Postinfluenza Bacterial Pneumonia Research Articles

A bacterial vesicle-based pneumococcal vaccine against influenza-mediated secondary Streptococcus pneumoniae pulmonary infection

Streptococcus pneumoniae (Spn) is a common pathogen causing a secondary bacterial infection following influenza which leads to severe morbidity and mortality during seasonal and pandemic influenza. Therefore, there is an urgent need to develop bacterial vaccines that prevent severe post-influenza bacterial pneumonia. Here, an improved Yersinia pseudotuberculosis strain (designated as YptbS46) possessing an Asd+ plasmid pSMV92 could synthesize high amounts of the Spn pneumococcal surface protein A (PspA) antigen and monophosphoryl lipid A as an adjuvant. The recombinant strain produced outer membrane vesicles (OMVs) enclosing a high amount of PspA protein (designated as OMV-PspA). A prime-boost intramuscular immunization with OMV-PspA induced both memory adaptive and innate immune responses in vaccinated mice, reduced the viral and bacterial burden, and provided complete protection against influenza-mediated secondary Spn infection. Also, the OMV-PspA immunization afforded significant cross-protection against the secondary Spn A66.1 infection and long-term protection against the secondary Spn D39 challenge. Our study implies that an OMV vaccine delivering Spn antigens can be a new promising pneumococcal vaccine candidate.

Detailed Mechanisms Underlying Neutrophil Bactericidal Activity against Streptococcus pneumoniae.

Neutrophils are an essential cellular component of innate immunity and control bacterial infections through a combination of intracellular and extracellular killing methods. Although the importance of neutrophils has been established, the exact methods used to handle particular bacterial challenges and the efficiency of bacterial killing remain not well understood. In this study, we addressed how neutrophils eliminate Streptococcus pneumoniae (Spn), a leading cause of community acquired and post-influenza bacterial pneumonia. We analyzed killing methods with variable bacterial:neutrophil concentrations and following priming with PAM3CSK4 (P3CSK), an agonist for Toll-like-receptor 2 (TLR2). Our results show that murine neutrophils display surprisingly weak bactericidal activity against Spn, employing a predominantly extracellular mode of killing at lower concentrations of bacteria, whereas challenges with higher bacterial numbers induce both extracellular and intracellular elimination modes but require TLR2 activation. TLR2 activation increased reactive oxygen species (ROS) and neutrophil extracellular trap (NET) formation in response to Spn. Despite this, supernatants from P3CSK-stimulated neutrophils failed to independently alter bacterial replication. Our study reveals that unstimulated neutrophils are capable of eliminating bacteria only at lower concentrations via extracellular killing methods, whereas TLR2 activation primes neutrophil-mediated killing using both intracellular and extracellular methods under higher bacterial burdens.

Type I IFN Signaling Is Essential for Preventing IFN-γ Hyperproduction and Subsequent Deterioration of Antibacterial Immunity during Postinfluenza Pneumococcal Infection.

Postinfluenza bacterial pneumonia is a significant cause of hospitalization and death in humans. The mechanisms underlying this viral and bacterial synergy remain incompletely understood. Recent evidence indicates that influenza-induced IFNs, particularly type I IFN (IFN-I) and IFN-γ, suppress antibacterial defenses. In this study, we have investigated the relative importance and interplay of IFN-I and IFN-γ pathways in influenza-induced susceptibility to Streptococcus pneumoniae infection. Using gene-deficient mouse models, as well as in vivo blocking Abs, we show that both IFN-I and IFN-γ signaling pathways contribute to the initial suppression of antibacterial immunity; however, IFN-γ plays a dominant role in the disease deterioration, in association with increased TNF-α production and alveolar macrophage (AM) depletion. We have previously shown that IFN-γ impairs AM antibacterial function and thereby acute bacterial clearance. The findings in this study indicate that IFN-γ signaling also impairs AM viability and αβ T cell recruitment during the progression of influenza/S. pneumoniae coinfection. Macrophages insensitive to IFN-γ mice express a dominant-negative mutant IFN-γR in mononuclear phagocytes. Interestingly, macrophages insensitive to IFN-γ mice exhibited significantly improved recovery and survival from coinfection, despite delayed bacterial clearance. Importantly, we demonstrate that IFN-I receptor signaling is essential for preventing IFN-γ hyperproduction and animal death during the progression of postinfluenza pneumococcal pneumonia.

