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. Although rodents are the most common species used, their unique anatomy and molecular responses to infection limits their extrapolation to human disease. Alternatively, 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, such as the development of drotrecogin alpha. However, despite successful sepsis interventions in NHP models, there are still no FDA-approved sepsis therapies. Going forward, limited NHP studies will focus on novel sepsis targets and new pharmacologic agents with high potential for translation to human disease. This review highlights major NHP models of bacterial sepsis and their relevance to clinical medicine.

A trade-off between resistance to infection and reproduction in primate evolution

“…An evolutionary implication of our findings is that Old World primates, including humans, appear to be at a higher risk of developing sepsis in response to bacterial infection. In strong support of this notion, humans are more susceptible to develop septic shock when challenged by bacterial lipopolysaccharide (LPS), as compared to other mammalian lineages (Chen et al, 2019). Whether this can be explained by intrinsic characteristics of human immunity and/or the capacity to establish disease tolerance to infection (Martins et al, 2019;Medzhitov et al, 2012), is unclear.…”

Recurrent Urinary Tract Infection: A Mystery in Search of Better Model Systems

“…Non-human primate (NHP) models benefit from their high similarity with humans. To our knowledge there are no papers describing an NHP model for UTI ( Chen et al., 2019 ), but they have been used in the past for UTI vaccine studies (reviewed in ( O’Brien et al., 2016 ) and viral studies (reviewed in ( Estes et al., 2018 ). However, their expense, ethical issues and specialized facilities pose significant drawbacks.…”

Staphylococcus aureus Host Tropism and Its Implications for Murine Infection Models

“…Nevertheless, depending on the research question at hand, they might be more suitable than murine models when investigating certain virulence factors that show a low activity in mice, such as the use of rabbits for studying PVL, HlgCB, or modified LukAB [ 143 , 144 , 162 ]. Because of their close relatedness to humans, nonhuman primates would theoretically be an excellent model for S. aureus research [ 163 , 164 , 165 ], but—apart from serious ethical issues—the immense financial and laborious burdens associated with such experimental settings often deter most laboratories.…”