Animal Models of Emerging Viral Infection

Clinical Center

Investigators

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Abstract

Project 1: In this study, we will expose pregnant rhesus macaques to ZIKV in the first, second, or third trimesters of their 165-day gestational period. Following exposure, we will investigate fetal brain development and evolution of brain injury using serial fetal brain imaging (MRI and ultrasound), and monitor the appearance of a maternal serum marker of fetal brain injury. We will also sample the amniotic fluid to assess viral replication. Postnatally, we will humanely euthanize one newborn/dam pair from each cohort for detailed viral pathologic studies. We will then longitudinally observe the surviving infants for neurological abnormalities and the persistence of viremia. We will infect both infants born to ZIKV-infected mothers after passive immunity wanes and aged-matched control animals born to uninfected mothers. This manuscript in nearing submission. Project 2: We developed a supportive critical care model in 5 Kg Indian Origin Rhesus Macaques under biosafety level (BSL) 2 conditions. In this model, animals are provided care and physiologic monitoring similar to that provided to humans in the intensive care unit. Animals are deeply sedated, placed on mechanical ventilation, and closely monitored by trained bedside technicians. In this setting fluid status, serum electrolyte and glucose levels, and acid-base status can be frequently monitored and closely adjusted. Similarly, this model allows for titration of continuous infusion of multiple vasopressors to maintain blood pressure and frequent dosing of medications such as empiric antibiotics and stress-dose steroids which are standard of care in humans with vasopressor-refractory shock. This level of care cannot be provided to awake animals with tethered indwelling vascular catheters. Measurement of physiologic parameters including cardiac output and pulmonary artery occlusion pressure (PAOP) allows one to differentiate between the 4 categories of shock (i.e., hypovolemic, cardiogenic, obstructive, and distributive), which is essential to optimizing clinical management of severe infections. The contribution of the different categories of shock to EVD pathophysiology remains incompletely characterized. The pulmonary artery (PA) catheter utilized in this model remains the gold standard for assessing volume status and physiology of shock in humans. Specifically, the PA catheter provides a direct measure of cardiac output and an estimate of ventricular pre-load (intravascular volume status) and peripheral vascular resistance (determination of peripheral vasodilation), which can be intermittently assessed at the bedside to guide blood pressure management with titration of intravenous fluids and vasopressors. The PA catheter has been safely implemented in this model and provides reliable physiologic data consistent with those observed in humans. A manuscript describing the ICU model absent infection is nearing submission. The first round of bacterial sepsis studies has been completed and is in a data-analysis phase. Transition of the ICU model into BSL-4 has been approved and is in the early implementation stage.