Influenza and secondary bacterial pneumonia: Modulation of the host anti-viral immune response and the interferon paradox.

摘要

In 1918 the influenza virus (flu), in terms of total fatalities, was responsible for the worst pandemic the world has ever seen. The major cause of death is now attributed to secondary bacterial pneumonia. Flu infection itself was not the major cause of death. The most common pathogen responsible for fatality post-flu is believed to be Streptococcus pneumoniae, and this is the still the case regarding the recent 2009 pandemic H1N1 strain of "swine flu". Secondary bacterial pneumonias continue be the most common cause of death resulting from influenza, even after the advent of antibiotics, and the most common pathogen that is responsible for this continues to be Streptococcus pneumoniae. This is especially true in regard to the young and healthy members of society that do not have any co-morbid conditions during pandemic influenza outbreaks unlike the very old and young that are typically the victims following seasonal flu.;Type I interferons (IFN) are essential to minimize viral infection. These innate cytokines have numerous beneficial functions. However, influenza has developed multiple mechanisms that perturb the host interferon response, altering the levels, and timing, of the expression of these cytokines that thereby render them potentially detrimental to the host. The major hypothesis of this work focuses on the relative beneficial and/or detrimental role that type I IFN may have in the context of host immunity. We hypothesize that type I IFN has evolved to be beneficial, yet flu virulence factors perturb the ability of type I IFN to act in a beneficial role post-flu and instead augments the risk of SBP. Volatile anesthetics appear to ameliorate this.;In agreement with our hypothesis and past experimental findings, we found that 1) Halothane effectively mitigated the risk of secondary bacterial pneumonia post-flu. 2) This was dependent upon mitigation of the effects of type I IFN by halothane. 3) Using nanoparticle based therapeutics, restoration of type I IFN at an early, appropriate time point following flu infection has the potential to minimize influenza burden, and potentially inhibit risk of pneumococcal secondary pneumonia.;The findings from these studies have immediate clinical pertinence. Given that patients presenting with symptoms of upper respiratory tract infections may not be at increased risk of pulmonary complications if anesthetized with volatile anesthetics. Additionally, this work identifies novel mechanisms through which flu, its sequelae, and potentially other viral infections, may be thwarted through novel host immune-modulatory mechanisms.