Peroxisome Proliferator-Activated Receptor Gamma (PPAR) Suppresses Inflammation and Bacterial Clearance during Influenza-Bacterial Super-Infection.

Radha Gopal,Helen E Rich,Philip J Seger,Angelico Mendy,Lacee J Richwalls,Shivani Patel,Michael A Marinelli,John F Alcorn,Kevin J Mchugh,Erick Forno,Jennifer A Grousd

doi:10.3390/v11060505

Abstract

Influenza virus is among the most common causes of respiratory illness worldwide and can be complicated by secondary bacterial pneumonia, a frequent cause of mortality. When influenza virus infects the lung, the innate immune response is activated, and interferons and inflammatory mediators are released. This “cytokine storm” is thought to play a role in influenza-induced lung pathogenesis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor super-family. PPARγ has numerous functions including enhancing lipid and glucose metabolism and cellular differentiation and suppressing inflammation. Synthetic PPARγ agonists (thiazolidinediones or glitazones) have been used clinically in the treatment of type II diabetes. Using data from the National Health and Nutrition Examination Survey (NHANES), diabetic participants taking rosiglitazone had an increased risk of mortality from influenza/pneumonia compared to those not taking the drug. We examined the effect of rosiglitazone treatment during influenza and secondary bacterial (Methicillin resistant Staphylococcus aureus) pneumonia in mice. We found decreased influenza viral burden, decreased numbers of neutrophils and macrophages in bronchoalveolar lavage, and decreased production of cytokines and chemokines in influenza infected, rosiglitazone-treated mice when compared to controls. However, rosiglitazone treatment compromised bacterial clearance during influenza-bacterial super-infection. Both human and mouse data suggest that rosiglitazone treatment worsens the outcome of influenza-associated pneumonia.

Highlights

Influenza, while being a common illness, takes a heavy toll on the healthcare system as the Center for Disease Control and Prevention estimates that between 12,000 and 56,000 deaths have occurred annually in the United States since 2010
We examined the role of rosiglitazone treatment during influenza infection and influenza-bacterial super-infection by determining influenza viral burden, viral-induced interferons and their downstream stimulated genes, inflammatory cellular responses, and pro- and anti-inflammatory cytokines in the lung
We first determined whether rosiglitazone treatment is associated with mortality from influenza-related pneumonia in humans, using data on diabetic patients from National Health and Nutrition Examination Survey (NHANES)

Summary

Introduction

While being a common illness, takes a heavy toll on the healthcare system as the Center for Disease Control and Prevention estimates that between 12,000 and 56,000 deaths have occurred annually in the United States since 2010. Influenza induces Type I, Type II, and Type III interferons, which are responsible for interfering with viral replication in infected cells [1,2,3,4,5]. Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been shown as a significant source of mortality during influenza-associated secondary bacterial infection [13,14,15]. We have shown that type I IFN and STAT1 inhibit the S. aureus-induced Type 17 response, thereby decreasing bacterial clearance during influenza-bacterial super-infection [23,24,25]. Our recent study has shown that the STAT2 signaling suppress macrophage activation and bacterial clearance during influenza-bacterial super-infection [26]

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Conclusion