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The capillaries in the brain, the smallest blood vessels, are different from usual capillaries in that the lining cells are very tightly joined together not allowing diffusion of microbes, large particles and hydrophilic (water soluble) particles.  They do allow small hydrophobic molecules in, such as oxygen, carbon dioxide and hormones. Just outside of the vessels is the basement membrane of the extracellular space—a solid sheet of molecules made of collagen, laminin and many other complex molecules.
The cerebral spinal fluid flows in the middle of three membrane barriers called the meninges. Many different kinds of bacteria and virus attack the brain. Worldwide, a large number of people die from bacterial meningitis and malaria. Microbes are able to build a niche in specific regions of the brain, based on special characteristics of their entry process, and the special receptors for specific microbes that exist on the surface of neurons and glia. When microbes are able to enter the brain, some attack neurons; others such as polio, attack oligodendrocytes, the cells that make myelin. One of the main ways that products are taken into the blood is through an active process where cells’ membranes merge with a sac (vesicle)  transporting it through the cell and secreting it on the other side into the blood stream (endocytosis and exocytosis). Some microbes disturb the blood brain barrier (BBB) such as adenovirus or Nipah virus, which cause hemorrhage with brain infection.
The monkey HIV, called SIV (for simian) enters the lining cells and multiplies inside the cell. Cytokine communication occurs between immune and brain cells and these also help allow WBCs to cross. Herpes, HIV, SIV, and measles reproduce in T cells and in monocytes and are carried into the brain by these immune cells.
The bacteria listeria monocytogenes and the infamous Toxoplasma gondii, which causes mental effects in animals (including humans), also use monocytes to cross. There are many different other cytokine signals and techniques involving white blood cells that are used by many other microbes including Trypanosoma, causing sleeping sickness.
West Nile virus is stopped by Toll-like receptors, which trigger immune factors like TNF (tumor necrosis factor.) TNF stops blood cells from entering.
Even without entering the brain proper, malaria parasites in red blood cells create signals that make the RBC stick to the vessel lining cells. There are many other mechanisms used by other microbes including stimulating a neurotransmitter receptor that causes the scaffolding to change, allowing gaps in the lining cells. Other microbes stay in the choroid plexus cells and from there send signals that cause inflammation in the ventricles. Peripheral nerves in the body are protected because lining cells called the perineurium and endoneural vessels surround them. Viruses with an envelope—rabies and herpes—are similar to a vesicle, which merges with the membrane and releases the virus into the cell.
Those viruses that don’t use their own envelope, but rather a cellular vesicle, leave no immune traces. Rabies is carried by an endosome (vesicle) retrograde from the tip of the axon all the way back to the nucleus. Recently, it was shown that when the herpes virus takes over the dynein motor it actually alters the energy mechanism (ATP source) and speeds it up.
Ganglia are not as protected as CNS and ganglia cells come in contact with blood and interstitial matrix and therefore immune T cells that stop microbes.
Ssome viruses that make it into the brain stay there in a hibernating state, but then re activate and travel to the periphery to go to the skin in order to spread to others.
Several viruses in the CNS are secreted in vesicles from neurons and then taken up by microglia, where they are broken up into pieces of proteins that can be presented to T cells in MHC. Other microbes in neurons, such as rabies, trigger signals that suppress immune activity such as HLA-G1 that protects them. Behavior in animals, including humans, can change based on where the microbe attacks the brain.

