Secondary Bacterial Pneumonia Research Articles

Nrf2 Regulates Inflammation by Modulating Dendritic Cell-T Cell Crosstalk during Viral-Bacterial Superinfection.

Every year millions of people are infected with influenza, which can be complicated by secondary bacterial pneumonia. One factor that may contribute to increased susceptibility to secondary bacterial infection is the modulation of inflammatory cytokines. NF erythroid 2-related factor 2 (Nrf2) has been shown to be a master regulator of the antioxidant response and various inflammatory cytokines. To test the role of Nrf2 during viral-bacterial superinfection, we used a mouse model of influenza-Staphylococcus aureus superinfection with wild-type (WT) or Nrf2-deficient (Nrf2-/-) mice. Loss of Nrf2 reduced influenza burden and increased S. aureus burden during superinfection. Additionally, Nrf2-/- mice had increased abundance of conventional type 1 dendritic cells (DCs). We then tested the interaction between DCs and T cells using an invitro model of bone marrow-derived DCs with OVA and OT-II T cells. In this system, Nrf2-/- DCs promoted a Th2/regulatory T cell response as opposed to a Th1/Th17 response by WT DCs. This was recapitulated invivo with superinfected Nrf2-/- mice having increased regulatory T cell populations. We also observed an increased median survival time of Nrf2-/- superinfected mice, due at least in part to increased IL-10 signaling, as anti-IL-10R Ab treatment reduced median survival time to levels seen in WT mice. Overall, these data suggest that loss of Nrf2 promotes differential T cell skewing mediated by DCs that promote a regulatory phenotype, increasing superinfection survival time, despite increased bacterial burden.

Microbial dynamics and pulmonary immune responses in COVID-19 secondary bacterial pneumonia

Secondary bacterial pneumonia (2°BP) is associated with significant morbidity following respiratory viral infection, yet remains incompletely understood. In a prospective cohort of 112 critically ill adults intubated for COVID-19, we comparatively assess longitudinal airway microbiome dynamics and the pulmonary transcriptome of patients who developed 2°BP versus controls who did not. We find that 2°BP is significantly associated with both mortality and corticosteroid treatment. The pulmonary microbiome in 2°BP is characterized by increased bacterial RNA mass and dominance of culture-confirmed pathogens, detectable days prior to 2°BP clinical diagnosis, and frequently also present in nasal swabs. Assessment of the pulmonary transcriptome reveals suppressed TNFα signaling in patients with 2°BP, and sensitivity analyses suggest this finding is mediated by corticosteroid treatment. Further, we find that increased bacterial RNA mass correlates with reduced expression of innate and adaptive immunity genes in both 2°BP patients and controls. Taken together, our findings provide fresh insights into the microbial dynamics and host immune features of COVID-19-associated 2°BP, and suggest that suppressed immune signaling, potentially mediated by corticosteroid treatment, permits expansion of opportunistic bacterial pathogens.

Whooping cough – a recurrent epidemic

Abstract Background Whooping cough (WC), or Pertussis, is a vaccine-preventable and highly contagious infectious disease. Although it has a relatively low fatality rate, approximately 13% of reported cases develop secondary bacterial pneumonia. This was because of several recurrent epidemics across Europe in the last decades, with the latest beginning in mid-2023 and still ongoing. The Central Region of Portugal is currently being affected, and this study aims to describe the current epidemic at the regional level. Methods Data from epidemiological inquiries of confirmed and probable cases of WC pertaining to the Central Region of Portugal from January 2020 till April 2024 was gathered from the mandatory report national epidemiological surveillance system (SINAVE). Both a temporal comparison of number of cases and a statistical space-time scan with permutation were conducted (software SaTScan v10.) Results A comparison by month of reported cases shows an increase in cases from September 2023 until December 2023 followed by an exponential increase from January 2024 until April 2024 denoting an ongoing epidemic. In the statistical space-time analysis of 107 reported cases between September 2023 and April 2024, 8 nonsignificant clusters were identified with different locations involved in non-overlapping periods. Conclusions The finding of several unrelated clusters, even though nonsignificant, during a short time period indicates that Pertussis transmission is ongoing at the local level probably through asymptomatic or barely symptomatic cases that act as reservoirs. Clinicians must hold a high clinical suspicion for a timely diagnosis, treatment and report and health authorities must reinforce control measures to limit the spread of this disease. Key messages • Pertussis remains a disease of significant concern recurrent outbreaks across Europe show that public health local authorities have an important role in timely management of cases and outbreaks. • Local level transmission and intervention may play a pivotal role in the epidemiologic dynamic of Pertussis.

