BIO80001 Advanced Topics in Biotechnology

Background

A recent trial has shown that SARS-CoV-2 is well known for the infection of nerve cells and of blood flow impeding the central nervous system. The short- and long-term wellbeing of the world's millions is also affected by the COVID-19. Because of the relatively new territories of SARS-CoV-2 virus, the disease-causing virus, scientists are still looking at how it works inside different bodies. Binding the lung tissue to angiotensin converting 2 (ACE 2) receptors on the cell surfaces - SARS-CoV-2 infects the lung tissue (Briguglio et al. 2020). The virus can invade a cell and cause respiratory symptoms including shortness of breath and dry cough once it is bonded to a cell.

Recent research has shown, however, that the virus can also affect cells in the brain and spinal cord of the CNS. The increased patient numbers with neurological symptoms such as dizziness, stroke, confusion, coma can be explained. This study complements previous research by analysing nervous cell infection mechanisms. The team used three separate brain models to investigate the scope and effect of the infection: human brain organoids, genetically modified mice and autopsy of those who have been killed with COVID-19. Increased levels of cell death were also recorded near these infected cells (Butowt and Bilinska 2020). It turned out, however, that the rest were not tainted with these dead cells. Either infection or cell death was possible, but seldom for both. Cells were susceptible. The researchers then compared infected cell genes with those of neighbouring uninfected cells in order to further explore this (Natoli et al. 2020). The cells were found to show higher metabolism that permitted an efficient replication of the virus and the supply of oxygen to surrounding cells to be reduced. These results indicate that the infected cells survive and surround the virus to change the metabolism of the cells.

Recent researchers then utilised a model of mouse for look at CNS infection in a whole organism. They have GM genetically-modified the mouse to produce human ACE2 proteins to closely mimic infection in humans (Natoli et al. 2020). The researchers observed high levels of infected nerve cells after infecting the mice. These levels have been correlated with major blood vessel changes — changes that can disturb the brain's oxygen supply. The study also compared lung infection and CNS infection in mice and found a slightly more lethal CNS infection. Neuronal infection caused a loss of weight and death in the mouse even with lower viral doses. Finally, three patients died of extreme COVID-19 complications investigated the brain regions. Airborne malfunction and admission to the intensive care unit have all occurred (Pennisi et al. 2020). The cell death and tissue damage in the form of ischemic infarcts— areas of the dead tissue caused by an insufficiency in blood flow were seen in the infected brain areas. These infarcts were caused by oxygen and blood flow disturbances. They looked like those found in organoid and mouse models of the brain, which also demonstrated a lack of oxygen.

Problem definition

Every experiment or research is performed either to confirm a previously performed one or to find out something new from them. The main problem associated with the previous experiment is that the researchers failed to image the whole neuronal region of brain affected by COVID 19. On the other hand, it has also been found that since animal studies were performed mainly, and human studies were lacking, the imaging process was never thought to be much useful as systems differ between humans and animals. In other words, it can be said that this experiment will be based on solving this imaging problem of brain neuronal cells affected by SARS COV 2.

Planning to solve the problem

Chemical and electrical signals are continually flashing through brains as one travel through the globe so a camera with high speed and a brain window will be needed to capture their flickering ways. Berkley, University of California - researchers now developed such a camera: a microscope which can picture the mouse's brain 1,000 times per second, capturing electric pulses passing through the neuron for the first time. The modern technique of imaging incorporates fluorescence microscopy – 2 photon with all-optical laser scanning in the state-of-the-art microscope, which can imagine a two-dimensional slice up to 3000 times a second through the mouse brain neo-cortex (Singal, Jaiswal and Seth 2020).

This method is now used to clock electric signal signals from neuroscientists such as the microscopes as they spread around the brains and eventually search for disease-related transmission problems. One major benefit of this technique is that neuroscientists are able, from other brain cells, including those that do not cause a cell to fire, to monitor hundreds to ten thousand of inputs received from any given brain cell (Natoli et al. 2020). These inserts — whether thrilling or inhibiting the neuron — eventually add up to a crescendo that activates the cell to fire a possible action, which transmits information to other neurons.

Although the full brain coverage and single neuron resolution of the light sheet microscopy (LSM) has been shown in zebrafish, it does not follow the fast movement of fish quickly. In LSM, the sample from its side, which is hard to incorporate with a tracking device, is also illuminated. Conventional Light Field Microscopy (LFM) is an alternative that is promising due to its high imaging speed (Stefano et al. 2021). Specialized LFMs have also been recently developed for monitoring neural activity with temporal data that depend on fluorescent signals spatiotemporal sparsity and cannot be used in the moving animals.

Based on the general light field theorem, the newly developed XLFM can acquire 3D information from a single camera frame. The restriction of a spatial resolution to the volume cover of images in traditional LFM put upon XLFM was considerably relaxed. This accomplishment is focused on optics and computing techniques (Vellieux et al. 2020). First, the rear pupil of the image objective was placed on a customised lens array instead of on the imaging plane such as LFM. An ideal 2D spatially invariant point spreading function (PSF), which in practise was approximately spatially invariant, could therefore be defined and measured.

