Ebola Hemorrhagic Shock Syndrome-on-a-Chip

Abstract

Ebola virus, for which we lack effective countermeasures, causes hemorrhagic fever in humans, with significant case fatality rates. Lack of experimental human models for Ebola hemorrhagic fever is a major obstacle that hinders the development of treatment strategies. Here, we model the Ebola hemorrhagic syndrome in a microvessel-on-a-chip system and demonstrate its applicability to drug studies. Luminal infusion of Ebola virus-like particles leads to albumin leakage from the engineered vessels. The process is mediated by the Rho/ROCK pathway and is associated with cytoskeleton remodeling. Infusion of Ebola glycoprotein (GP 1,2) generates a similar phenotype, indicating the key role of GP 1,2 in this process. Finally, we measured the potency of a recently developed experimental drug FX06 and a novel drug candidate, melatonin, in phenotypic rescue. Our study confirms the effects of FX06 and identifies melatonin as an effective, safe, inexpensive therapeutic option that is worth investigating in animal models and human trials.

Treatment of ebola and other infectious diseases: melatonin “goes viral”

“…The most complete documentation illustrating the efficacy of melatonin to thwart Ebola virulence is the recent detailed study of Junaid et al (71). This group specifically tested melatonin against Ebola-mediated hemorrhagic shock, which is the most prominent and deadly feature of an infection of this type.…”

“…Junaid and coworkers initially grew microvessels using human endothelial cells (HUVECs) adjacent to a collagen type I network (71). To ensure the endothelial cells exhibited the physiological barrier function of in vivo capillaries, the authors examined the potential transport of albumin through the endothelial wall into the collagen matrix and found no albumin leaked from the experimental vessel.…”

“…Currently, no reliable treatments are available which seriously impact the course or outcome of such infections. Defining some of the molecular processes, as identified by Junaid and co-workers (71), is a much-needed advance in seeking a treatment for this ravaging disease. While neither FX06 nor melatonin are virucidal agents, they do significantly alter the course of hemorrhagic shock syndrome via different means under experimental conditions as shown by Junaid et al (71) and as summarized in figure 3.…”

Endothelial Semaphorin 3F Maintains Endothelial Barrier Function and Inhibits Monocyte Migration

“…The morphological change strongly indicates the possibility of impaired endothelial barrier function after reduction of SEMA3F expression. To test this postulation we assessed the effect of SEMA3F KD on endothelial barrier function through the use of electric cell-substrate impedance sensing (ECIS) [13] and the more physiological 3D-endothelial tube in a microfluidics platform [14]. With each method we found that, targeted reduction of SEMA3F in ECs resulted in impaired barrier function ( Figure 6A Next, we assessed whether loss of barrier function upon SEMA3F knock down alters monocyte transendothelial migration with monocyte chemotaxis over Transwell filters containing endothelial monolayers with SEMA3F knock down or control cells.…”

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

“…Melatonin is a naturally occurring molecule assumed to be present in every species [ 19 ]. Due to its antioxidant, anti-inflammatory, as well as other properties [ 20 , 21 , 22 , 23 , 24 , 25 ], it has been speculated to be a promising molecule for treating COVID-19 patients [ 18 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ], and also other deadly viral infectious diseases [ 48 , 49 , 50 , 51 ]. A small scale clinical trial has also shown promising results [ 52 ].…”