Pandemic Influenza Infection Promotes Streptococcus pneumoniae Infiltration, Necrotic Damage, and Proteomic Remodeling in the Heart

Adverse cardiac events are a common complication of viral and bacterial pneumonia. For over a century, it has been recognized that influenza infection promotes severe forms of pulmonary disease mainly caused by the bacterium Streptococcus pneumoniae .

Download Full-text

Allergic Airway Disease Prevents Lethal Synergy of Influenza A Virus-Streptococcus pneumoniaeCoinfection

mBio ◽

10.1128/mbio.01335-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 4

Author(s):

Sean Roberts ◽

Sharon L. Salmon ◽

Donald J. Steiner ◽

Clare M. Williams ◽

Dennis W. Metzger ◽

...

Keyword(s):

Influenza Virus ◽

Streptococcus Pneumoniae ◽

Influenza Infection ◽

Airway Disease ◽

Allergic Airway Disease ◽

Bacterial Clearance ◽

Content Type ◽

Ifn Γ ◽

The Impact ◽

First Time

ABSTRACTFatal outcomes following influenza infection are often associated with secondary bacterial infections. Allergic airway disease (AAD) is known to influence severe complications from respiratory infections, and yet the mechanistic effect of AAD on influenza virus-Streptococcus pneumoniaecoinfection has not been investigated previously. We examined the impact of AAD on host susceptibility to viral-bacterial coinfections. We report that AAD improved survival during coinfection when viral-bacterial challenge occurred 1 week after AAD. Counterintuitively, mice with AAD had significantly deceased proinflammatory responses during infection. Specifically, both CD4+and CD8+T cell interferon gamma (IFN-γ) responses were suppressed following AAD. Resistance to coinfection was also associated with strong transforming growth factor β1 (TGF-β1) expression and increased bacterial clearance. Treatment of AAD mice with IFN-γ or genetic deletion of TGF-β receptor II expression reversed the protective effects of AAD. Using a novel triple-challenge model system, we show for the first time that AAD can provide protection against influenza virus-S. pneumoniaecoinfection through the production of TGF-β that suppresses the influenza virus-induced IFN-γ response, thereby preserving antibacterial immunity.IMPORTANCEAsthma has become one of the most common chronic diseases and has been identified as a risk factor for developing influenza. However, the impact of asthma on postinfluenza secondary bacterial infection is currently not known. Here, we developed a novel triple-challenge model of allergic airway disease, primary influenza infection, and secondaryStreptococcus pneumoniaeinfection to investigate the impact of asthma on susceptibility to viral-bacterial coinfections. We report for the first time that mice recovering from acute allergic airway disease are highly resistant to influenza-pneumococcal coinfection and that this resistance is due to inhibition of influenza virus-mediated impairment of bacterial clearance. Further characterization of allergic airway disease-associated resistance against postinfluenza secondary bacterial infection may aid in the development of prophylactic and/or therapeutic treatment against coinfection.

Download Full-text

Antimicrobial Activity of Solithromycin against Serotyped Macrolide-Resistant Streptococcus pneumoniae Isolates Collected from U.S. Medical Centers in 2012

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04568-14 ◽

2015 ◽

Vol 59 (4) ◽

pp. 2432-2434 ◽

Cited By ~ 18

Author(s):

D. J. Farrell ◽

R. E. Mendes ◽

R. N. Jones

Keyword(s):

Antimicrobial Activity ◽

Streptococcus Pneumoniae ◽

Bacterial Pneumonia ◽

Multidrug Resistant ◽

Clinical Development ◽

Next Generation ◽

High Potency ◽

Content Type ◽

Medical Centers ◽

Data Support

ABSTRACTSolithromycin, a next-generation macrolide and novel fluoroketolide, was tested against a 2012 collection of serotyped U.S. macrolide-resistantStreptococcus pneumoniaeisolates associated with community-acquired bacterial pneumonia (CABP). Against all 272 isolates, solithromycin demonstrated high potency (MIC50/90, 0.06/0.25 μg/ml), and it inhibited all strains at MICs of ≤0.5 μg/ml, including the two most prevalent macrolide-resistant serotypes (19A and 35B). These data support the continued clinical development of solithromycin for the treatment of multidrug-resistant CABP.

Download Full-text

2473 Cardiac injury due to Streptococcus pneumoniae invasion during severe pneumococcal pneumonia in a novel nonhuman primate model

Journal of Clinical and Translational Science ◽

10.1017/cts.2018.51 ◽

2018 ◽

Vol 2 (S1) ◽

pp. 6-6

Author(s):

Luis F. Reyes ◽

Cecilia A. Hinojosa ◽

Nilam J. Soni ◽

Julio Noda ◽

Vicki T. Winter ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Pneumococcal Pneumonia ◽