A profile of delafloxacin in the treatment of adults with community-acquired bacterial pneumonia

Introduction Community-acquired bacterial pneumonia (CABP) is the most common infectious cause of hospital admission in adults, and poses a significant clinical and economic burden. At the same time, antimicrobial resistance is increasing worldwide with only a few new antibiotics developed in recent years. Delafloxacin is an anionic fluoroquinolone available in intravenous and oral formulations and with a broad spectrum of activity targeting Gram-positives, including methicillin-resistant Staphylococcus aureus (MRSA), gram-negative organisms, and atypical and anaerobic organisms. It also has a better adverse event profile compared to other fluoroquinolones. Areas covered This article reviews the current epidemiology of CABP, etiologic agents and current resistance rates, current treatment guidelines, characteristics of delafloxacin (chemistry, microbiology, PK/PD), clinical efficacy and safety in pneumonia and other indications, and regulatory affairs. Expert opinion : Delafloxacin’s susceptibility profile against respiratory pathogens, bioequivalent intravenous and oral formulations and favorable safety profile, support its use for the treatment of CABP. It could be useful as empirical treatment in countries with high rates of penicillin-resistant S. pneumoniae and in patients with suspected or documented pneumonia due to MRSA. In post-influenza staphylococcal bacterial pneumonia, MRSA could be also considered an important pathogen.

Associated virus-bacterial vaccine based on seasonal LAIV and S. pneumoniae chimeric peptide provide protection against post-influenza pneumococcal infection in mouse model

ABSTRACT Severe influenza complications are often caused by Streptococcus pneumoniae infection, which presents the most common cause of community-acquired pneumonia. We evaluated in a mouse model an associated virus-bacterial vaccine based on seasonal live influenza vaccines (LAIV) and S. pneumoniae chimeric protein comprising flagellin (PSPF). Intranasal immunization of mice with a complex of trivalent LAIV and PSPF caused an increased release of early cytokines in the lungs of mice. The immunogenicity of LAIV and PSPF in the associated vaccine composition was sometimes decreased compared to each vaccine preparation alone. Nevertheless, only vaccination of mice with LAIV+PSPF significantly reduced lethality and the bacterial load in the lungs in a model of post-influenza bacterial pneumonia. The study of the interactions of influenza viruses with bacterial peptides is important during the development of associated virus-bacterial vaccines intended for the prevention of severe post-influenza bacterial complications.

Examining protective efficacy of influenza virus NA-containing virus-like particles (VLP) in mouse model of post-influenza bacterial pneumonia caused by Staphylococcus aureus

Currently, pneumonia resulting from post-influenza infection still remains a pressing issue. In particular, virtually no studies regarding a role of immune response against influenza virus neuraminidase in regulating host susceptibility to subsequent bacterial superinfection are now available. Virus-like particles represent one of the new and promising approaches in contemporary virology for developing influenza vaccines and studying influenza virus proteins. Upon that, it is possible to obtain virus-like particles carrying individual influenza virus-derived proteins such as neuraminidase and hemagglutinin. This allows to get closer insight into potential role of individual influenza virus proteins for host immune response as well as assess a risk of developing secondary bacterial pneumonia. In this study we examined an immune response against influenza virus NA protein and its impact in generating resistance to secondary bacterial pneumonia by using neuraminidase-bearing virus-like particles. We used an experimental model of secondary bacterial pneumonia induced by Staphylococcus aureus after influenza infection. Animals were preliminarily vaccinated with virus-like particles carrying neuraminidase, hemagglutinin, or both (a cocktail of virus-like particles). In this model vaccinated animals were infected 21 days later with influenza viruses A/Puerto Rico/8/34 (H1N1) and reassortant strain NIBRG-121xp (A/California/04/2009 (pndm H1N1 2009) X A/Puerto Rico/8/34 ( H1N1) bearing surface proteins hemagglutinin and neuraminidase derived from the A/California/04/2009 virus as well as the internal proteins derived from A/Puerto Rico/8/34. Next, 5 days after influenza infection mice were infected with Staphylococcus aureus. Moreover, animals in one group were simultaneously vaccinated and infected with A/Puerto Rico/8/34 (H1N1) followed by inoculation on day 21 with reassortant virus NIBRG- 121xp. The protective vaccine activity was assessed by measuring survival rate, life expectancy and decreased body weight loss. The data obtained showed that virus-like particles containing neuraminidase revealed no protective activity. However, a cocktail of virus-like particles, containing hemagglutinin and neuraminidase, protected animals from lethal outcome as well as body weight loss. Moreover, the increase virus-like particles containing neuraminidase in the cocktail of virus-like particles (virus-like particles containing neuraminidase + hemagglutinin) led to elevated protective effect after vaccination that was comparable or even superior to that one in mice with post-infectious immunity.