The newly developed XLFM is based on the general light field theory and can gather 3D data from a single camera frame. The restriction of the spatial resolution to the volumetric imagery coverage in traditional LFM was relaxed considerably by XLFM. This achievement is based on optics and computer techniques (Stefano et al. 2021). First, the rear pupil of the image objective had an adjusted lens array instead of the imaging plane such as LFM. An ideal 2D spatially invariant point spreading function (PSF), which in practise was roughly spatially invariant, could therefore be defined and calculated. The PSF was thus invariant.

Therefore, it can be said that specialised light field microscopy can be used to image the whole brain neural system in SARS-COV 2 infected cells.

Significance and future directions

Light microscopy has been an important instrument in the observation of cellular properties for the neuroscientists because of the work of Cajal and Golgi. Ongoing progress has allowed the use of light to test the nervous system in many spatial scales. The same has been stated to show that ultra-structural scales that are finer than the optical diffraction limits. Other advances allow for quicker, higher-depth functional imagery in the brain tissue and greater volumes than was possible previously (Vellieux et al. 2020). Mobile, miniaturised fluorescence microscopes now allow free behavioural imagery in the brain. Early light microscopic studies treat images as pictorial evidence. Such photos were either directly viewed by the eye or photographed, but the details were both visually examined. Digital imaging and microscopy scan over the past few decades have turned data microscopes into a numerical format with a defined number of bits per pixel image. This transformation has encouraged image data analysis analytical approaches (Pennisi et al. 2020). Today, fast computers' ready access drives a new generation of microscopy techniques that hit even higher abstraction levels.

Future directions will be based on imaging the brain neuron cells in the same way as normal cells and tissues are imaged. The same can be stated to be possible if the LFM process is used in imaging of cells. Brain neural cells are hard to be imaged because in lies deep inside the organs system of the body and is under continuous movements due to signal transfer. However, this process has a bright future irrespective of the fact that only animal studies have been performed. In this way future improvements can be made on the above stated process of imaging brain neurons that are affected by SARS COV 2.

References

Briguglio, M., Bona, A., Porta, M., Dell'Osso, B., Pregliasco, F.E. and Banfi, G., 2020. Disentangling the hypothesis of host dysosmia and SARS-CoV-2: the bait symptom that hides neglected neurophysiological routes. Frontiers in Physiology, 11, p.671.

Butowt, R. and Bilinska, K., 2020. SARS-CoV-2: olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection. ACS chemical neuroscience, 11(9), pp.1200-1203.

Chen, R., Wang, K., Yu, J., Howard, D., French, L., Chen, Z., Wen, C. and Xu, Z., 2021. The Spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in the human and mouse brains. Frontiers in neurology, 11, p.1860.

Fenrich, M., Mrdenovic, S., Balog, M., Tomic, S., Zjalic, M., Roncevic, A., Mandic, D., Debeljak, Z. and Heffer, M., 2020. SARS-CoV-2 dissemination through peripheral nerves explains multiple organ injury. Frontiers in cellular neuroscience, 14, p.229.

Natoli, S., Oliveira, V., Calabresi, P., Maia, L.F. and Pisani, A., 2020. Does SARS‐Cov‐2 invade the brain? Translational lessons from animal models. European journal of neurology, 27(9), pp.1764-1773.

Pennisi, M., Lanza, G., Falzone, L., Fisicaro, F., Ferri, R. and Bella, R., 2020. SARS-CoV-2 and the nervous system: from clinical features to molecular mechanisms. International Journal of Molecular Sciences, 21(15), p.5475.

Singal, C.M.S., Jaiswal, P. and Seth, P., 2020. SARS-CoV-2, more than a respiratory virus: Its potential role in neuropathogenesis. ACS chemical neuroscience, 11(13), pp.1887-1899.

Song, E., Zhang, C., Israelow, B., Lu-Culligan, A., Prado, A.V., Skriabine, S., Lu, P., Weizman, O.E., Liu, F., Dai, Y. and Szigeti-Buck, K., 2021. Neuroinvasion of SARS-CoV-2 in human and mouse brain. Journal of Experimental Medicine, 218(3), p.e20202135.

Stefano, G.B., Ptacek, R., Ptackova, H., Martin, A. and Kream, R.M., 2021. Selective Neuronal Mitochondrial Targeting in SARS-CoV-2 Infection Affects Cognitive Processes to Induce ‘Brain Fog’and Results in Behavioral Changes that Favor Viral Survival. Medical science monitor: international medical journal of experimental and clinical research, 27, pp.e930886-1.

Vellieux, G., Sonneville, R., Vledouts, S., Jaquet, P., Rouvel-Tallec, A. and d’Ortho, M.P., 2020. COVID-19-Associated Neurological Manifestations: An Emerging Electroencephalographic Literature. Frontiers in Physiology, 11.

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