Analysis of ALS-related proteins during herpes simplex virus-2 latent infection

Abstract

Background Genetics 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. Methods We 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. Results In 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. Conclusions Latent 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.

C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age

“…By contrast, the risk haplotype was found to be associated with slightly higher expression of C9orf72 transcript variants 1 and 3 and lower expression of transcript variant 2 [25] and induced pluripotent stem cells edited with intermediate HREs and differentiated into neural progenitor cells showed an increase in transcript variant 3 and protein levels [10]. As stated above, C9orf72 protein expression is down-modulated by HSV-2 infection [38] while a cell type-dependent regulation of its levels via the ubiquitin-proteasome system and autophagy has been recently suggested [35]. Given the role of C9orf72 in TLR and type I IFN pathways [30,31], it is tempting to speculate that intermediate repeats, likely through gene expression modulation, may influence host response to infection with SARS-CoV-2 and perhaps further viruses.…”

“…We can hypothesize that harboring intermediate HREs in C9orf72 could contribute to negatively balancing the host innate immune response to SARS-Cov-2 infection leading to a more severe disease. A limit of our study is that we did not measure C9orf72 mRNA expression in patients' peripheral blood cells, however we thought that gene expression could be influenced not only by harboring intermediate repeats >10 units, as described above [10,25,34], but also by the clinical state, as suggested for HSV-2 infection [38], making it hard to discriminate between the two conditions. COVID-19 patients of the first cohort were enrolled after discharge, however they had been severe COVID-19 hospitalized patients (38.3% of them received MV or NIV) and most of them at the time of the recruitment in this study, during the follow-up, were still showing some signs of severe COVID-19.…”

“…Accumulating evidence supports the role of C9orf72 in regulating vesicle trafficking [15,18,52,53] and lysosomal degradation of inflammatory mediators, including TLRs and STING, leading to their prolonged inflammatory signaling [30,31]. Interestingly, the environment, especially variation in gut microorganisms, seems to directly influence the pathological phenotype of C9orf72 −/− mice [37] and HSV-2 latent infection in the spinal cord of mice results in altered microglia and leucocyte infiltration accompanied by a decrease in C9orf72 protein levels [38]. C9orf72 interacts with different Rab GTPases and might affect autophagy at many steps and through the regulation of mammalian target of rapamycin Complex 1 (mTORC1) [13].…”

“…We hypothesized that this effect may also reflect in host immune response to infections and that harboring C9orf72 HREs of intermediate length may then modulate this response. It has been recently found that gut microbiota may influence the autoinflammatory phenotype of C9orf72 −/− mice [37] and that Herpes Simplex Virus-2 (HSV-2) infection in spinal cord of mice results in the decrease of C9orf72 protein [38]. Apart from the above observations and the described role of C9orf72 in regulating TLR and type I IFN signaling in mice, there is no evidence of an involvement of the gene in host response to infectious diseases in humans.…”

The Influence of Virus Infection on Microglia and Accelerated Brain Aging

“…Influenza virus: [ 176 , 177 , 178 , 206 , 207 ]. Human herpes viruses: [ 179 , 187 , 188 , 189 , 208 , 209 , 210 , 211 , 212 , 213 ].…”