RARE PRESENTATION OF MEDIASTINAL ABSCESS SUPERINFECTION IN AN INFLUENZA B PATIENT

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Influenza is generally a self-limited infection, however complicated with bacterial superinfection, it has been associated with increased morbidity and mortality[1]. We present the first case report in the literature of an immunocompetent Influenza B patient complicated with methicillin-sensitive Staphylococcus aureus (MSSA) mediastinal abscess and necrotizing pneumonia. CASE PRESENTATION: A 33-year-old male patient with past medical history of asthma presented to ED with myalgias, productive cough with rusty sputum and intermittent low-grade fever for 2 weeks. Initial vitals showed temperature of 100.6 F, heart rate of 106 bpm, respiratory rate of 24 with normal blood pressure and oxygen saturation. Physical examination was unremarkable. Initial workup revealed leukocytosis with WBC of 18 k/ul. CXR showed asymmetric enlargement of the right hilum with suspicion of central mass and to further analyze CT Chest with IV contrast was done showing consolidation in the right lower lobe (RLL) with mass-like consolidation in right hilum with mediastinal extension. (Figure 1) Patient was treated empirically with Piperacillin/Tazobactam, Vancomycin and Azithromycin. Nasopharyngeal swab for Influenza B PCR came back positive and blood cultures grew MSSA after which antibiotics were de-escalated to Oxacillin. His hospital course was complicated by clinical deterioration and repeat CT Chest revealed RLL Necrotizing Pneumonia and anterior mediastinal abscess. (Figure 2) He had emergent median sternotomy with radical thymectomy and debridement of mediastinal tissues. No histological evidence of malignancy was present, and cultures grew MSSA. He improved clinically and was discharged on IV oxacillin course for 6 weeks. His follow up CT chest showed complete resolution of mediastinal and resolving RLL infiltrate. DISCUSSION: Pneumonia is considered the most common complication of influenza. It could be primary viral pneumonia or secondary to bacterial superinfection due to epithelium disruption and alteration in host immunity response. Mediastinal abscess has not been reported before in the literature as post influenza complication. Our case is first in literature for such life-threatening complication and the key to success is early imaging detection, keeping high level of suspicion when the patient is not responding appropriately to the initial therapy and aggressive surgical and medical management. CONCLUSIONS: Clinical deterioration or inappropriate response to antibiotic therapy in post influenza bacterial pneumonia should raise the suspicion for uncommon complications such as mediastinal abscess and should be investigated with advanced imaging, CT chest with IV contrast or MRI. Reference #1: Martin, C.M., et al., Asian influenza A in Boston, 1957-1958. I. Observations in thirty-two influenza-associated fatal cases. AMA Arch Intern Med, 1959. 103(4): p. 515-31. DISCLOSURES: No relevant relationships by Saira Afzal, source=Web Response No relevant relationships by Mahmoud Alwakeel, source=Web Response No relevant relationships by kuttetoor Gopalakrishna, source=Web Response No relevant relationships by Talha Saleem, source=Web Response

Respiratory Barrier as a Safeguard and Regulator of Defense Against Influenza A Virus and Streptococcus pneumoniae.

