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Influenza "Trains" the Host for Enhanced Susceptibility to Secondary Bacterial Infection
Kari Ann Shirey1, Darren J Perkins1, Wendy Lai1
1Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Abstract:
We previously reported that the Toll-like receptor 4 (TLR4) antagonist Eritoran blocks acute lung injury (ALI) therapeutically in mouse and cotton rat models of influenza. However, secondary (2°) bacterial infection following influenza virus infection is associated with excess morbidity and mortality. Wild-type (WT) mice infected with mouse-adapted influenza A/Puerto Rico/8/34 virus (PR8) and, 7 days later, with Streptococcus pneumoniae serotype 3 (Sp3) exhibited significantly enhanced lung pathology and lethality that was reversed by Eritoran therapy after PR8 infection but before Sp3 infection. Cotton rats infected with nonadapted pH1N1 influenza virus and then superinfected with methicillin-resistant Staphylococcus aureus also exhibited increased lung pathology and serum high-mobility-group box 1 (HMGB1) levels, both of which were blunted by Eritoran therapy. In mice, PR8 infection suppressed Sp3-induced CXCL1 and CXCL2 mRNA, reducing neutrophil infiltration and increasing the bacterial burden, all of which were reversed by Eritoran treatment. While beta interferon (IFN-β)-deficient (IFN-β-/-) mice are highly susceptible to PR8, they exhibited delayed death upon Sp3 superinfection, indicating that while IFN-β was protective against influenza, it negatively impacted the host response to Sp3 IFN-β-treated WT macrophages selectively suppressed Sp3-induced CXCL1/CXCL2 transcriptionally, as evidenced by reduced recruitment of RNA polymerase II to the CXCL1 promoter. Thus, influenza establishes a "trained" state of immunosuppression toward 2° bacterial infection, in part through the potent induction of IFN-β and its downstream transcriptional regulation of chemokines, an effect reversed by Eritoran.IMPORTANCE Enhanced susceptibility to 2° bacterial infections following infection with influenza virus is a global health concern that accounts for many hospitalizations and deaths, particularly during pandemics. The complexity of the impaired host immune response during 2° bacterial infection has been widely studied. Both type I IFN and neutrophil dysfunction through decreased chemokine production have been implicated as mechanisms underlying enhanced susceptibility to 2° bacterial infections. Our findings support the conclusion that selective suppression of CXCL1/CXCL2 represents an IFN-β-mediated "training" of the macrophage transcriptional response to TLR2 agonists and that blocking of TLR4 therapeutically with Eritoran after influenza virus infection reverses this suppression by blunting influenza-induced IFN-β.
Insights
Influenza infection impairs the immune response to secondary bacterial infections by inducing a "trained" immunosuppression, partly via beta interferon (IFN-β). Eritoran, a Toll-like receptor 4 (TLR4) antagonist, reverses this effect, improving outcomes in influenza and bacterial coinfection models.
Area of Science:
- Immunology
- Infectious Diseases
- Pulmonology
Background:
- Secondary bacterial infections post-influenza significantly increase morbidity and mortality.
- Influenza virus infection can lead to a compromised host immune response against subsequent bacterial pathogens.
- Understanding the mechanisms of this impaired immunity is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the therapeutic potential of the Toll-like receptor 4 (TLR4) antagonist Eritoran in mitigating lung pathology and mortality associated with secondary bacterial infections following influenza.
- To elucidate the immunological mechanisms, particularly the role of beta interferon (IFN-β), underlying the enhanced susceptibility to secondary bacterial infections after influenza.
Main Methods:
- Utilized mouse and cotton rat models infected sequentially with influenza viruses and bacteria (Streptococcus pneumoniae or Staphylococcus aureus).
- Administered Eritoran therapeutically after primary influenza infection but before secondary bacterial challenge.
- Assessed lung pathology, lethality, bacterial burden, and host immune responses, including chemokine production (CXCL1, CXCL2) and inflammatory cell infiltration.
- Investigated the role of IFN-β using IFN-β-deficient mice and in vitro studies with macrophages.
Main Results:
- Eritoran therapy significantly reversed influenza-induced lung pathology and lethality in secondary bacterial coinfection models.
- Influenza infection suppressed bacterial-induced CXCL1 and CXCL2 chemokine expression, leading to reduced neutrophil infiltration and increased bacterial burden, effects reversed by Eritoran.
- Beta interferon (IFN-β) played a dual role: protective against influenza but detrimental to the host response against secondary S. pneumoniae infection.
- IFN-β-treated macrophages demonstrated suppressed transcription of CXCL1/CXCL2, indicating a mechanism for 'trained' immunosuppression.
Conclusions:
- Influenza virus infection establishes a state of 'trained' immunosuppression towards secondary bacterial infections, mediated in part by IFN-β-induced transcriptional suppression of chemokines.
- Therapeutic blockade of TLR4 with Eritoran effectively reverses this IFN-β-driven immunosuppression, offering a potential strategy to combat severe outcomes of influenza and bacterial coinfections.