Tissue Damage and Brain Inflammation in COVID-19

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the global pandemic of coronavirus disease 2019 (COVID-19).

While primarily affecting the lungs and causing pneumonia and acute respiratory distress syndrome (ARDS), it has become evident that SARS-CoV-2 can also affect other organs, including the kidneys, brain, heart, liver, and more, potentially leading to multi-organ failure [1].

Neurological complications associated with SARS-CoV-2 infection have been increasingly recognized, with a significant focus on the damage to the olfactory system and the resulting brain inflammation [2,3]. This article aims to explore the pathogenesis mechanisms underlying these neurological complications.

Olfactory System Damage and its Prevalent Complications: One of the highly prevalent neurological complications observed in COVID-19 patients is the damage to the olfactory system. Olfactory dysfunction, including loss of smell (anosmia) and altered sense of smell (hyposmia), has been reported as a common symptom [4,5].

Other complications associated with olfactory system damage include fatigue and depressive symptoms. When these symptoms persist beyond the acute phase of infection, a condition known as long COVID can develop [6-8]. Long COVID refers to the continuation or development of new symptoms that persist for at least 2 months after the initial SARS-CoV-2 infection, with over 200 different symptoms reported [9].

Olfactory System: A Gateway for SARS-CoV-2: The olfactory system, responsible for our sense of smell, plays a vital role in detecting and recognizing odors. Olfactory epithelial cells lining the nasal cavity express high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), making them susceptible to SARS-CoV-2 infection [25,26]. ACE2 acts as a receptor for the spike protein of SARS-CoV-2, facilitating viral entry into the host cells. TMPRSS2 primes the spike protein, enabling its fusion with the host cell membrane and subsequent viral entry. The abundant expression of ACE2 and TMPRSS2 in olfactory epithelial cells renders them vulnerable to SARS-CoV-2 invasion.

Olfactory System Damage in COVID-19: Numerous studies have documented olfactory dysfunction as a prominent symptom in COVID-19 patients. Anosmia (loss of smell) and hyposmia (reduced sense of smell) are commonly reported, sometimes even preceding other clinical manifestations of the disease. Olfactory dysfunction can range from mild to severe and may persist for an extended period, even after other symptoms have resolved. This observation strongly suggests that SARS-CoV-2 directly targets and damages olfactory epithelial cells, impairing the olfactory system’s function.

Olfactory Bulb: A Site of Inflammation: The olfactory bulb, located at the base of the brain, receives signals from olfactory epithelial cells and plays a crucial role in processing olfactory information. Emerging evidence indicates that SARS-CoV-2 infection can lead to olfactory bulb damage and subsequent inflammation. Autopsy studies have revealed degeneration and inflammation in the olfactory bulb of COVID-19 patients, despite limited viral proliferation within the CNS [27,28,29]. This suggests that factors beyond direct viral invasion contribute to olfactory bulb damage and inflammation.

The Link Between Olfactory System Damage and Brain Inflammation: Research involving animal models and surgical disruption of olfactory bulb function, such as olfactory bulbectomy (OBX), has provided insights into the relationship between olfactory system damage and brain inflammation. Studies have shown that OBX-induced disruption of olfactory bulb function can lead to neuroinflammation in regions connected to the olfactory system [30,31,32]. Similarly, in COVID-19, olfactory bulb damage caused by SARS-CoV-2 infection may trigger an inflammatory response in the brain, contributing to neurological complications.

Elevated Intracellular Calcium: a Potential Mechanism: Intracellular calcium plays a crucial role in various cellular processes, including cell signaling, apoptosis, and inflammation. Interestingly, both SARS-CoV-2 spike protein and the human herpesvirus-6 (HHV-6) protein SITH-1 have been implicated in elevating intracellular calcium levels in olfactory system cells. Studies have shown that increased intracellular calcium in olfactory epithelial cells can lead to cell damage and apoptosis [33]. The spike protein’s ability to elevate intracellular calcium levels may contribute to olfactory system damage and subsequent brain inflammation in COVID-19.

Implications for Long COVID: Long COVID, a condition characterized by persistent symptoms following the acute phase of COVID-19, has gained significant attention. Neurological symptoms, including fatigue, cognitive dysfunction, and depressive symptoms, are prevalent in individuals experiencing long COVID. While the exact mechanisms underlying long COVID are still unclear, it is postulated that persistent olfactory system damage and brain inflammation may contribute to these long-term neurological complications. Further research is necessary to elucidate the precise relationship between olfactory system damage, brain inflammation, and the development of long COVID.

Understanding Long COVID and the Need for Treatment: Long COVID has gained recognition as a post-COVID-19 condition, and it has been included in the International Classification of Diseases (ICD-10). The World Health Organization (WHO) defines long COVID as the presence of symptoms lasting for at least 2 months with no other explanation, including common symptoms such as fatigue, shortness of breath, and cognitive dysfunction [9].

Despite several established and developing treatments for COVID-19, there is currently no specific treatment available for long COVID [10-16]. This highlights the importance of understanding the underlying mechanisms to develop effective interventions.

Tissue Damage and Brain Inflammation in COVID-19: In typical viral infections, tissue damage results from the proliferation of the virus within the affected tissues. However, autopsies of COVID-19 patients have shown tissue degeneration in the brain without direct evidence of central nervous system (CNS) damage caused by SARS-CoV-2 proliferation [19,20,21,3,22].

Additionally, studies have suggested that cognitive impairment in long COVID can occur even in the absence of SARS-CoV-2 infection and with limited histopathologic changes in the brains of affected individuals [23,24]. These findings suggest that factors other than viral proliferation may contribute to the neurological symptoms observed in COVID-19.

The Role of Olfactory System Damage and Brain Inflammation: The olfactory system, particularly the olfactory epithelial cells, serves as the primary target for SARS-CoV-2 infection due to the abundant expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) [25,26].

Olfactory bulb damage has been documented in COVID-19 patients [27,28,29]. Interestingly, studies have shown that surgical disruption of olfactory bulb function, such as olfactory bulbectomy, can induce brain inflammation [30,31,32]. This suggests a possible connection between olfactory bulb damage caused by SARS-CoV-2 and the subsequent onset of brain inflammation.

Intracellular Calcium and Olfactory System Damage: Studies have indicated that damage to olfactory system cells, particularly in the olfactory bulb, is associated with an increase in intracellular calcium levels in olfactory epithelial cells [33]. Previous research involving the human herpesvirus-6 (HHV-6) protein SITH-1, known to elevate calcium levels in olfactory cells, demonstrated its ability to induce apoptosis in the olfactory bulb and cause depression [34].

Notably, the spike protein of SARS-CoV-2 has also been shown to elevate intracellular calcium levels in cells [35]. Based on this information, a mouse model expressing the spike protein in the nasal cavity was created to further investigate its effects.

Conclusion: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) not only affects the respiratory system but also poses a threat to the central nervous system. Olfactory system damage, particularly in olfactory epithelial cells and the olfactory bulb, plays a crucial role in the pathogenesis of neurological complications associated with COVID-19. The abundant expression of ACE2 and TMPRSS2 in olfactory system cells renders them susceptible to SARS-CoV-2 infection, leading to olfactory dysfunction. Furthermore, olfactory bulb damage and subsequent inflammation may contribute to brain-related symptoms. Understanding the intricate mechanisms underlying these processes is essential for the development of targeted interventions and therapies for individuals experiencing neurological complications associated with COVID-19.

References:https://www.cell.com/iscience/fulltext/S2589-0042(23)01031-3

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