Development of a Novel Preclinical Model of Pneumococcal Pneumonia in Nonhuman Primates

Abstract

Pneumococcal pneumonia is a leading cause of bacterial infection and death worldwide. Current diagnostic tests for detecting Streptococcus pneumoniae can be unreliable and can mislead clinical decision-making and treatment. To address this concern, we developed a preclinical model of pneumococcal pneumonia in nonhuman primates useful for identifying novel biomarkers, diagnostic tests, and therapies for human S. pneumoniae infection. Adult colony-bred baboons (n = 15) were infected with escalating doses of S. pneumoniae (Serotype 19A-7). We characterized the pathophysiological and serological profiles of healthy and infected animals over 7 days. Pneumonia was prospectively defined by the presence of three criteria: (1) change in white blood cell count, (2) isolation of S. pneumoniae from bronchoalveolar lavage fluid (BALF) or blood, and (3) concurrent signs/symptoms of infection. Animals given 10(9) CFU consistently met our definition and developed a phenotype of tachypnea, tachycardia, fever, hypoxemia, and radiographic lobar infiltrates at 48 hours. BALF and plasma cytokines, including granulocyte colony-stimulating factor, IL-6, IL-10, and IL-1ra, peaked at 24 to 48 hours. At necropsy, there was lobar consolidation with frequent pleural involvement. Lung histopathology showed alveolar edema and macrophage influx in areas of organizing pneumonia. Hierarchical clustering of peripheral blood RNA data at 48 hours correctly identified animals with and without pneumonia. Dose-dependent inoculation of baboons with S. pneumoniae produces a host response ranging from spontaneous clearance (10(6) CFU) to severe pneumonia (10(9) CFU). Selected BALF and plasma cytokine levels and RNA profiles were associated with severe pneumonia and may provide clinically useful parameters after validation.

Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1

“…2 and 3). These findings were corroborated with an in vivo baboon infection model that reflects human pathology (19), where the administration of low-dose inhaled CO reduced urinary LTE 4 , a well-appreciated marker of systemic LT biosynthesis (Fig. 9).…”

“…Baboon sepsis was initiated as before (19). Adult male colony-bred baboons (Papio cynocephalus) were housed in the Duke University Vivarium (Durham, NC) and handled in accordance with American Association for Accreditation of Laboratory Animal Care guidelines.…”

“…Systemic inflammation including sepsis produces potent LM, such as cysteinyl LTs, which provoke airway smooth muscle contraction, edema, and further inflammation (21,25). To assess the extent to which CO regulates cysteinyl LT levels in primates during lung infections, we employed a nonhuman primate (baboon) model of pneumonia (19). Infection was initiated by direct inoculation of S. pneumoniae into both lungs.…”

The Regulation of Proresolving Lipid Mediator Profiles in Baboon Pneumonia by Inhaled Carbon Monoxide

“…Using an automated approach, authenticated standards for SPMs, their related pathway markers and known proinflammatory LMs, along with enhanced sensitivity, we can now perform targeted LM metabololipidomic profiling of each of these autacoid pathways (26). In the present report, we identified SPM in a baboon model of Streptococcus pneumoniae pneumonia (9), the most common cause of bacterial pneumonia in humans (27,28). This model 5 was employed to investigate the temporal SPM production, regulation, and relationship to other inflammatory LM during acute inflammation in order to assess processes that may lead to failed lipid mediator class switching and chronic inflammation.…”

“…These agents work to limit the infection but may not be sufficient for resolution of severe pneumonia with acute lung injury (ALI). (6)(7)(8)(9).…”