Clinical Laboratory Values as Early Indicators of Ebola Virus Infection in Nonhuman Primates

Reisler, Ronald B.; Yu, Chenggang; D’Onofrio, M.; Warren, Travis K.; Wells, Jay; Stuthman, Kelly S.; Garza, Nicole L.; Vantongeren, Sean A.; Donnelly, Ginger; Kane, Christopher D.; Kortepeter, Mark G.; Bavari, Sina; Cardile, Anthony P.

doi:10.3201/eid2308.170029

Cited by 13 publications

(7 citation statements)

References 44 publications

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“…The finding that pathological evidence of pancreatitis was relatively rare (6%) in the rhesus IM EBOV-Kikwit model was not surprising, given our previous observations that significant biochemical evidence of pancreatitis, elevations of serum lipase, were not observed in three NHP IM models: EBOV-Kikwit or EBOV-Makona in rhesus macaques and EBOV-Kikwit in Cynomolgus macaques [ 21 ]. While some authors have reported hyperamylasemia in human EBOV in the past [ 29 ], it is entirely possible that the hyperamylasemia observed in human EBOV cases may not have been a marker for pancreatic injury but may have been either salivary in origin, a marker of intestinal injury, or renal failure [ 31 ].…”

Section: Discussionmentioning

confidence: 91%

“…In the rhesus IM EBOV-Kikwit model, EBOV is believed to spread from the initial muscle infection site via antigen presenting cells (APCs)–monocytes, macrophages, and dendritic cells to regional lymph nodes, likely via lymphatics and the bloodstream and then rapidly disseminates throughout the entire host [ 20 ]. EBOV RNA is detectable as early as 3 DPI and peaks at 5–7 DPI [ 21 ]. In this model, we found that GALT is significantly affected in terminal disease, with pathological changes observed in animals that succumbed as early as 5 DPI.…”

Section: Discussionmentioning

confidence: 99%

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Ebola Virus Causes Intestinal Tract Architectural Disruption and Bacterial Invasion in Non-Human Primates

Reisler

Zeng

Schellhase

et al. 2018

Viruses

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In the 2014–2016 West Africa Ebola Virus (EBOV) outbreak, there was a significant concern raised about the potential for secondary bacterial infection originating from the gastrointestinal tract, which led to the empiric treatment of many patients with antibiotics. This retrospective pathology case series summarizes the gastrointestinal pathology observed in control animals in the rhesus EBOV-Kikwit intramuscular 1000 plaque forming unit infection model. All 31 Non-human primates (NHPs) exhibited lymphoid depletion of gut-associated lymphoid tissue (GALT) but the severity and the specific location of the depletion varied. Mesenteric lymphoid depletion and necrosis were present in 87% (27/31) of NHPs. There was mucosal barrier disruption of the intestinal tract with mucosal necrosis and/or ulceration most notably in the duodenum (16%), cecum (16%), and colon (29%). In the intestinal tract, hemorrhage was noted most frequently in the duodenum (52%) and colon (45%). There were focal areas of bacterial submucosal invasion in the gastrointestinal (GI) tract in 9/31 (29%) of NHPs. Only 2/31 (6%) had evidence of pancreatic necrosis. One NHP (3%) experienced jejunal intussusception which may have been directly related to EBOV. Immunofluorescence assays demonstrated EBOV antigen in CD68+ macrophage/monocytes and endothelial cells in areas of GI vascular injury or necrosis.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Ebola Virus Causes Intestinal Tract Architectural Disruption and Bacterial Invasion in Non-Human Primates

Reisler

Zeng

Schellhase

et al. 2018

Viruses

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“…These panels collectively provided results for 46 clinical laboratory parameters. Viral RNA copy numbers were determined using quantitative real-time PCR (qRT-PCR) [ 27 , 28 ].…”

Section: Methodsmentioning

confidence: 99%

Virulence of Marburg Virus Angola Compared to Mt. Elgon (Musoke) in Macaques: A Pooled Survival Analysis