Antibiotic use during influenza infection augments lung eosinophils that impair immunity against secondary bacterial pneumonia.

A leading cause of mortality after influenza infection is the development of a secondary bacterial pneumonia. In the absence of a bacterial superinfection, prescribing antibacterial therapies is not indicated but has become a common clinical practice for those presenting with a respiratory viral illness. In a murine model, we found that antibiotic use during influenza infection impaired the lung innate immunologic defenses toward a secondary challenge with methicillin-resistant Staphylococcus aureus (MRSA). Antibiotics augment lung eosinophils, which have inhibitory effects on macrophage function through the release of major basic protein. Moreover, we demonstrated antibiotic treatment during influenza infection causes a fungal dysbiosis that drive lung eosinophilia and impair MRSA clearance. Finally, we evaluated three cohorts of hospitalized patients and found eosinophils positively correlated with antibiotic use, systemic inflammation, and worsened outcomes. Altogether, our work demonstrates a detrimental effect of antibiotic treatment during influenza infection that has harmful immunologic consequences via recruitment of eosinophils to the lungs thereby increasing the risk of developing a secondary bacterial infection.

Protective Effects from Prior Pneumococcal Vaccination in Patients with Chronic Airway Diseases during Hospitalization for Influenza-A Territory-Wide Study.

Influenza is an important respiratory viral pathogen in adults, with secondary bacterial pneumonia being a common complication. While pneumococcal vaccines can prevent pneumococcal pneumonia and invasive pneumococcal disease, whether they can also prevent the severe in-hospital outcomes among patients hospitalized for influenza has not been examined. A territory-wide retrospective study was conducted in Hong Kong, which included all adult patients having chronic airway diseases (asthma, bronchiectasis, and chronic obstructive pulmonary disease) hospitalized for influenza and who had received seasonal influenza vaccine. The occurrence of secondary bacterial pneumonia, mortality, and other severe in-hospital outcomes were compared among subjects with or without pneumococcal vaccination. There was a total of 3066 eligible patients who were hospitalized for influenza in public hospitals in Hong Kong from 1 January 2016 to 30 June 2023. Completed pneumococcal vaccination with PSV23/PCV13 conferred protection against secondary bacterial pneumonia, all-cause mortality, and respiratory cause of mortality with adjusted odds ratios of 0.74 (95% CI = 0.57-0.95, p = 0.019), 0.12 (95% CI = 0.03-0.53, p = 0.005), and 0.04 (95% CI = 0.00-0.527, p = 0.0038), respectively.

New insights into the pathogenesis of SARS-CoV-2 during and after the COVID-19 pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the respiratory distress condition known as COVID-19. This disease broadly affects several physiological systems, including the gastrointestinal, renal, and central nervous (CNS) systems, significantly influencing the patient's overall quality of life. Additionally, numerous risk factors have been suggested, including gender, body weight, age, metabolic status, renal health, preexisting cardiomyopathies, and inflammatory conditions. Despite advances in understanding the genome and pathophysiological ramifications of COVID-19, its precise origins remain elusive. SARS-CoV-2 interacts with a receptor-binding domain within angiotensin-converting enzyme 2 (ACE2). This receptor is expressed in various organs of different species, including humans, with different abundance. Although COVID-19 has multiorgan manifestations, the main pathologies occur in the lung, including pulmonary fibrosis, respiratory failure, pulmonary embolism, and secondary bacterial pneumonia. In the post-COVID-19 period, different sequelae may occur, which may have various causes, including the direct action of the virus, alteration of the immune response, and metabolic alterations during infection, among others. Recognizing the serious adverse health effects associated with COVID-19, it becomes imperative to comprehensively elucidate and discuss the existing evidence surrounding this viral infection, including those related to the pathophysiological effects of the disease and the subsequent consequences. This review aims to contribute to a comprehensive understanding of the impact of COVID-19 and its long-term effects on human health.

