Work developed in collaboration with Utah State University has just been published in Scientific Reports, from the Nature group
Work published by professor Alexandre Leite Rodrigues de Oliveira, from the Department of Structural and Functional Biology - Anatomy area - of the Institute of Biology (IB) at Unicamp, caught the attention of professor John Morrey, from Utah State University, Utah, USA, who proposed to the professor the development of joint work with a view to investigating an important side effect of Zika virus infection, which affects a portion of patients. It is an inflammation of the nerves at the site of their formation (nerve roots), close to the spinal cord, which in some cases causes temporary paralysis and may leave sequelae. The reasons that lead to the paralysis of a small proportion of those infected are still little known, but it manifests itself after the main symptoms in the form of a syndrome, which is a set of signs and symptoms observable in several different pathological processes and without a specific cause. The occurrences associated with Zika infection are similar to those observed in the well-known Guillain-Barré syndrome, which is an autoimmune disease, in which the immune system itself attacks some structures of the nervous system, causing functional impairment. In this case, the organism attacks the nerves at the interface of the spinal cord, central nervous system and peripheral nervous system. This inflammation in the nerve roots triggers a series of symptoms such as loss of muscle strength and paralysis to varying degrees. The disease reaches a peak and recovery is generally slow.
The curious thing, explains the professor, is that in places where a Zika outbreak occurs, cases of Guillain-Barré syndrome also increase greatly: “This correlation led us to be interested in understanding why it occurs and what cellular mechanisms generate such losses. functions that affect a significant number of people. The study of these mechanisms is important to eventually enable appropriate treatment and prevent the change from taking on greater dimensions.” So, the study resulted from the repercussions that Zika infection generates on the nervous system and focused specifically on the motor neurons of the spinal cord, which connect the central nervous system and the muscles of the limbs. They constitute the final element of the motor pathway and when affected can cause paralysis in the muscles they innervate.
Oliveira clarifies the mechanism: spinal motor neurons receive information from a large number of other neurons from the spinal cord and brain that contribute to generating movement. This occurs through contacts called synapses – a meeting between neurons where the transmission of nerve impulses occurs – which can be excitatory or inhibitory. When these neurons communicate, neurotransmitters are released that stimulate motor neurons, generating action potential, which manifests itself in muscle contraction. When the flow of information coming from neurons preceding motor neurons is affected, the resulting motor function is compromised. So, he says: “Basically we studied how, in the face of viral infection with Zika, these interactions between spinal cord neurons and motor neurons change and how they impact motor coordination.” O article resulting from the work has just been published in Scientific Reports, from the Nature group.
Transmission electronic microscopy
Zika infection acts preferentially on motor neurons, possibly due to their size and complexity, which should facilitate the reproduction of the virus, affecting its metabolism and affecting its connections with pre-synaptic neurons. The researcher adds: “We effectively found in the study with mice that at the peak of the disease, when paralysis appears, there is a significant loss of contact with several neurons, called synaptic loss, both in excitatory and inhibitory synapses, as if the motor neuron shut down. of the circuits in which it is integrated.” As paralysis is reversible, the occurrence is temporary, and as the inflammation in the nervous system regresses, the connections are remade and the animal regains movement.
This correlation between synaptic plasticity and the peak of paralysis was what caught the researcher's attention as it is similar to what occurs in other situations of degenerative diseases such as, for example, multiple sclerosis. By the way, he recalls that, in previous works, when studying the effects of the evolution of multiple sclerosis on motor neurons, he found that the effect was very similar, in terms of losses, because as they undergo changes, the symptoms of the disease worsen. manifest. As multiple sclerosis is often characterized by flare-ups and remissions, it has been observed that it is during flare-ups that the animal loses motor function, when inflammation and synaptic disconnection actually occur.
The analysis of this synaptic dynamics can only be done in detail using transmission electron microscopy, an area in which the researcher has worked over the years and which determined the cooperation with Professor John Morrey, who is a virologist and specialist in establishing the mechanics of viruses. and dedicated to studying the characteristics of viral infections. The interest in understanding the effects of inflammation in the spinal cord at an ultrastructural level motivated the joint work, which included in Brazil the collaboration of PhD student in Cellular and Structural Biology Mateus Vidigal de Castro, one of the co-authors of the work, who assisted in the preparation and ultrastructural analysis. of the material used. It was through these analyzes that the researchers were able to quantify the loss of synapses and demonstrate that exactly at the moment of paralysis, significant losses of nerve endings, both excitatory and inhibitory, occur in animals. In a period of ten days, the cycle of loss of motor function is completed and functional recovery occurs.
The main finding of the work was to show that the inflammatory effect brings together Zika and Guillain-Barré syndromes. The difference is that, in the case of Zika, the mechanisms that lead to synaptic loss are not known in detail, while in Guillain-Barré syndrome it is known that the production of autoantibodies that have specific targets occurs, such as gangliosides, which are lipids that are part of the membranes of neurons and the myelin sheath, resulting in demyelination of nerve roots, impairing the conduction of nerve impulses. Something similar happens in the case of Zika, as it was experimentally found, through electrophysiological analyses, that it reduced the conduction speed of neuron axons.
In summary, the motor neuron that has a cell body in the central nervous system, in the spinal cord, is made up of an extension that is the axon, which goes to the muscle and carries information to it. When receiving stimulation from pre-synaptic neurons, motor neurons generate an action potential (nerve impulse) that travels along the axon to the muscle. For this stimulus to proceed at the expected speed, the axon has an electrical insulation made up of the so-called myelin sheath, which is nothing more than a lipid insulator that causes the electrical stimulus to travel through the axon at a high speed. With damage to this sheath, conduction speed drops and affects the efficiency of muscle contraction. In Guillain-Barré syndrome exactly this occurs: part of myelin is attacked by the immune system and therefore the speed of nerve impulse conduction drops, resulting in impaired muscle contraction, loss of muscle strength and even paralysis.
Different, but similar
“In Zika infection, in addition to synaptic loss, there is also a loss of nerve conduction in this initial region of the nerve, which is compatible with what is seen in Guillain-Barré syndrome, explains Oliveira. So, according to the researcher, there is a conjunction of factors that occur both in the body of the motor neuron and in the circuits in which it is integrated, which determine clinical effects, including the possibility of paralysis.
Although there is similarity between the events related to Guillain-Barré and Zika syndromes, one arises from an autoimmune response and the other from an infection. In one case, antibodies are produced that attack the body's own structures, unlike the immune system, which has the function of attacking pathogens foreign to the body. In the other case, the problem results from the action of the infection attacking motor neurons. These are supposedly different diseases, although very similar, to the point that the authors of the research proposed the use of the animal model they used to better understand Guillain-Barré disease because, in some aspects, the mechanism of evolution is very similar. In the case of Zika, researchers focused on the transformations that occurred and not on the mechanism resulting from the infection. In other words, they established the correlation between the morphological transformations and the animal's clinical signs, without considering the occurrences from a molecular point of view.
