Microglia, the Double-Edged Sword
The Protective and Pathological Roles of Microglia in Viral Encephalitis
Background
We’re all aware of viral infections and most of us succumb to at least one every year. But while viruses are common, we know relatively little of how our body reacts to some of the more deadly infections. This particular experiment was done using model mice to determine how microglia function in viral encephalitis. Let’s define a few terms first, though. As you might know, the mammalian body houses immune cells that are always patrolling for foreign bodies, whether it be a virus or some other invader. But the brain gets its own specialized immune cells called microglia that are sequestered to the central nervous system (CNS), consisting of the brain and spinal cord. Viral encephalitis is inflammation of the brain caused by a viral infection, which often results in lasting neurocognitive sequelae (these are basically new issues from an old condition or illness). The paper runs over several viruses from herpes to West Nile and Zika, illustrating the high morbidity from the viruses, their lasting sequelae, and how the immune system (IS) responds to these invasions.
Immune Recruitment: Adaptive and Immune
The blood-brain barrier (BBB) physically separates the CNS from the rest of the body’s circulation, and as a result, there are few things that can pass through the “wall” it creates. Microglia are a specialized population of myeloid cells, a cell line that typically arises from a progenitor cell during hematopoiesis (the formation of blood’s cellular components). Since microglia are so specific to the CNS and are unable to enter via the circulation, they arise from localized proliferation rather than the usual progenitor. This seclusion and self-regeneration make microglia a unique cell population. To track microglial movement, researchers used a fluorescence fate-mapping system. This is a procedure that tags cells during development in order to track their differentiation and movement, mapping out their “fate” in fluorescence after development and in adult stages. Using this system, the researchers observed that microglia have different turnover rates depending on the area of the brain they localize to. But how are their numbers affected during infection? Originally, it was thought that no other cells, immune or otherwise, could make it past the BBB even during an infection. In the last several years, though, scientists have discovered that in the presence of disease, monocytes (members of the innate IS) are able to infiltrate the CNS. Specifically discussing Ly6Chi monocytes, which are pro-inflammatory cells, it was found that their accumulation in the CNS can either have a protective or pathogenic affect. Chemokine receptor 2 (CCR2), expressed on monocytes, is necessary for both the accumulation of Ly6Chi monocytes in the CNS as a protective mechanism, as well as the initiation of autoimmune encephalomyelitis (the inflammation of both the brain and spinal cord).
Scientists tested mouse models with West Nile virus (WNV) encephalitis and their results showed that the addition of Ly6Chi monocytes in the CNS appeared to be critical for host defense. But when they inhibited monocyte entry into the CNS by blocking CCR2, they also noticed enhanced protection in the lethal WNV encephalitis model. All this is about as confusing as anything could get and their conclusion seems frustratingly simple: Ly6Chi monocytes have a complicated role in viral encephalitis. Focusing back on microglia, the researchers conceded that there are very few studies that have been able to look at the mechanisms microglia use in their reaction towards infection. However, they do know that in their response, microglia recruit both innate and adaptive immune responses by sensing damaged cells via purinergic receptors, which are important in the functioning of most mammalian CNSs. Microglia are necessary in the early and chronic phases of viral encephalitis for the recruitment and re-activation of T-cells (which are part of the adaptive IS) in the CNS, presenting antigens that are thought to be essential for that T-cell response.
While microglia are important for host survival and protection from viral encephalitis, studies have also implied that they have roles in the pathological stripping of neurons (the removal of synapses from neural cell bodies), and neuronal apoptosis as a result of the inflammatory response. Basically, microglia have an array of mechanisms to sense virally infected neurons and isolate them. They recruit T-cells to the CNS by presenting antigens in response to the early phase of viral encephalitis, and during the chronic phase, it seems they may re-activate those T-cells. The mechanisms of microglia are still largely unknown, but research is showing that while they are important in protection, they can also cause neuronal damage in the process. Even after the infection has been eradicated, damage can still occur which can lead to long-lasting neurocognitive sequelae.
