Respiratory Viral Infection-Induced Microbiome Alterations and Secondary Bacterial Pneumonia

Abstract

Influenza and other respiratory viral infections are the most common type of acute respiratory infection. Viral infections predispose patients to secondary bacterial infections, which often have a more severe clinical course. The mechanisms underlying post-viral bacterial infections are complex, and include multifactorial processes mediated by interactions between viruses, bacteria, and the host immune system. Studies over the past 15 years have demonstrated that unique microbial communities reside on the mucosal surfaces of the gastrointestinal tract and the respiratory tract, which have both direct and indirect effects on host defense against viral infections. In addition, antiviral immune responses induced by acute respiratory infections such as influenza are associated with changes in microbial composition and function ("dysbiosis") in the respiratory and gastrointestinal tract, which in turn may alter subsequent immune function against secondary bacterial infection or alter the dynamics of inter-microbial interactions, thereby enhancing the proliferation of potentially pathogenic bacterial species. In this review, we summarize the literature on the interactions between host microbial communities and host defense, and how influenza, and other acute respiratory viral infections disrupt these interactions, thereby contributing to the pathogenesis of secondary bacterial infections.

Keywords: bacterial pneumonia; gut microbiome; host-microbe interaction; influenza; respiratory viral infection; viral-bacterial interaction.

Figure 1

Shifts in the mouse gut microbiome in the setting of influenza infection. During an acute respiratory viral infection, changes in the bacterial composition of the gut microbiome can be observed despite the absence of detectable virus in the gastrointestinal compartment. This suggests that systemic immune signals, physiologic changes (e.g., weight loss), and other still unknown factors are disrupting the normal ecology of the gut, thereby leading to dysbiosis. However, the majority of these studies have been conducted in laboratory animals housed under SPF conditions. It remains to be determined whether human patients and mammalian hosts with more diverse baseline gut microbiota (i.e., mice in the wild), exhibit similar qualitative or quantitative changes.

Figure 2

Effects of antibiotic pre-treatment on immune responses to influenza, Streptococcus pneumoniae, and Lipoteichoic acid (LTA). The effects of the gut microbiome on immune responses to respiratory pathogens have been investigated by administration of oral antibiotics to generate alterations in the gut flora, followed by acute infection, and analyzing host immune responses compared to non-antibiotic-pretreated animals. Multiple aspects of innate and adaptive immune responses are altered in antibiotic treated animals, including decreased antibody production, decreased phagocytic activity, and decreased inflammatory cytokine production by innate immune cells (e.g., alveolar and peritoneal macrophages) following ex vivo stimulation with TLR ligands.

Figure 3

Changes in the human upper respiratory tract microbiome following viral exposure. Given that bacterial pneumonia frequently arises as a result of aspirated bacterial pathogens, a potential mechanism by which viral infections might increase the risk of secondary bacterial infections is through increased colonization of the upper respiratory tract by bacterial pathogens. In human subjects, live attenuated influenza vaccine (LAIV) and human rhinovirus (hRV) have been shown to disrupt the local host bacterial community, with increased relative abundance of potential pathogens (or pathobionts), such as Staphylococcal and Neisseria species. The major changes in the upper respiratory tract microbiome are highlighted here.

Figure 4

Model of viral induced susceptibility to secondary infections.