Abstract
BackgroundGenetics have provided hints on potential molecular pathways involved in neurodegenerative diseases (NDD). However, the number of cases caused exclusively by genetic alterations is low, suggesting an important contribution of environmental factors to NDDs. Among these factors, viruses like herpes simplex viruses (HSV-2), capable of establishing lifelong infections within the nervous system (NS), are being proposed to have a role in NDDs. Despite promising data, there is a significant lack of knowledge on this and an urgent need for more research.MethodsWe have set up a mouse model to study HSV latency and its associated neuroinflammation in the spinal cord. The goal of this model was to observe neuroinflammatory changes caused by HSV latent infections, and if those changes were similar to alterations observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients.ResultsIn infected spinal cords, we have observed a strong leukocyte infiltration and a severe alteration of microglia close to motor neurons. We have also analyzed ALS-related proteins: we have not found changes in TDP-43 and Fus in neurons, but interestingly, we have found decreased protein levels of C9orf72, of which coding gene is severely altered in some familial forms of ALS and is critical for microglia homeostasis.ConclusionsLatent infection of HSV in the spinal cord showed altered microglia and leukocyte infiltration. These inflammatory features resembled to those observed in the spinal cord of ALS patients. No changes mimicking ALS neuropathology, such as TDP-43 cytoplasmic inclusions, were found in infected spinal cords, but a decrease in protein levels of C9orf72 was observed. Then, further studies should be required to determine whether HSV-2 has a role in ALS.
Highlights
Genetics have provided hints on potential molecular pathways involved in neurodegenerative diseases (NDD)
Twentyfour DPI, more than 95% of infected mice survived and we considered that herpes simplex viruses (HSV)-2 has established latency
We stained spinal cord (SC) sections using HSV antibodies; usually, no viral antigens were detected in infected SCs, in rare occasions isolated cells appear to be positive for HSV, a phenomenon expected during latency [11, 12]
Summary
Genetics have provided hints on potential molecular pathways involved in neurodegenerative diseases (NDD). Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are members of the herpes virus family of DNA viruses They are extremely efficient human pathogens with symptoms that range from asymptomatic infections and Cabrera et al Journal of Neuroinflammation (2020) 17:371 cold/genital sores to severe neurological diseases when replicate within the NS [6, 7]. Once the nerve ending is infected, HSV particles are retrogradely transported to the cell body of the neuron. When HSV reach the neural cell body, viral DNA is released into the nucleus. During this process, neuronal antiviral response alerts the immune system (IS) and leukocytes get infiltrated into the NS [8, 9]. Latency is not a stationary state, and evidence suggest HSV DNA remains active during latency [11,12,13], forcing the IS to surveille constantly infected neurons, maintaining a persistent neuroinflammation [8, 9]
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