The Impact of Viral Infection on Microglia and the Aging of the Brain

A growing school of thought sees persistent viral infection as an important contributing factor in age-related neurodegeneration. The widely varying burden of infection that is present in the population could help to explain the puzzling epidemiology of conditions such as Alzheimer's disease, in that only some of the people with evident risk factors in fact go on to develop dementia. A simplistic view of the role of viral infection, particularly by persistent herpesviruses, is that it produces chronic inflammation in brain tissue, and that inflammation contributes to the many forms of molecular pathology observed in neurodegenerative conditions.

The immune system of the brain is distinct from that of the rest of the body, the two sides separated by the blood-brain barrier surrounding blood vessels in the central nervous system. In recent years, increasing attention has been given to the age-related dysfunction of innate immune cells in the brain, the microglia, and the contribution of that dysfunction to neurodegeneration. Microglia in older individuals are more inflammatory in general, and some become senescent, producing an outsized amount of pro-inflammatory signals. Studies in mice have shown that using senolytic drugs to clear senescent cells, including senescent microglia, from the brain can reverse neuroinflammation and pathology characteristic of neurodegenerative conditions. The interesting question is to what degree this inflammatory microglial dysfunction is the consequence of persistent infection in the population as a whole.

The Influence of Virus Infection on Microglia and Accelerated Brain Aging

The physiological function of resting, non-activated microglia in brain homeostasis is not well understood. Activated microglia may acquire paradoxical, opposite functions, either supporting regeneration and repair, or driving neuroinflammation. The triggers and mechanisms driving the cells towards one or the opposite functional direction are not well understood. However, inflammatory microglia can be harmful and destructive to the brain, whereas regenerative microglia may interfere with physiological brain remodeling processes.

Microglia are essential to the healthy brain, as they contribute to many brain functions and help sustain the physiological brain structure. Belonging to the innate immune system of the brain, microglia contribute to an immune response against any brain-invading agent, as well as following traumatic and neurovascular brain damage. They help with resolving tissue damage and support regeneration and restauration of structure and function. However, microglia may get out of control and out of balance resulting in augmenting brain damage or sustaining chronic pathologies like neuroinflammation and inducing or enhancing neurodegeneration. In such case, microglia may enhance brain aging.

The more we age, the more our immune system gets toward a more inflammatory status. The increased systemic inflammatory immune status also affects microglia, resulting in decreased physiological neuroregeneration and remodeling. The inflammatory status is certainly enhanced and accelerated through frequent or chronic viral infections. The increased and chronic inflammatory status in the brain may contribute to neurodegeneration due to increased neuronal cell death and reduced neurogenesis, reduced remodeling and irreparable damage to the neuronal network, resulting in an enhanced or accelerated brain aging process.

In the context of microglia and viral infection, most research has been done in HIV, where the association has been shown for neurocognitive decline. However, there is little information available about the cellular and molecular mechanisms that contribute to or influence the chronic HIV infection and corresponding involvement of microglia, which requires more future research. The same accounts for other viruses, including flaviviruses, human herpes viruses, and SARS-CoV-2.

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