The primary function of the respiratory system of gas exchange renders it vulnerable to environmental pathogens that circulate in the air. Physical and cellular barriers of the respiratory tract mucosal surface utilize a variety of strategies to obstruct microbe entry. Physical barrier defenses including the surface fluid replete with antimicrobials, neutralizing immunoglobulins, mucus, and the epithelial cell layer with rapidly beating cilia form a near impenetrable wall that separates the external environment from the internal soft tissue of the host. Resident leukocytes, primarily of the innate immune branch, also maintain airway integrity by constant surveillance and the maintenance of homeostasis through the release of cytokines and growth factors. Unfortunately, pathogens such as influenza virus and Streptococcus pneumoniae require hosts for their replication and dissemination, and prey on the respiratory tract as an ideal environment causing severe damage to the host during their invasion. In this review, we outline the host-pathogen interactions during influenza and post-influenza bacterial pneumonia with a focus on inter- and intra-cellular crosstalk important in pulmonary immune responses.

Survival during influenza-associated bacterial superinfection improves following viral- and bacterial-specific monoclonal antibody treatment.

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.

INDUCTION OF SECONDARY BACTERIAL PNEUMONIA IN MICE INFECTED WITH PANDEMIC AND LABORATORY STRAINS OF THE H1N1 INFLUENZA VIRUS

Aim. In this study we developed and characterized a mouse model of secondary S. aureus and S. pneumoniae pneumonia following influenza virus infection with H1N1 pandemic and laboratory strains and their reassortment. Materials and methods. BALB/с mice were infected intranasally with A/California/04/2009/(H1N1 pndm), A/Puerto Rico/8/34 or their reassortment NIBRG-121xp followed by different strains of S. аureus и S. pneumoniae. The pathogenicity of infection was assessed by mouse survival and weight change, viral titre and bacterial count in the lungs. Results. It was shown that the infection of mice with three strains of the H1N1 influenza virus with a comparable level of pathogenicity leads to a different severity of secondary bacterial infection. The mouse adapted A/California/04/2009 pandemic strain possessed the greatest ability to alter antibacterial immunity. Conclusion. An experimental model of post-influenza bacterial pneumonia utilizing three strains of the H1N1 influenza virus and various strains of S. aureus or S. pneumoniae was established. The ability of viruses to provoke bacterial superinfection of different severity is characterized.

Immunomodulators targeting MARCO expression improve resistance to postinfluenza bacterial pneumonia.

Downregulation of the alveolar macrophage (AM) receptor with collagenous structure (MARCO) leads to susceptibility to postinfluenza bacterial pneumonia, a major cause of morbidity and mortality. We sought to determine whether immunomodulation of MARCO could improve host defense and resistance to secondary bacterial pneumonia. RNAseq analysis identified a striking increase in MARCO expression between days 9 and 11 after influenza infection and indicated important roles for Akt and Nrf2 in MARCO recovery. In vitro, primary human AM-like monocyte-derived macrophages (AM-MDMs) and THP-1 macrophages were treated with IFNγ to model influenza effects. Activators of Nrf2 (sulforaphane) or Akt (SC79) caused increased MARCO expression and a MARCO-dependent improvement in phagocytosis in IFNγ-treated cells and improved survival in mice with postinfluenza pneumococcal pneumonia. Transcription factor analysis also indicated a role for transcription factor E-box (TFEB) in MARCO recovery. Overexpression of TFEB in THP-1 cells led to marked increases in MARCO. The ability of Akt activation to increase MARCO expression in IFNγ-treated AM-MDMs was abrogated in TFEB-knockdown cells, indicating Akt increases MARCO expression through TFEB. Increasing MARCO expression by targeting Nrf2 signaling or the Akt-TFEB-MARCO pathway are promising strategies to improve bacterial clearance and survival in postinfluenza bacterial pneumonia.

Antibacterial, antifungal, and antiviral effects of three essential oil blends.

New agents that are effective against common pathogens are needed particularly for those resistant to conventional antimicrobial agents. Essential oils (EOs) are known for their antimicrobial activity. Using the broth microdilution method, we showed that (1) two unique blends of Cinnamomum zeylanicum, Daucus carota, Eucalyptus globulus and Rosmarinus officinalis EOs (AB1 and AB2; cinnamon EOs from two different suppliers) were active against the fourteen Gram‐positive and ‐negative bacteria strains tested, including some antibiotic‐resistant strains. Minimal inhibitory concentrations (MICs) ranged from 0.01% to 3% v/v with minimal bactericidal concentrations from <0.01% to 6.00% v/v; (2) a blend of Cinnamomum zeylanicum, Daucus carota, Syzygium aromaticum, Origanum vulgare EOs was antifungal to the six Candida strains tested, with MICs ranging from 0.01% to 0.05% v/v with minimal fungicidal concentrations from 0.02% to 0.05% v/v. Blend AB1 was also effective against H1N1 and HSV1 viruses. With this dual activity, against H1N1 and against S. aureus and S. pneumoniae notably, AB1 may be interesting to treat influenza and postinfluenza bacterial pneumonia infections. These blends could be very useful in clinical practice to combat common infections including those caused by microorganisms resistant to antimicrobial drugs.

