Organ-on-Chip models for studying virus-host interactions
by Barry Rockx, Department of Viroscience, Erasmus University Medical Center
Over the past few decades, newly emerging viruses have triggered international concern, raised scientific challenges, caused major human suffering and imposed enormous economic damage on an almost yearly basis. Due to the rapid developments in the field of next generation sequencing, more and more new viral sequences are detected in a variety of species every year. While the majority of these viruses will not impact human health, many of the newly emerged viruses that caused large outbreaks in humans in the past decades, such as Ebola, Nipah, influenza, SARS and MERS, have emerged from animals.
Sin Nombre Hantavirus that can cause Hantavirus pulmonary syndrome (HPS) is carried in rodent droppings, especially the deer mouse. Sickness begins with fever and muscle aches, followed by shortness of breath and coughing. Photo Credit: CDC/Cynthia Goldsmith.
Following detection of a new virus, there is a pressing need to know what the potential public health impact may be in order to prevent a possible pandemic. Key questions to be answered in order to respond rapidly to emerging viruses are:
- by what possible routes the virus can transmit to humans
- can it be transmitted between humans?
- can it cause severe disease in humans?
- what is the efficacy of current or experimental therapeutic strategies against this new virus?
While these questions are focused on the impact on human health, the same questions are important for veterinary pathogens as well.
Urgent need for new models
The ability of a virus to efficiently replicate and transmit to and between humans is key to emerging virus adaptation to the human host. These important properties are often explored by use of in vivo models. However, for many viruses an animal model that accurately mimics the disease progression and pathogenesis, does not exist. In the case of new viruses, it requires testing and characterizing multiple in vivo models in order to identify the model which best recapitulates the often severe disease seen in humans. Such studies are time consuming and often require expensive biocontainment facilities and expertise, which are not available everywhere.
Organ-on-Chip models can help to predict pandemic risk
In recent years I have been following the field of Organ-on-Chip models with great interest, as I believe these models might be a powerful tool for studying virus-host interactions. I have enjoyed the discussions at the hDMT theme group meetings, the annual hDMT consortium meetings as well as the recent International Organ-on-Chip symposium in Eindhoven.
The availability of Organ-on-Chip models that can accurately predict the response in a host (human or animal) will have a profound effect on the ability to accurately predict the susceptibility, pathogenicity and transmission risk following introduction of new microorganisms. In addition, these models will be instrumental in understanding the pathogenesis of infectious disease and developing and testing preventive and therapeutic strategies.
Of course, there are many technical issues to overcome, such as developing a compact system that is self-contained and can be easily decontaminated so that it can be used under higher biocontainment levels in order to work with infectious agents. But I look forward to exploring the possibilities and continuing collaborations in this exciting field.
Cell tropism of Nipah virus (NiV) in human lung xenografts. Lung sections are stained by immunofluorescent detection of Nipah virus nucleoprotein (red), CD31 (green) and nucleus (blue). CD31 positive endothelium of pulmonary vasculature is positive for Nipah virus antigen (40× magnification). NiV is a member of the genus Henipavirus (family Paramyxoviridae) that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%). Photo credits: Valbuena G, Halliday H, Borisevich V, Goez Y, Rockx B (2014) A Human Lung Xenograft Mouse Model of Nipah Virus Infection. PLoS Pathog 10(4): e1004063. doi:10.1371/journal.ppat.1004063