Evidence for Rho-dependent control of a virulence switch in Acinetobacter baumannii.

Acinetobacter baumannii is a significant cause of infections in the healthcare setting. More recently, A. baumannii has been a leading cause of secondary bacterial pneumonia in patients infected with SARS-CoV-2 and the overall frequency of A. baumannii infection increased 78% during the COVID-19 pandemic. A. baumannii can exist in virulent or avirulent subpopulations and this interconversion is mediated by the expression of a family of TetR-type transcriptional regulators. In this study, we demonstrate that Rho is a key regulatory component in the expression of these TetR regulators. Overall, this study is the first to address a role for Rho in A. baumannii and provides additional evidence for the role of Rho in regulating diversity in bacterial subpopulations.

The ER-Golgi transport of influenza virus through NS1-Sec13 association during virus replication.

Influenza A virus is a respiratory virus that can cause complications such as acute bronchitis and secondary bacterial pneumonia. Drug therapies and vaccines are available against influenza, albeit limited by drug resistance and the non-universal vaccine administration. Hence there is a need for host-targeted therapies against influenza to provide an effective alternative therapeutic target. Sec13 was identified as a novel host interactor of influenza. Endoplasmic reticulum-to-Golgi transport is an important pathway of influenza virus replication and viral export. Specifically, Sec13 has a functional role in influenza replication and virulence.

Predictive value of methicillin-resistant staphylococcus aureus nasal swab in patients with COVID-19 pneumonia and secondary bacterial pneumonia

ObjectiveTo determine the performance measures of admission methicillin-resistant Staphylococcus aureus (MRSA) nasal swabs for MRSA bacterial pneumonia in patients co-infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MethodsThe study included patients admitted with SARS-CoV-2-positive nasopharyngeal specimens, MRSA nasal screens, and bacterial cultures to assess secondary MRSA pneumonia. Results293 patients and 662 microbiological cultures evaluated. Overall, the specificity (91.8% [95% CI 88.6% to 95%]) and negative predictive value (NPV 97.4% [95% CI 95.4% – 99.3%]) of MRSA nasal swabs was high. However, the sensitivity (46.2%; 95% CI 19.1% to 73.3%) and positive predictive value (PPV 20.7%; 95% CI 59.5 – 35.4%) were low. Those patients in the MRSA nasal swab negative group had a shorter median duration of linezolid therapy. ConclusionsSARS-CoV-2 infection doesn't reduce the specificity or negative predictive value of MRSA nasal swabs for secondary MRSA pneumonia.

Clinical characteristics and risk factors associated with secondary bacterial pneumonia among COVID-19 patients in ICU.

COVID-19 and secondary infections developing during COVID-19 follow-up are one of the most important causes of morbidity and mortality in intensive care units (ICU). In this study, we aimed to determine the frequency, microbiology, risk factors, and outcomes of secondary bacterial pneumonia in hospitalized patients due to COVID-19. We studied all patients with bacterial pneumonia developed in patients with severe COVID-19 infection in the COVID-19 intensive care unit in a single-center hospital between March 16, 2020 and June 17, 2020. Patients hospitalized and followed up in the ICU for respiratory failure were examined in terms of secondary infection affecting morbidity and mortality. Ninety-six (20%) of 471 patients had secondary bacterial pneumonia, respectively; of the leading pathogens were Acinetobacter baumannii (44.8%) and Klebsiella pneumoniae (39.6%), followed by Pseudomonas aeruginosa (4.2%), Escherichia coli (3.1%), methicillin-resistant Staphylococcus aureus (MRSA) (3.1%), Streptococcus pneumoniae (3.1%), and Methicillin-susceptible Staphylococcus aureus (MSSA) (1%). The mortality rate among infected (75% / 47.5%) was significantly higher than in uninfected patients. Associated with the development of secondary bacterial pneumonia in COVID-19 patients; corticosteroid therapy [odds ratio (OR) 6250, 95% confidence interval (CI) 1.383-28.571, p = 0.017), corticosteroid dose (OR 8.862 CI 2.299-70.258, p= 0.006), duration of mechanical ventilation (OR 1.199 CI) 1.088-1.322, p< 0.001). Secondary bacterial pneumonia was found to be associated with the severity and survival of the disease in patients admitted to ICU due to COVID-19. Duration of mechanical ventilation and use of corticosteroids and high-dose corticosteroids are risk factors for secondary bacterial pneumonia.

