Eicosanoid-Activated PPARα Inhibits NFκB-Dependent Bacterial Clearance During Post-Influenza Superinfection.
Ontology highlight
ABSTRACT:
SUBMITTER: Lucarelli R
PROVIDER: S-EPMC9289478 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Influenza kills 30,000 to 40,000 people each year in the United States and causes 10 times as many hospitalizations. A common complication of influenza is bacterial superinfection, which exacerbates morbidity and mortality from the viral illness. Recently, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as the dominant pathogen found in bacterial superinfection, with Streptococcus pneumoniae a close second. However, clinicians have few tools to treat bacterial superinfection. Current therapy for influenza/bacterial superinfection consists of treating the underlying influenza infection and adding various antibiotics, which are increasingly rendered ineffective by rising bacterial multidrug resistance. Several groups have recently proposed the use of the antiviral cytokine interferon lambda (IFN-?) as a therapeutic for influenza, as administration of pegylated IFN-? improves lung function and survival during influenza by reducing the overabundance of neutrophils in the lung. However, our data suggest that therapeutic IFN-? impairs bacterial clearance during influenza superinfection. Specifically, mice treated with an adenoviral vector to overexpress IFN-? during influenza infection exhibited increased bacterial burdens upon superinfection with either MRSA or S. pneumoniae Surprisingly, adhesion molecule expression, antimicrobial peptide production, and reactive oxygen species activity were not altered by IFN-? treatment. However, neutrophil uptake of MRSA and S. pneumoniae was significantly reduced upon IFN-? treatment during influenza superinfection in vivo Together, these data support the theory that IFN-? decreases neutrophil motility and function in the influenza-infected lung, which increases the bacterial burden during superinfection. Thus, we believe that caution should be exercised in the possible future use of IFN-? as therapy for influenza.
| S-EPMC6479047 | biostudies-literature
Project description: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 PPARγagonists (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.
| S-EPMC6630660 | biostudies-literature
Project description:The transcription factor, T-bet, regulates type 1 inflammatory responses against a range of infections. Here, we demonstrate a previously unaddressed role of T-bet, to influenza virus and bacterial superinfection. Interestingly, we found that T-bet deficiency did not adversely affect the efficacy of viral clearance or recovery compared to wild-type hosts. Instead, increased infiltration of neutrophils and production of Th17 cytokines (IL-17 and IL-22), in lungs of influenza virus-infected T-bet-/- mice, were correlated with survival advantage against subsequent infection by Streptococcus pneumoniae Neutralization of IL-17, but not IL-22, in T-bet-/- mice increased pulmonary bacterial load, concomitant with decreased neutrophil infiltration and reduced survival of T-bet-/- mice. IL-17 production by CD8+, CD4+ and ?? T cell types was identified to contribute to this protection against bacterial superinfection. We further showed that neutrophil depletion in T-bet-/- lungs increased pulmonary bacterial burden. These results thus indicate that despite the loss of T-bet, immune defences required for influenza viral clearance are fully functional, which in turn enhances protective type 17 immune responses against lethal bacterial superinfections.
| S-EPMC6315292 | biostudies-other
Project description:The transcription factor, T-bet, regulates type 1 inflammatory responses against a range of infections. Here, we demonstrate a previously unaddressed role of T-bet, to influenza virus and bacterial superinfection. Interestingly, we found that T-bet deficiency did not adversely affect the efficacy of viral clearance or recovery compared to wild-type hosts. Instead, increased infiltration of neutrophils and production of Th17 cytokines (IL17 and IL-22), in lungs of influenza virus infected T-bet-/- mice was correlated with survival advantage against subsequent infection by Streptococcus pneumoniae. Neutralization of IL-17, but not of IL-22 in T-bet-/- mice increased pulmonary bacterial load, concomitant with decreased neutrophil infiltration and reduced survival of T-bet-/- mice. IL-17 production by CD8+, CD4+ and γδ T cell types were identified to contribute to this protection against bacterial superinfection. We further showed that neutrophil depletion in T-bet-/- lungs increased pulmonary bacterial burden. These results thus indicate that despite the loss of T-bet, immune defences required for influenza viral clearance are fully functional, which in turn enhances protective type 17 immune responses against lethal bacterial superinfections.
