Fig. 6.

Potential mechanisms underlying female-specific risks of long-COVID symptoms. Estrogen and factors related to the X chromosome and female gut microbiome can modulate immune responses. Specifically, these factors can influence the humoral response. This may lead to less severe COVID-19 cases; however, it can result in the persistence of COVID-19 remnants and subsequent long-COVID symptoms. The presence of an additional X chromosome in females might elevate the expression of ACE2, further contributing to the sustained presence of COVID-19 in the system. Moreover, COVID-19 can disrupt immune tolerance mechanisms, leading to the generation of autoreactive immune cells and antibodies. This phenomenon may occur through processes, such as molecular mimicry. When COVID-19 gains access to the central nervous system (CNS), it utilizes various pathways, including the direct invasion of CNS cells, retrograde axonal transport, and penetration through the endothelial cells of the blood-brain barrier. Once inside the CNS, COVID-19 can prompt microglial cells to release proinflammatory agents, leading to mitochondrial dysfunction and oxidative stress. This cascade of events leads to neuroinflammation, demyelination, and neurodegeneration. Collectively, these processes may increase the vulnerability of females to long-COVID neurological complications.