The Proximity of Viruses and Exosomes in the Age of Social Distancing
Dr. Fatah Kashanchi, Professor and Director at the George Mason University’s Laboratory of Molecular Virology, shares with us his vision on the status quo of COVID-19 testing and the role of exosomes as putative factors of viral spread
Viruses are infectious biological entities usually containing a nucleic acid in a lipoprotein envelope. They are found abundantly in almost every biological system on Earth. However, they are also responsible for causing a variety of diseases, often difficult to cure, due to their ability to integrate and copy themselves within the host cells. The world has witnessed a number of viral plagues in the past- Ebola Virus (EBOV), Human Immunodeficiency Virus (HIV) and most recently, the novel Severe Acute Respiratory Syndrome causing Corona Virus (SARS-CoV-2)- one of the largest RNA viruses identified so far. Exosomes are a type of Extracellular Vesicle (EV), produced by cells with the ability to insert themselves into other cells. There is a high level of scientific and medical interest in the relationships between viruses and exosomes.
In respect of SARS-CoV-2, regulatory agencies are under pressure to make the conventionally red taped clinical trials more ‘adaptive’ and to speed up the time for their clinical availability. With a broader scope for drug discovery, virologists are looking to find distinctive therapeutic targets from new virulence pathways. Professor and Director at the George Mason University’s Laboratory of Molecular Virology, Dr. Fatah Kashanchi has been lately working on recognising the inter-relationship between exosomes secreted from virus infected cells (SARS-CoV-2, EBOV, HIV) in humanised mouse models and novel molecular mechanisms of viral pathogenesis. Dr. Kashanchi has served as an editorial board member and reviewer of authoritative journals like The Journal of Biological Chemistry (JBC), Retrovirology, Virology, PLoS, Cell, Nature Medicine, Nature Communications and Scientific Reports. We had a discussion with him on the status quo of COVID-19 testing and the probability of beating the current SARS-CoV-2 pandemic in comparison to past epidemics.
In the first half of 2010, Dr. Kashanchi assumed his current role at George Mason University. The same decade also saw the outburst of one of the deadliest epidemics in history- The Ebola outbreak (2014-16). Dr. Kashanchi recalls, “One of my colleagues at CDC while working with EBOV patients observed the presence of antigens after months of infection." This was unusual since the filovirus and its symptoms had long subsided. What could be the cause? Based on his prior research, Dr. Kashanchi reasoned that there could be a cytoplasmic RNA virus playing hide and seek with the body’s immune system, perhaps related to the relapse of EBOV Disease (EVD).
To answer this important question, the Kashanchi lab conducted BSL-4 (highest level of biosafety containment) experiments on VP40, the primary matrix protein in EBOV, and found that it is secreted in exosomes. EVs from wild-type EBOV-infected cells were isolated using Izon’s qEV Size Exclusion Chromatography (SEC) columns. The study established that VP40 was linked to these EVs. The investigation further disclosed how the Endosomal Sorting Complexes Required for Transport (ESCRT) proteins assisted the packaging of VP40 into the exosomes2. ESCRT proteins regulate the recognition of specific cargo; its packing into nascent vesicles and finally pinching them off from the membrane. Viral RNA machinery exploits the ESCRT sequence to slide into exosomes as viral proteins / nucleic acids to produce pro-viral effects as well as cell cycle aberrations in quiescent cells expediting viral spread.
- Sampey, G. C. et al. Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA. J. Biol. Chem. 291, 1251–1266 (2016).
- Pleet, M. L. et al. Ebola Virus VP40 Modulates Cell Cycle and Biogenesis of Extracellular Vesicles. The Journal of Infectious Diseases 218, S365–S387 (2018).
- Iwasaki, A. & Yang, Y. The potential danger of suboptimal antibody responses in COVID-19. Nat Rev Immunol (2020) doi:10.1038/s41577-020-0321-6.