| S-SCDT-EMBOJ-2018-99176 | biostudies-other
Project description:Postinfluenza bacterial superinfections cause increased morbidity and mortality compared with singular infection with influenza during both pandemics and seasonal epidemics. Vaccines and current treatments provide limited benefit, a rationale to conduct studies utilizing alternative therapies. FY1 and an optimized version, MEDI8852, anti-influenza HA mAbs, have been shown to neutralize influenza virus during singular influenza infection. MEDI4893*, an anti-Staphylococcus aureus α-toxin mAb, has been shown to improve survival when administered prophylactically prior to S. aureus pneumonia. Our objective was to determine if mAbs can improve survival during postinfluenza bacterial pneumonia. We administered FY1 in a murine model of postinfluenza methicillin-resistant S. aureus (MRSA) pneumonia and observed improved survival rates when given early during the course of influenza infection. Our findings indicate decreased lung injury and increased uptake and binding of bacteria by macrophages in the mice that received FY1 earlier in the course of influenza infection, corresponding to decreased bacterial burden. We also observed improved survival when mice were treated with a combination of FY1 and MEDI4893* late during the course of postinfluenza MRSA pneumonia. In conclusion, both FY1 and MEDI4893* prolong survival when used in a murine model of postinfluenza MRSA pneumonia, suggesting pathogen-specific mAbs as a possible therapeutic in the context of bacterial superinfection.
| S-EPMC6675563 | biostudies-literature
Project description:Bacterial co-infections represent a major clinical complication of influenza. Host-derived interferon (IFN) increases susceptibility to bacterial infections following influenza, but the relative roles of type-I versus type-II IFN remain poorly understood. We have used novel mouse models of co-infection in which colonizing pneumococci were inoculated into the upper respiratory tract; subsequent sublethal influenza virus infection caused the bacteria to enter the lungs and mediate lethal disease. Compared to wild-type mice or mice deficient in only one pathway, mice lacking both IFN pathways demonstrated the least amount of lung tissue damage and mortality following pneumococcal-influenza virus superinfection. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to co-infected wild-type mice. The most effective treatment regimen was staggered neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of type-II IFN, which was consistent with the expression and reported activities of these IFNs during superinfection. These results are the first to directly compare the activities of type-I and type-II IFN during superinfection and provide new insights into potential host-directed targets for treatment of secondary bacterial infections during influenza.
| S-EPMC7978370 | biostudies-literature
Project description:Influenza A is a highly contagious respiratory virus that causes seasonal epidemics and occasional worldwide pandemics. The primary cause of influenza-related mortality is bacterial superinfection. There are numerous mechanisms by which preceding influenza infection attenuates host defense, allowing for increased susceptibility to bacterial pneumonia. Herein, we demonstrate that influenza inhibits Staphylococcus aureus-induced production of interleukin-33 (IL-33). Restoration of IL-33 during influenza A and methicillin-resistant S. aureus superinfection enhanced bacterial clearance and improved mortality. Innate lymphoid Type 2 cells and alternatively activated macrophages are not required for IL-33-mediated protection during superinfection. We show that IL-33 treatment resulted in neutrophil recruitment to the lung, associated with improved bacterial clearance. These findings identify a novel role for IL-33 in antibacterial host defense at the mucosal barrier.