Inflammatory monocytes enhance disease progression during post-influenza MRSA pneumonia

Abstract Morbidity associated with influenza pandemics of the last century has been significantly associated with secondary bacterial infections. It is generally believed that the enhanced susceptibility to secondary bacterial infection is due to influenza-suppressed innate immunity. Interestingly, preceding influenza infection does not inhibit inflammatory cell recruitment during secondary bacterial infection. In fact, due to the recruitment of inflammatory monocytes, there are increased numbers of phagocytes in influenza and bacterial coinfected airways. The protective role of monocytes during influenza infection alone is well recognized; however, it is not clear how this phagocyte population contributes to post-influenza bacterial pneumonia. Using CC-Chemokine Receptor 2 deficient (CCR2−/−) mice defective in airway monocyte recruitment, we are currently investigating the role of inflammatory monocytes during influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection. Specifically, C57BL/6 mice were infected intranasally with a sublethal dose of PR8 and subsequently MRSA on day seven post-influenza infection. Despite their delay in viral clearance, coinfected CCR2−/− mice exhibited significantly reduced bacterial burdens and importantly, improved survival rates compared with WT mice. Moreover, pro-inflammatory cytokine response in coinfected CCR2−/− mice was significantly decreased, suggesting an attenuation in lung inflammation. In summary, we found that by inhibiting bacterial clearance and perpetuating lung inflammation, inflammatory monocytes exacerbate adverse disease outcome during post-influenza MRSA pneumonia.

Role of Autophagy and Apoptosis in the Postinfluenza Bacterial Pneumonia.

The risk of influenza A virus (IAV) is more likely caused by secondary bacterial infections. During the past decades, a great amount of studies have been conducted on increased morbidity from secondary bacterial infections following influenza and provide an increasing number of explanations for the mechanisms underlying the infections. In this paper, we first review the recent research progress that IAV infection increased susceptibility to bacterial infection. We then propose an assumption that autophagy and apoptosis manipulation are beneficial to antagonize post-IAV bacterial infection and discuss the clinical significance.

MicroRNA-155 regulates host immune response to postviral bacterial pneumonia via IL-23/IL-17 pathway

Postinfluenza bacterial pneumonia is associated with significant mortality and morbidity. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. miR-155 has recently emerged as a crucial regulator of innate immunity and inflammatory responses and is induced in macrophages during infection. We hypothesized upregulation of miR-155 inhibits IL-17 and increases susceptibility to secondary bacterial pneumonia. Mice were challenged with 100 plaque-forming units H1N1 intranasally and were infected with 10(7) colony-forming units of MRSA intratracheally at day 5 postviral challenge. Lungs were harvested 24 h later, and expression of miR-155, IL-17, and IL-23 was measured by real-time RT-PCR. Induction of miR-155 was 3.6-fold higher in dual-infected lungs compared with single infection. miR-155(-/-) mice were protected with significantly lower (4-fold) bacterial burden and no differences in viral load, associated with robust induction of IL-23 and IL-17 (2.2- and 4.8-fold, respectively) postsequential challenge with virus and bacteria, compared with WT mice. Treatment with miR-155 antagomir improved lung bacterial clearance by 4.2-fold compared with control antagomir postsequential infection with virus and bacteria. Moreover, lung macrophages collected from patients with postviral bacterial pneumonia also had upregulation of miR-155 expression compared with healthy controls, consistent with observations in our murine model. This is the first demonstration that cellular miRNAs regulate postinfluenza immune response to subsequent bacterial challenge by suppressing the IL-17 pathway in the lung. Our findings suggest that antagonizing certain microRNA might serve as a potential therapeutic strategy against secondary bacterial infection.

