The continued pressure of COVID-19 on public health worldwide underlines the need for a better understanding of the mechanisms of disease caused by severe acute respiratory syndrome coronavirus-2. Though many animal models are readily available for use, the nonhuman primate (NHP) models are considered the gold standard in recapitulating disease progression in humans. In this review, we highlight the relevant research since the beginning of the pandemic to critically evaluate the importance of this model. We characterize the disease's clinical manifestations, aspects of viral replication and shedding, induction of the host's immune response, and pathological findings that broaden our understanding of the importance of NHPs in research to strengthen our public health approach to the pandemic. 

Pathogenesis of severe acute respiratory syndrome coronavirus-2 in nonhuman primates.

Besides respiratory illness, SARS-CoV-2, the causative agent of COVID-19, leads to neurological symptoms. The molecular mechanisms leading to neuropathology after SARS-CoV-2 infection are sparsely explored. SARS-CoV-2 enters human cells via different receptors, including ACE-2, TMPRSS2, and TMEM106B. In this study, we used a human-induced pluripotent stem cell-derived neuronal model, which expresses ACE-2, TMPRSS2, TMEM106B, and other possible SARS-CoV-2 receptors, to evaluate its susceptibility to SARS-CoV-2 infection. The neurons were exposed to SARS-CoV-2, followed by RT-qPCR, immunocytochemistry, and proteomic analyses of the infected neurons. Our findings showed that SARS-CoV-2 infects neurons at a lower rate than other human cells; however, the virus could not replicate or produce infectious virions in this neuronal model. Despite the aborted SARS-CoV-2 replication, the infected neuronal nuclei showed irregular morphology compared to other human cells. Since cytokine storm is a significant effect of SARS-CoV-2 infection in COVID-19 patients, in addition to the direct neuronal infection, the neurons were treated with pre-conditioned media from SARS-CoV-2-infected lung cells, and the neuroproteomic changes were investigated. The limited SARS-CoV-2 infection in the neurons and the neurons treated with the pre-conditioned media showed changes in the neuroproteomic profile, particularly affecting mitochondrial proteins and apoptotic and metabolic pathways, which may lead to the development of neurological complications. The findings from our study uncover a possible mechanism behind SARS-CoV-2-mediated neuropathology that might contribute to the lingering effects of the virus on the human brain.

Neuroproteomic Analysis after SARS-CoV-2 Infection Reveals Overrepresented Neurodegeneration Pathways and Disrupted Metabolic Pathways

Additional file 1: Figure S1. Three brains, sham, 1 and 7 days post-TBI were stained with Nissl and hematoxylin and eosin (H &amp; E) stain to show the morphological damage to the cortex of TBI as compared to sham. Figure S2. A. Comparison was showed between different sample processing strategy and MS acquisition methods. Of all the methods, sample processing with trifluroethanol followed by FAIMS CV voltage of -50 and stepped collision energy yielded the maximum number of proteins. B. The same protocol yielded a corresponding peptide number of 5000 with the individual samples peptide number ranging between 6000–8000. C. Venn diagram depicts the improvement in protein yield with CV 50 as compared to CV 35 and D. using stepped and fixed collision energies. Figure S3. A. Microdissection by LCM yielded approximately a cut of 40,000 um2 in PL, which was reduced to almost half in post TBI samples. On the contrary, area sections stayed consistent in rest of the sub- regions. B. The Pyramidal layer shows shrinkage on 1 and 7 days post-TBI. Figure S4. Clustering of stimulation time expression patterns in identified proteins from (A) DG1, (B) DG2, (C) SM1 and (D) PL subregions with 9 kinds of rising or falling patterns using the fuzzy c-means algorithm. Warm and cold colors indicate low and high deviation from the consensus profile, respectively. Figure S5. Immunofluorescence was performed by using CD44 and GFAP antibody on mice brain sections belonging to Sham, and 1-day post-TBI and 7-day post-TBI groups. CD44 showed significant upregulation at day 7 for all sub-regions except SM which also showed upregulation in day 1. This observation was also supported by our proteomics results from different sub-regions at different time-points. We observed similar correspondence between the proteomics and the IHC dataset of GFAP which showed prominent expression on day-7 as compared to day-1 and sham. ns – not significant; * p &lt; 0.05. 

Additional file 1 of Mapping dynamic molecular changes in hippocampal subregions after traumatic brain injury through spatial proteomics

Abstract Background Traumatic brain injury (TBI) often results in diverse molecular responses, challenging traditional proteomic studies that measure average changes at tissue levels and fail to capture the complexity and heterogeneity of the affected tissues. Spatial proteomics offers a solution by providing insights into sub-region-specific alterations within tissues. This study focuses on the hippocampal sub-regions, analyzing proteomic expression profiles in mice at the acute (1 day) and subacute (7 days) phases of post-TBI to understand subregion-specific vulnerabilities and long-term consequences. Methods Three mice brains were collected from each group, including Sham, 1-day post-TBI and 7-day post-TBI. Hippocampal subregions were extracted using Laser Microdissection (LMD) and subsequently analyzed by label-free quantitative proteomics. Results The spatial analysis reveals region-specific protein abundance changes, highlighting the elevation of FN1, LGALS3BP, HP, and MUG-1 in the stratum moleculare (SM), suggesting potential immune cell enrichment post-TBI. Notably, established markers of chronic traumatic encephalopathy, IGHM and B2M, exhibit specific upregulation in the dentate gyrus bottom (DG2) independent of direct mechanical injury. Metabolic pathway analysis identifies disturbances in glucose and lipid metabolism, coupled with activated cholesterol synthesis pathways enriched in SM at 7-Day post-TBI and subsequently in deeper DG1 and DG2 suggesting a role in neurogenesis and the onset of recovery. Coordinated activation of neuroglia and microtubule dynamics in DG2 suggest recovery mechanisms in less affected regions. Cluster analysis revealed spatial variations post-TBI, indicative of dysregulated neuronal plasticity and neurogenesis and further predisposition to neurological disorders. TBI-induced protein upregulation (MUG-1, PZP, GFAP, TJP, STAT-1, and CD44) across hippocampal sub-regions indicates shared molecular responses and links to neurological disorders. Spatial variations were demonstrated by proteins dysregulated in both or either of the time-points exclusively in each subregion (ELAVL2, CLIC1 in PL, CD44 and MUG-1 in SM, and SHOC2, LGALS3 in DG). Conclusions Utilizing advanced spatial proteomics techniques, the study unveils the dynamic molecular responses in distinct hippocampal subregions post-TBI. It uncovers region-specific vulnerabilities and dysregulated neuronal processes, and potential recovery-related pathways that contribute to our understanding of TBI’s neurological consequences and provides valuable insights for biomarker discovery and therapeutic targets. 

Mapping dynamic molecular changes in hippocampal subregions after traumatic brain injury through spatial proteomics.

pdf/the-compounding-roles-of-gut-immune-brain-axis-and-covid19-6bvsvz35ekxd.pdf

The compounding roles of gut-immune-brain axis and COVID19 in manifestation of idiopathic Parkinson’s disease

https://doi.org/10.1016/j.mcpro.2023.100523

Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates

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Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates