SARS-CoV-2, or COVID-19, remains mysterious even in a “post-COVID” era. Researchers have yet to discover the full extent of its expression, especially concerning its neurological effects. 30-40% of patients develop neurological symptoms like headache and dizziness, and 30% of these patients see symptoms remaining after the typical recovery infection period of COVID-19 (colloquially termed long COVID) [1]. Furthermore, in autopsy and brain scan studies, researchers have observed a decrease in grey matter and brain lesions. Damage to the brain can be severe, as it can cause problems in learning, memory, focus, and mental health, and these cells never grow back at the same rate, or barely grow at all. One recent study has discovered a link between the lungs and the brain that may help us begin to explain these neurological symptoms. These discoveries promise the development of further understanding of SARS-Cov-2 and its effects on the central nervous system [1].

The complexities of COVID-19 may lie in the blood-brain barrier. The blood-brain barrier, or BBB, is a protective barrier around the brain that filters out toxins and infectious agents [2]. Neurological symptoms of COVID led researchers to examine the BBB’s role in the infection, drawing from information about other diseases like HSV-1 and Zika virus. These diseases have similar neurological symptoms and also infiltrate the BBB. To model the interaction of the lungs and the brain, the researchers used model systems called “organ chips,” which are reconstructions of human organs that mimic the environment of their real-life counterparts (Fig. 1) [2]. 

Figure 1: An integrated lung-brain model, depicting the blood-brain barrier and alveolar chips, can help study how viruses like SARS-CoV-2 interact with the human body. It features detailed images of specialized 'chips' representing lung and brain cells, offering insights into the complex cellular structures involved in the body's response to infections [2].

When the researchers directly infected the BBB chip with SARS-CoV-2, they found only mild changes [1]. The spike protein – the main agent of COVID-19 infections – was found in low qualities in the BBB chip. However, when the researchers infected the alveolus chip, which corresponds to cells inside human lungs, they found high amounts of spike protein in its medium (the fluid inside the chip). Though spike protein content in the BBB remained low, injecting the BBB chip with the infected alveolar chip medium caused stark changes in health compared to when it was infected alone [1].

The infection changed cell integrity and structure in the BBB [1]. Epithelial cells, which form the lining of blood vessels and other non-neuronal cells, lost their ability to regenerate and were observed to have increased permeability. This decrease in structural integrity, along with a similar observed effect in the alveolar chip, indicates that inflammatory cells were able to travel much more easily between the two chips than normal. Cytokines, which are inflammatory immune cells, could thus enter the brain faster. Immune cells cause inflammation, and in turn cell death, which can lead to impaired learning and memory, as well as depression, anxiety, and other health effects common in COVID. In fact, by using genetic sequencing, the researchers determined that the virus was likely influencing genes that control permeability and immune function. The cells were generating immune factors at a higher level and structural proteins at a lower level [1]. 

By using a unique model system, researchers were able to achieve a new understanding of COVID. This study provides evidence that lung infection, rather than direct brain infection, may cause the unique neuropathology of SARS-CoV-2, giving insight into the potential communication between the brain and other organs during infections such as COVID.

References:

[1] Wang, P., Jin, L., Zhang, M., Wu, Y., Duan, Z., Guo, Y., Wang, C., Guo, Y., Chen, W., Liao, Z., Wang, Y., Lai, R., Lee, L. P., & Qin, J. (2024). Blood-brain barrier injury and neuroinflammation induced by SARS-CoV-2 in a lung-brain microphysiological system. Nature biomedical engineering, 8(8), 1053–1068. https://doi.org/10.1038/s41551-023-01054-w

[2] Wang, P., Jin, L., Zhang, M., Wu, Y., Duan, Z., Guo, Y., Wang, C., Guo, Y., Chen, W., Liao, Z., Wang, Y., Lai, R., Lee, L. P., & Qin, J. (2024). Blood-brain barrier injury and neuroinflammation induced by SARS-CoV-2 in a lung-brain microphysiological system. [Figure 2]. Nature biomedical engineering https://doi.org/10.1038/s41551-023-01054-w