Blair

Keshtkar-Jahromi

Psoter

et al. 2018

Viruses

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Angola variant (MARV/Ang) has replaced Mt. Elgon variant Musoke isolate (MARV/MtE-Mus) as the consensus standard variant for Marburg virus research and is regarded as causing a more aggressive phenotype of disease in animal models; however, there is a dearth of published evidence supporting the higher virulence of MARV/Ang. In this retrospective study, we used data pooled from eight separate studies in nonhuman primates experimentally exposed with either 1000 pfu intramuscular (IM) MARV/Ang or MARV/MtE-Mus between 2012 and 2017 at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). Multivariable Cox proportional hazards regression was used to evaluate the association of variant type with time to death, the development of anorexia, rash, viremia, and 10 select clinical laboratory values. A total of 47 cynomolgus monkeys were included, of which 18 were exposed to MARV/Ang in three separate studies and 29 to MARV/MtE-Mus in five studies. Following universally fatal Marburg virus exposure, compared to MARV/MtE-Mus, MARV/Ang was associated with an increased risk of death (HR = 22.10; 95% CI: 7.08, 68.93), rash (HR = 5.87; 95% CI: 2.76, 12.51) and loss of appetite (HR = 35.10; 95% CI: 7.60, 162.18). Our data demonstrate an increased virulence of MARV/Ang compared to MARV/MtE-Mus variant in the 1000 pfu IM cynomolgus macaque model.

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“…NHP models of EBOV infection have provided the most informative data related to the pathology and host response. In rhesus ( Macaca mulatta ) and cynomolgus ( Macaca fascicularis ) macaques infected with 1000 PFU of EBOV (intramuscular route), viremia is initially detected 3–4 days after infection, often coinciding with a febrile response [5, 6]. Monocytes/macrophages and dendritic cells are the first cell types that are infected; virus then spreads to the regional lymph nodes, liver and spleen by the movement of infected cells and free virus into the bloodstream.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the plasma proteome of nonhuman primates during Ebola virus disease or melioidosis: a host response comparison

et al. 2019

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BackgroundIn-depth examination of the plasma proteomic response to infection with a wide variety of pathogens can assist in the development of new diagnostic paradigms, while providing insight into the interdependent pathogenic processes which encompass a host’s immunological and physiological responses. Ebola virus (EBOV) causes a highly lethal infection termed Ebola virus disease (EVD) in primates and humans. The Gram negative non-spore forming bacillus Burkholderia pseudomallei (Bp) causes melioidosis in primates and humans, characterized by severe pneumonia with high mortality. We sought to examine the host response to infection with these two bio-threat pathogens using established animal models to provide information on the feasibility of pre-symptomatic diagnosis, since the induction of host molecular signaling networks can occur before clinical presentation and pathogen detection.MethodsHerein we report the quantitative proteomic analysis of plasma collected at various times of disease progression from 10 EBOV-infected and 5 Bp-infected nonhuman primates (NHP). Our strategy employed high resolution LC–MS/MS and a peptide-tagging approach for relative protein quantitation. In each infection type, for all proteins with > 1.3 fold abundance change at any post-infection time point, a direct comparison was made with levels obtained from plasma collected daily from 5 naïve rhesus macaques, to determine the fold changes that were significant, and establish the natural variability of abundance for endogenous plasma proteins.ResultsA total of 41 plasma proteins displayed significant alterations in abundance during EBOV infection, and 28 proteins had altered levels during Bp infection, when compared to naïve NHPs. Many major acute phase proteins quantitated displayed similar fold-changes between the two infection types but exhibited different temporal dynamics. Proteins related to the clotting cascade, immune signaling and complement system exhibited significant differential abundance during infection with EBOV or Bp, indicating a specificity of the response.ConclusionsThese results advance our understanding of the global plasma proteomic response to EBOV and Bp infection in relevant primate models for human disease and provide insight into potential innate immune response differences between viral and bacterial infections.Electronic supplementary materialThe online version of this article (10.1186/s12014-019-9227-3) contains supplementary material, which is available to authorized users.

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Clinical Laboratory Values as Early Indicators of Ebola Virus Infection in Nonhuman Primates

Cited by 13 publications

References 44 publications

Ebola Virus Causes Intestinal Tract Architectural Disruption and Bacterial Invasion in Non-Human Primates

Ebola Virus Causes Intestinal Tract Architectural Disruption and Bacterial Invasion in Non-Human Primates

Virulence of Marburg Virus Angola Compared to Mt. Elgon (Musoke) in Macaques: A Pooled Survival Analysis

Characterization of the plasma proteome of nonhuman primates during Ebola virus disease or melioidosis: a host response comparison

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