Protecting Against Post-influenza Bacterial Pneumonia by Increasing Phagocyte Recruitment and ROS Production

Seasonal and especially pandemic influenza predispose patients to secondary bacterial pneumonias, which are a major cause of deaths and morbidity. Staphylococcus aureus is a particularly common and deadly form of post-influenza pneumonia, and increasing staphylococcal drug resistance makes the development of new therapies urgent. We explored an innate immune-mediated model of the lung to define novel mechanisms by which the host can be protected against secondary staphylococcal pneumonia after sub-lethal influenza infection. We found that stimulating the innate immunity in the lung by overexpression of GM-CSF will result in resistance to S. aureus pneumonia after sublethal influenza infection. Resistance was mediated by alveolar macrophages and neutrophils, and was associated with increased production of reactive oxygen species (ROS) by alveolar macrophages. Resistance was abrogated by treatment with agents that scavenged ROS. We conclude that stimulating innate immunity in the lung markedly reduces susceptibility to post-influenza staphylococcal pneumonia and that this may represent a novel immunomodulatory strategy for prevention and treatment of secondary bacterial pneumonia after influenza.

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Introduction: Multiple cell surface proteins are glycosylated including TLR ligands. Sialic acid is a common terminal moiety on such proteins and can be removed by pathogen expressed neuraminidases. Desialylation is common in the airway in influenza and is an important aspect of post influenza bacterial pneumonia. Methods: Airway and monocyte cell lines and peritoneal macrophages were treated with NANase (neuraminidase) which hydrolyzes predominantly α(2-3) glycosidic linkages of terminal sialic acids. Desialylation was assessed by flow cytometry as was the expression of TLR2 and TLR4. After NANase treatment (60 min) cells were treated with either TLR2 or 4 ligands and cytokines were measured. Activation of phosho p38, IkB was done by WB and AP-1 and NFkB by EMSA. Results: NANase treatment decreased cell surface sialic acid by 50%. Removal of this amount of sialic acid did not significantly change the expression of TLR2 or 4 on the cell surface of BEAS 2B, J774 or PMs and western blot confirmed no change. After NANase followed by treatment with either TLR ligand treatment, IL-8 was increased in BEAS 2B and TNFa was increased in J774 and PM culture supernatant. In J774 cells and BEAS2b cells, NANase + TLR ligand did not augment phosphorylation of p38 or degradation of IkB and did induce exaggerated AP1 or NFKB activity by EMSA. Conclusions: We conclude that cell surface desialylation can enhance the sensitivity to TLR ligands without activation of conventional signaling elements. Removal of sialic acid may open other pathways for TLR ligand signaling.

New Look at an Old Problem: Bacterial Superinfection after Influenza

This commentary highlights the important role of bacterial superinfection in the morbidity and mortality of influenza virus infection.

Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice

Influenza-related complications continue to be a major cause of mortality worldwide. Due to unclear mechanisms, a substantial number of influenza-related deaths result from bacterial superinfections, particularly secondary pneumococcal pneumonia. Here, we report what we believe to be a novel mechanism by which influenza-induced type I IFNs sensitize hosts to secondary bacterial infections. Influenza-infected mice deficient for type I IFN-alpha/beta receptor signaling (Ifnar-/- mice) had improved survival and clearance of secondary Streptococcus pneumoniae infection from the lungs and blood, as compared with similarly infected wild-type animals. The less effective response in wild-type mice seemed to be attributable to impaired production of neutrophil chemoattractants KC (also known as Cxcl1) and Mip2 (also known as Cxcl2) following secondary challenge with S. pneumoniae. This resulted in inadequate neutrophil responses during the early phase of host defense against secondary bacterial infection. Indeed, influenza-infected wild-type mice cleared secondary pneumococcal pneumonia after pulmonary administration of exogenous KC and Mip2, whereas neutralization of Cxcr2, the common receptor for KC and Mip2, reversed the protective phenotype observed in Ifnar-/- mice. These data may underscore the importance of the type I IFN inhibitory pathway on CXC chemokine production. Collectively, these findings highlight what we believe to be a novel mechanism by which the antiviral response to influenza sensitizes hosts to secondary bacterial pneumonia.