Immune predisposition drives susceptibility to pneumococcal pneumonia after mild influenza A virus infection in mice.

A frequent sequela of influenza A virus (IAV) infection is secondary bacterial pneumonia. Therefore, it is clinically important to understand the genetic predisposition to IAV and bacterial coinfection. BALB/c and C57BL/6 (B6) mice were infected with high or low-pathogenic IAV and Streptococcus pneumoniae (SPn). The contribution of cellular and molecular immune factors to the resistance/susceptibility of BALB/c and B6 mice were dissected in nonlethal and lethal IAV/SPn coinfection models. Low-virulent IAV X31 (H3N2) rendered B6 mice extremely susceptible to SPn superinfection, while BALB/c mice remained unaffected. X31 infection alone barely induces IFN-γresponse in two strains of mice; however, SPn superinfection significantly enhances IFN-γ production in the susceptible B6 mice. As a result, IFN-γ signaling inhibits neutrophil recruitment and bacterial clearance, leading to lethal X31/SPn coinfection in B6 mice. Conversely, the diminished IFN-γ and competent neutrophil responses enable BALB/c mice highly resistant to X31/SPn coinfection. The results establish that type 1 immune predisposition plays a key role in lethal susceptibility of B6 mice to pneumococcal pneumonia after mild IAV infection.

Increased Fungal Infection Mortality Induced by Concurrent Viral Cellular Manipulations.

Certain respiratory fungal pathogen mono-infections can cause high mortality rates. Several viral pathogen mono-infections, including influenza viruses and coronaviruses including SARS-CoV-2, can also cause high mortality rates. Concurrent infections by fungal pathogens and highly manipulative viral pathogens can synergistically interact in the respiratory tract to substantially increase their mortality rates. There are at least five viral manipulations which can assist secondary fungal infections. These viral manipulations include the following: (1) inhibiting transcription factors and cytokine expressions, (2) impairing defensive protein expressions, (3) inhibiting defenses by manipulating cellular sensors and signaling pathways, (4) inhibiting defenses by secreting exosomes, and (5) stimulating glucocorticoid synthesis to suppress immune defenses by inhibiting cytokine, chemokine, and adhesion molecule production. The highest mortality respiratory viral pandemicsup to now have had substantially boosted mortalities by inducing secondary bacterial pneumonias. However, numerous animal species besides humans are also carriers of endemic infections by viral and multidrug-resistant fungal pathogens. The vast multi-species scope of endemic infection opportunities make it plausible that the pro-fungal manipulations of a respiratory virus can someday evolve to enable a very high mortality rate viral pandemic inducing multidrug-resistant secondary fungal pathogen infections. Since such pandemics can quickly spread world-wide and outrun existing treatments, it would be worthwhile to develop new antifungal treatments well before such a high mortality event occurs.

Simulation of optimal dose regimens of photoactivated curcumin for antimicrobial resistance pneumonia in COVID-19 patients: A modeling approach.

