Nonhuman primate species as models of human bacterial sepsis

Abstract

Sepsis involves a disordered host response to systemic infection leading to high morbidity and mortality. Despite intense research, targeted sepsis therapies beyond antibiotics have remained elusive. The cornerstone of sepsis research is the development of animal models to mimic human bacterial infections and test novel pharmacologic targets. Nonhuman primates (NHPs) have served as an attractive, but expensive, animal to model human bacterial infections due to their nearly identical cardiopulmonary anatomy and physiology, as well as host response to infection. Several NHP species have provided substantial insight into sepsis-mediated inflammation, endothelial dysfunction, acute lung injury, and multi-organ failure. The use of NHPs has usually focused on translating therapies from early preclinical models to human clinical trials. However, despite successful sepsis interventions in NHP models, there are still no FDA-approved sepsis therapies. This review highlights major NHP models of bacterial sepsis and their relevance to clinical medicine.

Fig. 1

(a) Simplified rationale for performing studies in NHP sepsis models of antibody inhibition of TNF-α and IL-6. Lipopolysaccharide (LPS) or E. coli are shown binding to a TLR4 surface receptor of a monocyte which initiates downstream signal transduction (yellow lightning bolt) and transcriptional upregulation of TNF-α. TNF-α further activates other pro- and anti-inflammatory cytokines, including IL-6. Both cytokines promote hypercoagulability by upregulating tissue factor (TF) expression. TNF-α also simultaneously promotes and inhibits fibrinolysis via activation of tPA and PAI-1/2, respectively (see Fig. 1b). (b) Multiple therapeutics are shown inhibiting different components of the extrinsic coagulation pathway. These drugs were tested using LPS or E. coli NHP sepsis models. Abbreviations: Ab, antibody; APC, activated protein C; F3, factor 3; iFVIIa, site inactivated factor VIIa; IL6, interleukin 6; LPS, lipopolysaccharide; PAI-1/2, plasminogen activator inhibitor 1/2; rhATIII, recombinant human antithrombin III; SIRS, systemic inflammatory response syndrome; TF, tissue factor; TLR4, toll-like receptor 4; TNF, tumor necrosis factor.