication and carriage. Viral-induced inflammation enhances expression of bacterial virulence factors (eg, pneumolysin) and increases release of bacteria from biofilms in the upper respiratory tract to a planktonic state, which in turn increases bacterial dissemination to the lower respiratory tract. Primary influenza infection followed by secondary bacterial inoculation yields excess cytokine and chemokine production with numerous downstream consequences, as depicted within a single alveolus and described within the main text of this Review. Excess type I interferon secretion yields overabundant, mixed, immature and mature neutrophil recruitment, which leads to severe immunopathology, particularly because of neutrophil ROS secretion and development of neutrophil extracellular traps, which further increases the inflammatory response. Excess type I and II interferons reduce recruitment of monocytes or macrophages by blunting Nod2 signalling and enhancing anti-inflammatory IL-10 secretion, which could also increase production of type II interferons, with reduced macrophage function and increased apoptosis. Excess inflammation is exacerbated by viral-mediated reduced secretion of amphiregulin and other factors important for tissue regeneration, which adds to the reduced alveolar and endothelial integrity and leads to capillary leakage, pulmonary oedema, and bacterial bloodstream invasion. Cytokine storm or bacterial overgrowth often result in irreparable damage to the lower respiratory tract and alveolar sacs, which results in severe pneumonia, sepsis, and often death. PAFr=platelet-activating-factor receptors. plgR=polymeric immunoglobulin receptors. ChoP=phosphorylcholine. cbpA= choline-binding protein A. PspA=pneumococcal surface protein A. ROS= reactive oxygen species. Nod2=nucleotide-binding, oligomerisation domain-containing protein 2. IL=interleukin. NA=neuraminidase. HA=haemagglutinin. APC=antigen-presenting cell. IFN=interferon. CCR-2=chemokine (C-C motif) receptor 2. CCL-2= monocyte chemotactic protein 1/chemokine ligand 2. NET=neutrophil extracellular traps. MARCO=macrophage receptor with collagenous structure. Th=T helper. KC= keratinocyte chemoattractant CXCL1. MIP-2=macrophage inflammatory protein CXCL2. NK=natural killer cell. IDO=indoleamine 2,3-dioxygenase. TLR=toll-like receptor. Ply=pneumolysin. γδT=γδ T cell.