Secondary antimicrobial resistance bacterial (AMR) pneumonia could lead to an increase in mortality in COVID-19 patients, particularly of geriatric patients with underlying diseases. The comedication of current medicines for AMR pneumonia with corticosteroids may lead to suboptimal treatment or toxicities due to drug-drug interactions (DDIs). This study aimed to propose new promising dosage regimens of photoactivated curcumin when co-administered with corticosteroids for the treatment of antimicrobial resistance (AMR) pneumonia in COVID-19 patients. A whole-body physiologically-based pharmacokinetic (PBPK) with the simplified lung compartments model was built and verified following standard model verification (absolute average-folding error or AAFEs). The pharmacokinetic properties of photoactivated were assumed to be similar to curcumin due to minor changes in physiochemical properties of compound by photoactivation. The acceptable AAFEs values were within 2-fold. The verified model was used to simulate new regimens for different formulations of photoactivated curcumin. The AAFEs was 1.12-fold. Original formulation (120 mg once-daily dose) or new intramuscular nano-formulation (100 mg with a release rate of 10/h given every 7 days) is suitable for outpatients with MRSA pneumonia to improve patient adherence. New intravenous formulation (2000 mg twice-daily doses) is for hospitalized patients with both MRSA and VRSA pneumonia. The PBPK models, in conjunction with MIC and applied physiological changes in COVID-19 patients, is a potential tool to predict optimal dosage regimens of photoactivated curcumin for the treatment of co-infected AMR pneumonia in COVID-19 patients. Each formulation is appropriate for different patient conditions and pathogens.

Deadly interactions: Synergistic manipulations of concurrent pathogen infections potentially enabling future pandemics

Certain monoinfections of influenza viruses and novel coronaviruses, including severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) are significant threats to human health. Concurrent infections by influenza viruses and coronaviruses increases their threat. Influenza viruses have eight manipulations capable of assisting SARS-CoV-2 and other coronaviruses, and several of these manipulations, which are not specific to viruses, can also directly or indirectly boost dangerous secondary bacterial pneumonias. The influenza virus manipulations include: inhibiting transcription factors and cytokine expression; impairing defensive protein expression; increasing RNA viral replication; inhibiting defenses by manipulating cellular sensors and signaling pathways; inhibiting defenses by secreting exosomes; stimulating cholesterol production to increase synthesized virion infectivities; increasing cellular autophagy to assist viral replication; and stimulating glucocorticoid synthesis to suppress innate and adaptive immune defenses by inhibiting cytokine, chemokine, and adhesion molecule production. Teaser: Rapidly spreading multidrug-resistant respiratory bacteria, combined with the far-reaching cellular defense manipulations of influenza virus benefiting evolving SARS-CoV-2 or other coronaviruses and/or respiratory bacteria, can enable severe future pandemics or co-pandemics.

Prevalence and Antibiotic Resistance Profile of Secondary Bacterial Pneumonia and Bloodstream Infections Among Hospitalized COVID-19 Patients and Their Relation to Procalcitonin

Prevalence and Antibiotic Resistance Profile of Secondary Bacterial Pneumonia and Bloodstream Infections Among Hospitalized COVID-19 Patients and Their Relation to Procalcitonin

ΔA146Ply-HA stem protein immunization protects mice against influenza A virus infection and co-infection with Streptococcus pneumoniae

Influenza virus (IV) is a common pathogen affecting the upper respiratory tract, that causes various diseases. Secondary bacterial pneumonia is a common complication and a major cause of death in influenza patients. Streptococcus pneumoniae (S. pneumoniae) is the predominant co-infected bacteria in the pandemic, which colonizes healthy people but can cause diseases in immunocompromised individuals. Vaccination is a crucial strategy for avoiding infection, however, no universal influenza vaccine (UIV) that is resistant to multiple influenza viruses is available. Despite its limited immunogenicity, the hemagglutinin (HA) stem is a candidate peptide for UIV. ΔA146Ply (pneumolysin with a single deletion of A146) not only retains the Toll-like receptor 4 agonist effect but also is a potential vaccine adjuvant and a candidate protein for the S. pneumoniae vaccine. We constructed the fusion protein ΔA146Ply-HA stem and studied its immunoprotective effect in mice infection models. The results showed that intramuscular immunization of ΔA146Ply-HA stem without adjuvant could induce specific antibodies against HA stem and specific CD4+ T and CD8+ T cellular immunity in BALB/c and C57BL/6 mice, which could improve the survival rate of mice infected with IAV and co-infected with S. pneumoniae, but the protective effect on BALB/c mice was better than that on C57BL/6 mice. ΔA146Ply-HA stem serum antibody could protect BALB/c and C57BL/6 mice from IAV, and recognized HA polypeptides of H3N2, H5N1, H7N9, and H9N2 viruses. Moreover, ΔA146Ply-HA stem intramuscular immunization had a high safety profile with no obvious toxic side effects. The results indicated that coupling ΔA146Ply with influenza protein as a vaccine was a safe and effective strategy against the IV and secondary S. pneumoniae infection.