Troponin I ◽

Cardiac Injury ◽

Severe Pneumonia ◽

Cardiac Events ◽

Cardiac Damage ◽

Nonhuman Primate Model ◽

Primate Model ◽

Adverse Cardiac Events

OBJECTIVES/SPECIFIC AIMS: The aims of this study are (1) to develop and characterize a novel nonhuman primate model of pneumococcal pneumonia that mimics human disease; and (2) determine whether Streptococcus pneumoniae can: (a) translocate to the heart, (b) cause adverse cardiac events, (c) induce cardiomyocyte death, and (d) lead to scar formation during severe pneumonia in baboons. METHODS/STUDY POPULATION: Six adult baboons (Papio cynocephalus) were surgically tethered to a monitoring system to continuously assess their heart rate, temperature, and electrocardiogram (ECG). A baseline transthoracic echocardiogram, 12-lead ECG, serum troponin-I levels, brain natriuretic peptide, and heart-type fatty acid binding protein (HFABP) levels were obtained before infection and at the end of the experiment to determine cardiovascular damage during pneumococcal pneumonia. Animals were challenged with 108 colony-forming units of S. pneumoniae in the right middle lobe using flexible bronchoscopy. Three baboons were rescued with ampicillin therapy (80 mg/kg/d) after the development of pneumonia. Cardiac damage was confirmed by examination of tissue sections using immunohistochemistry as well as electron and fluorescence microscopy. Western-blots and tissue staining were used to determine the presence of necroptosis (RIP3 and pMLKL) and apoptosis (Caspase-3) in the cardiac tissue. Cytokine and chemokine levels in the heart tissue were determined using Luminex technology. RESULTS/ANTICIPATED RESULTS: Four males (57%) and three (43%) females were challenged. The median age of all baboons was 11 (IQR, 10-19) years old, which corresponds to a middle-aged human. Infected baboons consistently developed severe pneumonia. All animals developed systemic inflammatory response syndrome with tachycardia, tachypnea, fever, and leukocytosis. Infection was characterized by initial leukocytosis followed by severe leukopenia on day 3 postinoculation. Non-specific ischemic alterations by ECG (ST segment and T-wave flattering) and in the premortem echocardiogram were observed. The median (IQR) levels of troponin I and HFABP at the end of the experiment were 3550 ng/mL (1717–5383) and 916.9 ng/mL (520.8–1323), respectively. Severe cardiomyopathy was observed using TEM and H&E stains in animals with severe pneumonia. Necroptosis was detected in cardiomyocytes of infected animals by the presence of pMLKL and RIP3 in cardiac tissues. Signs of cardiac remodeling indicated by disorganized collagen deposition was present in rescued animals but not in the other animals. DISCUSSION/SIGNIFICANCE OF IMPACT: We confirmed that baboons experience cardiac injury during severe pneumococcal pneumonia that is characterized by myocardial invasion, activation of necroptosis, and tissue remodeling in animals rescued by antimicrobial therapy. Cardiac damage by invading pneumococci may explain why adverse cardiac events that occur during and after pneumococcal pneumonia in adult human patients.

Download Full-text

Cell Invasion and Pyruvate Oxidase-Derived H2O2 Are Critical for Streptococcus pneumoniae-Mediated Cardiomyocyte Killing

Infection and Immunity ◽

10.1128/iai.00569-17 ◽

2017 ◽

Vol 86 (1) ◽

Cited By ~ 14

Author(s):

Terry Brissac ◽

Anukul T. Shenoy ◽

LaDonna A. Patterson ◽

Carlos J. Orihuela

Keyword(s):

Streptococcus Pneumoniae ◽

Neutralizing Antibodies ◽

Molecular Mechanisms ◽

Vascular Endothelial Cells ◽

Laminin Receptor ◽

Intracellular Replication ◽

Cardiac Events ◽

Cardiac Damage ◽

Pyruvate Oxidase ◽

Content Type

ABSTRACTStreptococcus pneumoniae(the pneumococcus) is the leading cause of community-acquired pneumonia and is now recognized to be a direct contributor to adverse acute cardiac events. During invasive pneumococcal disease,S. pneumoniaecan gain access to the myocardium, kill cardiomyocytes, and form bacterium-filled “microlesions” causing considerable acute and long-lasting cardiac damage. While the molecular mechanisms responsible for bacterial translocation into the heart have been elucidated, the initial interactions of heart-invadedS. pneumoniaewith cardiomyocytes remain unclear. In this study, we used a model of low multiplicity ofS. pneumoniaeinfection with HL-1 mouse cardiomyocytes to investigate these early events. Using adhesion/invasion assays and immunofluorescent and transmission electron microscopy, we showed thatS. pneumoniaerapidly adhered to and invaded cardiomyocytes. What is more, pneumococci existed as intravacuolar bacteria or escaped into the cytoplasm. Pulse-chase assays with BrdU confirmed intracellular replication of pneumococci within HL-1 cells. Using endocytosis inhibitors, bacterial isogenic mutants, and neutralizing antibodies against host proteins recognized byS. pneumoniaeadhesins, we showed thatS. pneumoniaeuptake by cardiomyocytes is not through the well-studied canonical interactions identified for vascular endothelial cells. Indeed,S. pneumoniaeinvasion of HL-1 cells occurred through clathrin-mediated endocytosis (CME) and independently of choline binding protein A (CbpA)/laminin receptor, CbpA/polymeric immunoglobulin receptor, or cell wall phosphorylcholine/platelet-activating factor receptor. Subsequently, we determined that pneumolysin and streptococcal pyruvate oxidase-derived H2O2production were required for cardiomyocyte killing. Finally, we showed that this cytotoxicity could be abrogated using CME inhibitors or antioxidants, attesting to intracellular replication ofS. pneumoniaeas a key first step in pneumococcal pathogenesis within the heart.