Examples include aggressive behavior from rabies in the brainstem, thalamus and hippocampus; and T. Microbes traverse a long tortuous route from the outside through skin, mucous, blood vessels, the many barriers to the brain, and the vast complexity of the neuron. What is quite remarkable is that in different parts of the journey, microbes use very specific complex cytokine signals and manufacture very specific shaped molecules. This entry was posted in Blog, Microbes and tagged Despite difficulties many microbes enter brain, Microbes must cross blood brain barrier to get into brain, Microbes must cross extracellular matrix to get into neurons, Microbes use complex signals to travel to brain, Microbes use cytokines to manipulate immune cells, Some microbes stay in neurons for years. Could it be possible that microbes and viruses are delivery devices, programmed by external systems that have the required level of “intelligence” and sufficient knowledge of complex life? But, with great ingenuity microbes have mechanisms of traversing the tortuous multi layered pathways into the brain.
The blood brain barrier is a term used for multiple different obstructions between particles and microbes in the blood and the extracellular fluid that lies between brain cells as well as the cerebrospinal fluid that surrounds the brain. Then, there is a layer of astrocyte end feet, which covers all surfaces of the blood vessels and determines the blood flow (the measure of MRI). Trypanosomiasis, neurocysticercosis, rabies, measles, polio, HIV, and henipavirus (from bats) all enter the brain. A previous post shows how intelligent T cells, as well as other immune cells, provide surveillance in the cerebrospinal fluid and control the inflammation response in the brain. A previous post noted that in different brain regions different cells have individually developed their own local immune systems targeted at very specific microbes.
The blood vessel lining cells, which protect the brain, do not take up vesicles as lining cells do in other parts of the body.
Some microbes make a specific molecule on their surface that attaches to the lining cells and then a special plasmid that causes disruption through signaling. It attaches to the lining cells and stimulates the immune factors in the cells, NF-kappa-beta and interferon regulatory factor that cause inflammation.
Although the brain was considered to have no immune cells previously, the post on Intelligent T cells shows that there are many blood cells in the CSF and some do cross into the brain. When the basement membrane opens from a special signal, WBCs can pass by the astrocytes end feet layer, a significant barrier surrounding blood vessels. A cytokine signal from astrocytes is triggered by these viruses, which calls for more monocytes.
Even with very few in the blood, some of the virus enter and infect neurons especially in the basal ganglia, thalamus, brainstem and cerebellum. The bacteria strep, pneumonia, Neisseria meningitides, haemophilus influenza and the fungus cryptococcus cause inflammation in the CSF.
This is done by triggering specific signals that cause the cells to take up and transmit vesicles. The axon is protected except at the end and there molecules can be taken into the cell and transported along the axon back to the nucleus. The virus lives first in skeletal muscle cells, then meets the axon at the neuromuscular junction and then can travel all the way up the spinal cord into the CNS.
Polio is transported by the dynein motors on microtubules rapidly, in addition to having a different separate very slow transport. It is not a passive passenger on the dynein motor but grabs the wheel and increases the throttle.
The T cell produces signals, such as interferon gamma, that stops the reproduction of the virus. In other cases, when T cell’s signals attempt to control the infection, they can, instead, alter and impair a neuron’s function. Invasion of the brain involves many different complex mechanisms each of which has to be in sequence.

It is remarkable that a tiny cell, or a virus ( which is, virtually, just a piece of DNA or RNA) can make these multiple different signaling molecules, or the specific shapes needed, or utilize complex mechanisms that overtake the energy supply of the dynein motors while travelling on microtubules. This trip takes many different stages, and each stage needs highly specific complex machinery and signaling with complex molecules. It consists of special tight junctions between cells lining the blood capillaries, a thick basement membrane and a thick and continuous layer of astrocyte end feet that fully surrounds the blood vessels.
These consist of proteoglycans, tenascin and linking proteins and are critical for synapses and neuroplasticity. When neurons are infected, they don’t display the MHC signals on the cell surface and therefore T cell don’t react to them (see post for discussion of the way T cells read MHC signals on cells).
Crossing these multiple barriers involve multiple different laminins and many different signaling cytokines. A new finding is that during the infection with malaria, many very small vesicles called micro-particles are released from the RBCs, WBCs, platelets and vessel lining cells. At times these reactions are quite complex with very specific cytokine signaling between microglia, macrophages, and T cells.
There are many different ways that the vesicles and envelopes are introduced into the cell using scaffolding machinery. Naegleria fowleri has been in the news recently for entering the brain of several children who swam in infested water (one recently as north as Minnesota).
Microbes are able to send their own complex signals and trigger immune cytokines and neurotransmitter signaling for the own advantage at every step of the complex journey.
Then, there is the dense interstitial matrix not attached to the basement membrane or perineural nets, but floating freely. In one way around the problem of crossing the lining cells, malaria doesn’t cross the blood brain barrier, but attaches to blood cells and vessels and causes trouble from there through signaling. Although most endothelial lining cells don’t bring in vesicles, a small class of cells in the basement membrane, called pericytes, do. These particles bind to macrophages and stimulate many signaling cytokines causing inflammation and malaria infection in the brain. The trick all of these pathogens use is to have a binding factor that is very similar to the surface of platelets and it stimulates specific cytokine signals (platelet activating factor, PAF).
These immune cells are prodded by signaling to disrupt the lining with inflammatory responses.  Monocytes with HIV inside can also cross the choroid plexus. In the autonomic system it travels to the salivary gland where it joins saliva and infects another human. These bring in HIV virus and transport it without multiplication all the way to the other side and into the brain. They cross by attaching to the venule (smallest veins) then, in steps, and with different complex mechanisms, traverse lining cells and, then, basement membrane cells.
These endosomes are kept at specific pH to stop the release of the virus until it has travelled all the way to the nucleus. After multiplying in the sensory neuron, it then travels again by retrograde transport into the CNS. By retrograde transport they can enter the limbic system and the monoamine systems of the brainstem.
It can travel in pieces or as a whole in vesicles, which are transported along microtubules.
One example goes to the serotonin center, the Raphe nucleus and causes life long low serotonin.

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