Pneumonia panel results and antibiotic prescribing in COVID-19 patients in 2020 versus 2022

Background: Antibiotics are frequently prescribed in patients with COVID-19 infections to treat secondary bacterial pneumonia. The pneumonia panel (PNP) is a molecular diagnostic tool that rapidly detects 33 bacterial and viral targets. The utility of this panel in COVID-19 patients and how it may direct antibiotic use is unknown. We sought to understand the utilization of PNP in patients with COVID-19 pneumonia over time by comparing clinical parameters, microbiologic results, and antibiotic use between May–December 2020 and January–July 2022. Methods: We implemented the PNP in May 2020 with antimicrobial stewardship guidance, provider education, and order restriction to critical care and infectious disease clinicians. From February–July 2021 prescribers received regular structured antimicrobial stewardship feedback regarding PNP results; from August 2021 to January 2022, no antimicrobial stewardship feedback was provided; from February to July 2022, intermittent feedback was provided. We compared PNP and culture results from sputum or bronchoalveolar lavage samples and antibiotic use and modification within 24 hours of PNP result from patients with confirmed COVID-19 pneumonia between May–December 2020 and January–July 2022. Clinical data and antibiotic use were abstracted through chart review. We excluded patients who died within 72 hours of PNP, those who had concurrent nonpulmonary infections, and those whose COVID-19 test was &gt;30 days prior. Results: We included 114 patients in 2020 and 71 patients in 2022. The overall median age was 61 years, 71% were male, and 66% were mechanically ventilated without statistical differences between the cohorts, including their comorbidities. Acute or worsening hypoxia remained the predominant indication for PNP (77% in 2020 vs 75% in 2022, NS). The median number of days between admission and PNP was 4 (IQR, 1–8) in 2020 versus 3 (IQR, 1–7), and the difference was not significant. PNP and culture results in Table 1 show that Staphylococcus aureus and Hemophilus influenzae were the pathogens most commonly identified. Table 2 describes empiric prescribing and modifications for commonly prescribed antibiotics. Prescribers used empiric cefepime and ceftriaxone more in 2020 and vancomycin more in the 2022 group; however, these were not statistically significant. Cefepime de-escalation was more common in 2022 (53% vs 28%; P = .03). Antibiotic modifications within 24 hours of PNP remained similar in 2020 vs 2022. Although vancomycin cessation was more common in 2020 (78%) versus 2022 (57%), the difference was not statistically significant. Conclusions: With ASP guidance, PNP may be a useful tool to stop or target antibiotics for secondary bacterial pneumonia in COVID-19 pneumonia. Early vancomycin cessation (prior to culture results) may be an enduring consequence of PNP implementation.Disclosures: None

Inhalation phage therapy as a new approach to preventing secondary bacterial pneumonia in patients with moderate to severe COVID-19: A double-blind clinical trial study.

Inhalation phage therapy is proposed as a replacement approach for antibiotics in the treatment of pulmonary bacterial infections. This study investigates phage therapy on bacterial pneumonia in patients with moderate to severe COVID-19 via the inhalation route. In this double-blind clinical trial, 60 patients with positive COVID-19 hospitalized in three central Mazandaran hospitals were chosen and randomly divided into two intervention and control groups. Standard country protocol drugs plus 10mL of phage suspension every 12h with a mesh nebulizer was prescribed for 7 days in the intervention group. The two groups were compared in terms of O2Sat, survival rate, severe secondary pulmonary bacterial infection and duration of hospitalization. Comparing the results between the intervention and control group, in terms of the trend of O2Sat change, negative sputum culture, no fever, no dyspnea, duration of hospitalization, duration of intubation and under ventilation, showed that the difference between these two groups was statistically different (P value<0.05). In conclusion, inhalation phage therapy may have a potential effect on secondary infection and in the outcome of COVID-19 patients. However, more clinical trials with control confounding factors are needed to further support this concept.

