Alterations in the Nasal Microbiome During Human Influenza Infections

Influenza is a leading cause of death in the United States and worldwide, resulting in approximately 40,000 deaths annually due to seasonal epidemics alone. A major complication of influenza infections resulting in lethality, particularly during pandemics, is secondary bacterial infections of the lung (pneumonia). Streptococcus pneumoniae, Staphylococcus aureus (especially methicillin-resistant S. aureus or MRSA), and Hemophilus influenzae are the most common pathogens associated with secondary bacterial infections, although other bacteria (e.g., Chlamydia, Klebsiella, etc.) are clinically observed. The mechanisms responsible for secondary bacterial infections are poorly understood, and currently, clinicians lack the ability to identify individuals at risk (let alone intervene therapeutically) for this deadly complication.

Bacterial colonization of the upper respiratory tract (e.g., nasal passages) frequently precedes the development of bacterial pneumonia, but how viral infections alter the microbial composition of the upper respiratory tract has not been investigated. Animal data from murine models of sequential influenza and bacterial infections suggest that either the viral infection itself or activation of the antiviral immune state enhances the susceptibility to bacterial infection of the lower respiratory tract (i.e., pneumonia), but this has yet to be examined in human patients. Since the nose is the main portal of entry for respiratory viruses, this location serves as a logical and easily accessible site for analyzing how viruses or host antiviral immune responses induce changes in the nasal microbiome, which may predict risk of secondary bacterial pneumonias. This comparative analysis of the microbial diversity found in the nasal passages of normal and influenza-infected individuals will provide insights into the interactions between commensal and pathogenic bacteria, as well as elucidate how viruses alter these relationships and enhance risk of secondary infections.

Our hypothesis is that viral-induced changes in the nasal microbiome foster growth of pathogenic bacteria and increase the risk of secondary bacterial pneumonia. To test this hypothesis, our aims for this proposal are as follows:

1. To identify baseline composition and kinetic changes in the nasal microflora (bacteria and viruses including flu) and antiviral immune responses after administering intranasal live attenuated influenza virus (i.e., Flumist vaccine) or saline mist to healthy subjects; 

2. To identify dynamic changes in nasal microbial composition during influenza infections and after resolution of infection, and correlate these changes with activation of antiviral immune pathways and clinical outcomes.

Funding