| S-EPMC5638662 | biostudies-literature
Project description:Influenza A viruses (IAV) can cause lung injury and acute respiratory distress syndrome (ARDS), which is characterized by accumulation of excessive fluid (edema) in the alveolar airspaces and leads to hypoxemia and death if not corrected. Clearance of excess edema fluid is driven mostly by the alveolar epithelial Na,K-ATPase and is crucial for survival of patients with ARDS. We therefore investigated whether IAV infection alters Na,K-ATPase expression and function in alveolar epithelial cells (AECs) and the ability of the lung to clear edema. IAV infection reduced Na,K-ATPase in the plasma membrane of human and murine AECs and in distal lung epithelium of infected mice. Moreover, induced Na,K-ATPase improved alveolar fluid clearance (AFC) in IAV-infected mice. We identified a paracrine cell communication network between infected and noninfected AECs and alveolar macrophages that leads to decreased alveolar epithelial Na,K-ATPase function and plasma membrane abundance and inhibition of AFC. We determined that the IAV-induced reduction of Na,K-ATPase is mediated by a host signaling pathway that involves epithelial type I IFN and an IFN-dependent elevation of macrophage TNF-related apoptosis-inducing ligand (TRAIL). Our data reveal that interruption of this cellular crosstalk improves edema resolution, which is of biologic and clinical importance to patients with IAV-induced lung injury.
| S-EPMC4811131 | biostudies-literature
Project description:RationalePulmonary infections can impair alveolar fluid clearance (AFC), contributing to formation of lung edema. Effects of influenza A virus (IAV) on AFC are unknown.ObjectivesTo determine effects of IAV infection on AFC, and to identify intercellular signaling mechanisms underlying influenza-mediated inhibition of AFC.MethodsBALB/c mice were infected intranasally with influenza A/WSN/33 (10,000 or 2,500 focus-forming units per mouse). AFC was measured in anesthetized, ventilated mice by instilling 5% bovine serum albumin into the dependent lung.Measurements and main resultsInfection with high-dose IAV resulted in a steady decline in arterial oxygen saturation and increased lung water content. AFC was significantly inhibited starting 1 hour after infection, and remained suppressed through Day 6. AFC inhibition at early time points (1-4 h after infection) did not require viral replication, whereas AFC inhibition later in infection was replication-dependent. Low-dose IAV infection impaired AFC for 10 days, but induced only mild hypoxemia. High-dose IAV infection increased bronchoalveolar lavage fluid ATP and UTP levels. Impaired AFC at Day 2 resulted primarily from reduced amiloride-sensitive AFC, mediated by increased activation of the pyrimidine-P2Y purinergic receptor axis. However, an additional component of AFC impairment was due to activation of A(1) adenosine receptors and stimulation of increased cystic fibrosis transmembrane regulator-mediated anion secretion. Finally, IAV-mediated inhibition of AFC at Day 2 could be reversed by addition of beta-adrenergic agonists to the AFC instillate.ConclusionsAFC inhibition may be an important feature of early IAV infection. Its blockade may reduce the severity of pulmonary edema and hypoxemia associated with influenza pneumonia.
| S-EPMC2577730 | biostudies-literature
Project description:Human rhinovirus is the most frequently isolated virus during severe exacerbations of chronic respiratory diseases, like chronic obstructive pulmonary disease. In this disease, alveolar macrophages display significantly diminished phagocytic functions that could be associated with bacterial superinfections. However, how human rhinovirus affects the functions of macrophages is largely unknown. Macrophages treated with HRV16 demonstrate deficient bacteria killing activity, impaired phagolysosome biogenesis and altered intracellular compartments. Using RNA sequencing, we identify the small GTPase ARL5b to be upregulated by the virus in primary human macrophages. Importantly, depletion of ARL5b rescues bacterial clearance and localization of endosomal markers in macrophages upon HRV16 exposure. In permissive cells, depletion of ARL5b increases the secretion of HRV16 virions. Thus, we identify ARL5b as a novel regulator of intracellular trafficking dynamics and phagolysosomal biogenesis in macrophages and as a restriction factor of HRV16 in permissive cells.
| S-SCDT-10_1038-S44319-024-00069-X | biostudies-other