Memory Th17 cell-mediated protection against lethal secondary pneumococcal pneumonia following influenza infection.

Streptococcus pneumoniae (Sp) frequently causes secondary pneumonia after influenza A virus (IAV) infection, leading to high morbidity and mortality worldwide. Concomitant pneumococcal and influenza vaccination improves protection against coinfection but does not always yield complete protection. Impaired innate and adaptive immune responses have been associated with attenuated bacterial clearance in influenza virus-infected hosts. In this study, we showed that preceding low-dose IAV infection caused persistent Sp infection and suppression of bacteria-specific T-helper type 17 (Th17) responses in mice. Prior Sp infection protected against subsequent IAV/Sp coinfection by improving bacterial clearance and rescuing bacteria-specific Th17 responses in the lungs. Furthermore, blockade of IL-17A by anti-IL-17A antibodies abrogated the protective effect of Sp preinfection. Importantly, memory Th17 responses induced by Sp preinfection overcame viral-driven Th17 inhibition and provided cross-protection against different Sp serotypes following coinfection with IAV. These results indicate that bacteria-specific Th17 memory cells play a key role in providing protection against IAV/Sp coinfection in a serotype-independent manner and suggest that a Th17-based vaccine would have excellent potential to mitigate disease caused by coinfection. IMPORTANCE Streptococcus pneumoniae (Sp) frequently causes secondary bacterial pneumonia after influenza A virus (IAV) infection, leading to increased morbidity and mortality worldwide. Current pneumococcal vaccines induce highly strain-specific antibody responses and provide limited protection against IAV/Sp coinfection. Th17 responses are broadly protective against Sp single infection, but whether the Th17 response, which is dramatically impaired by IAV infection in naïve mice, might be effective in immunization-induced protection against pneumonia caused by coinfection is not known. In this study, we have revealed that Sp-specific memory Th17 cells rescue IAV-driven inhibition and provide cross-protection against subsequent lethal coinfection with IAV and different Sp serotypes. These results indicate that a Th17-based vaccine would have excellent potential to mitigate disease caused by IAV/Sp coinfection.

Nontypeable Haemophilus influenzaespecific memory T H17 cells protect against secondary bacterial pneumonia following Influenza A virus infection

Abstract Nontypeable Haemophilus influenzae(NTHi) is one of the most common bacteria that cause secondary bacterial pneumonia following influenza A virus (IAV) infection, leading to hospitalization and death associated with IAV infection worldwide. Current efforts to develop vaccines against NTHi infection focus on inducing antibodies but are hindered by antigenic diversity among NTHi strains. Therefore, we interrogated the contribution of the memory T-helper type 17 (T H17) response in protective immunity against IAV/NTHi co-infection. We observed that co-infected mice exhibited prolonged NTHi infection in the lungs even at mild IAV infection and impaired NTHi-specific T H17 responses compared to NTHi mono-infected mice. However, immune mice that recovered from a prior NTHi infection were protected from homologous and heterologous secondary NTHi strains following IAV infection. Our data further revealed that memory NTHi-specific T H17 cells overcame IAV-driven impairments of anti-NTHi T H17 responses and were cross-reactive with different NTHi strains. Last, mice immunized with a NTHi protein that induced a strong T H17 memory response were broadly protected against diverse NTHi strains following challenge with IAV/NTHi co-infection. These results indicate that NTHi-specific memory T H17 cells are capable of providing serotype-independent protection against co-infection and demonstrate the advantage of developing broadly protective T H17-inducing vaccines against secondary bacterial pneumonia.