Download Full-text

Antimicrobial Susceptibilities and Serotypes of Streptococcus pneumoniae Isolates from Elderly Patients with Pneumonia and Acute Exacerbation of Chronic Obstructive Pulmonary Disease

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01546-10 ◽

2011 ◽

Vol 55 (6) ◽

pp. 2729-2734 ◽

Cited By ~ 13

Author(s):

Emilio Pérez-Trallero ◽

José M. Marimón ◽

Julián Larruskain ◽

Marta Alonso ◽

María Ercibengoa

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Streptococcus Pneumoniae ◽

Pulmonary Disease ◽

Acute Exacerbation ◽

Short Interval ◽

The Elderly ◽

Underlying Disease ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Content Type

ABSTRACTIn the elderly,Streptococcus pneumoniaeis the most common cause of pneumonia and one of the most frequently isolated pathogens in cases of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). This study was conducted to compare the pneumococcal isolates obtained during episodes of AECOPD and pneumonia in patients of ≥65 years old and to analyze whether in patients with AECOPD and pneumonia within a short interval, the same isolate caused both episodes. This laboratory-based study was performed between 2005 and 2008. Pneumococcal isolates from episodes of pneumonia (n= 401) and AECOPD (n= 398), matched one-to-one by date of isolation, were characterized. The serotypes and genotypes of other pneumococcal isolates causing pneumonia and AECOPD in the same patient were compared. In patients with pneumonia, COPD as an underlying disease was not associated with more-drug-resistant pneumococci. In contrast, isolates causing AECOPD showed higher rates of resistance than those causing pneumonia. Serotypes 1, 3, and 7F were more frequent in pneumonia. The same pneumococcus was involved in 25.7% (9/35 patients) of patients with two consecutive AECOPD episodes but in only 6.3% (2/32 patients) of COPD patients with pneumonia and exacerbation (Fisher's exact test;P= 0.047). Less invasive serotypes were isolated more often in AECOPD and were more resistant to antimicrobials. The presence of a specific pneumococcal serotype in AECOPD does not predict the etiology of subsequent pneumonia.

Download Full-text

Pharmacokinetic/Pharmacodynamic Evaluation of Solithromycin against Streptococcus pneumoniae Using Data from a Neutropenic Murine Lung Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02606-18 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 1

Author(s):

Olanrewaju O. Okusanya ◽

Alan Forrest ◽

Sujata M. Bhavnani ◽

Prabhavathi Fernandes ◽

Paul G. Ambrose ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Bacterial Pneumonia ◽

Lung Infection ◽

Free Drug ◽

Infection Model ◽

Total Drug ◽

Content Type ◽

Murine Lung ◽

Drug Plasma ◽

Atypical Pathogens

ABSTRACT Solithromycin (CEM-101) is a novel fluoroketolide antimicrobial agent with activity against typical and atypical pathogens associated with community-acquired bacterial pneumonia. Using a neutropenic murine lung infection model, the objectives of this study were to identify the pharmacokinetic/pharmacodynamic (PK/PD) index most closely associated with efficacy and the magnitude of such indices associated with solithromycin efficacy against Streptococcus pneumoniae. Plasma and epithelial lining fluid (ELF) samples for pharmacokinetics (PK) were collected serially over 24 hours from healthy mice administered single doses of solithromycin (0.625 to 40 mg/kg). Neutropenic CD-1 mice infected with 108 CFUs of one of five S. pneumoniae isolates were administered solithromycin (0.156 to 160 mg/kg/day) via oral gavage. Doses were administered in a fractionated manner for mice infected with one isolate, while mice infected with the remaining four isolates received solithromycin as either a regimen every 6 hours or every 12 hours. A three-compartment model best described solithromycin PK in the plasma and ELF (r2 = 0.935 and 0.831, respectively). The ratio of total-drug ELF to free-drug plasma area under the concentration-time curve (AUC) from time 0 to 24 hours was 2.7. Free-drug plasma and total-drug ELF AUC to minimum inhibitory concentration ratios (AUC/MIC ratios) were most predictive of efficacy (r2 = 0.851 and 0.850, respectively). The magnitude of free-drug plasma/total-drug ELF AUC/MIC ratios associated with net bacterial stasis and a 1- and 2-log10 CFU reduction from baseline was 1.65/1.26, 6.31/15.1, and 12.8/59.8, respectively. These data provided dose selection support for solithromycin for clinical trials in patients with community-acquired bacterial pneumonia.

Download Full-text