A Non-Human Primate Model of Severe Pneumococcal Pneumonia

Abstract

RationaleStreptococcus pneumoniae is the leading cause of community-acquired pneumonia and infectious death in adults worldwide. A non-human primate model is needed to study the molecular mechanisms that underlie the development of severe pneumonia, identify diagnostic tools, explore potential therapeutic targets, and test clinical interventions during pneumococcal pneumonia.ObjectiveTo develop a non-human primate model of pneumococcal pneumonia.MethodsSeven adult baboons (Papio cynocephalus) were surgically tethered to a continuous monitoring system that recorded heart rate, temperature, and electrocardiography. Animals were inoculated with 109 colony-forming units of S. pneumoniae using bronchoscopy. Three baboons were rescued with intravenous ampicillin therapy. Pneumonia was diagnosed using lung ultrasonography and ex vivo confirmation by histopathology and immunodetection of pneumococcal capsule. Organ failure, using serum biomarkers and quantification of bacteremia, was assessed daily.ResultsChallenged animals developed signs and symptoms of pneumonia 4 days after infection. Infection was characterized by the presence of cough, tachypnea, dyspnea, tachycardia and fever. All animals developed leukocytosis and bacteremia 24 hours after infection. A severe inflammatory reaction was detected by elevation of serum cytokines, including Interleukin (IL)1Ra, IL-6, and IL-8, after infection. Lung ultrasonography precisely detected the lobes with pneumonia that were later confirmed by pathological analysis. Lung pathology positively correlated with disease severity. Antimicrobial therapy rapidly reversed symptomology and reduced serum cytokines.ConclusionsWe have developed a novel animal model for severe pneumococcal pneumonia that mimics the clinical presentation, inflammatory response, and infection kinetics seen in humans. This is a novel model to test vaccines and treatments, measure biomarkers to diagnose pneumonia, and predict outcomes.

Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling

“…A full description of the NHP model of severe pneumococcal pneumonia has been previously published (28). Briefly, six (four males) healthy adult baboons (Papio cynocephalus)…”

“…Collection of blood for serum biomarkers and bacterial load estimation, acquisition of a 12-lead electrocardiogram (ECG), transthoracic echocardiogram, and bronchoalveolar lavage (BAL) were performed before the infection and at the end of the experiment prior to euthanasia (28). Continuous 24-hour temperature, heart rate, and 3-lead ECG were recorded throughout the experiment via a surgically implanted tether.…”

“…At the end of the experiment, the hearts were harvested and prepared for tissue experiments. Three NHP were treated with intravenous ampicillin (80mg/kg/day) for 7 days (i.e., convalescent group) (28). All ECGs were read by an expert electrophysiologist (AJR) who was blinded to the experiment results.…”

“…The cohort was divided in two groups to mimic the pre-antibiotic era and modern era of pneumonia patients (28). For the pre-antibiotic era group, we did not treat three NHP with antibiotics, and they were called the acute pneumonia and euthanized per protocol, 4-6 days post-infection.…”

“…Additionally, the potential underlying mechanisms of MACE during pneumococcal pneumonia have been described in rodent models, but it is speculative to extrapolate these findings to humans. To address this knowledge gap, we used a validated non-human primate model of severe pneumococcal pneumonia that closely mimics human disease (28) to explore the mechanisms of pneumococcal cytotoxicity on cardiomyocytes. Potential translation of these findings to humans includes identification of potential therapeutic targets to prevent MACE, and ultimately, improvement in clinical outcomes of patients with CAP.…”