bims-mevinf 2023-11-26 papers

Issue of 2023‒11‒26
three papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Biomolecules. 2023 Oct 30. pii: 1597. [Epub ahead of print]13(11):

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

Indranil Basak, Rhodri Harfoot, Jennifer E Palmer, Abhishek Kumar, Miguel E Quiñones-Mateu, Lucia Schweitzer, Stephanie M Hughes.

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.

Keywords: COVID-19; NeuroCOVID; SARS-CoV-2; apoptosis; iPSC-derived human neurons and astrocytes; mass spectrometry; metabolism; neurodegeneration; proteomics

DOI: https://doi.org/10.3390/biom13111597

Virol J. 2023 Nov 21. 20(1): 270

Systemic perturbations in amino acids/amino acid derivatives and tryptophan pathway metabolites associated with murine influenza A virus infection.

Huda A M Al-Shalan, Lu Zhou, Zhifan Dong, Penghao Wang, Philip K Nicholls, Berin Boughton, Philip A Stumbles, Wayne K Greene, Bin Ma.

BACKGROUND: Influenza A virus (IAV) is the only influenza virus causing flu pandemics (i.e., global epidemics of flu disease). Influenza (the flu) is a highly contagious disease that can be deadly, especially in high-risk groups. Worldwide, these annual epidemics are estimated to result in about 3 to 5 million cases of severe illness and in about 290,000 to 650,000 respiratory deaths. We intend to reveal the effect of IAV infection on the host's metabolism, immune response, and neurotoxicity by using a mouse IAV infection model.METHODS: 51 metabolites of murine blood plasma (33 amino acids/amino acid derivatives (AADs) and 18 metabolites of the tryptophan pathway) were analyzed by using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry with Electrospray Ionization at the acute (7 days post-infection (dpi)), resolution (14 dpi), and recovery (21 dpi) stages of the virus infection in comparison with controls.
RESULTS: Among the 33 biogenic amino acids/AADs, the levels of five amino acids/AADs (1-methylhistidine, 5-oxoproline, α-aminobutyric acid, glutamine, and taurine) increased by 7 dpi, whereas the levels of ten amino acids/AADs (4-hydroxyproline, alanine, arginine, asparagine, cysteine, citrulline, glycine, methionine, proline, and tyrosine) decreased. By 14 dpi, the levels of one AAD (3-methylhistidine) increased, whereas the levels of five amino acids/AADs (α-aminobutyric acid, aminoadipic acid, methionine, threonine, valine) decreased. Among the 18 metabolites from the tryptophan pathway, the levels of kynurenine, quinolinic acid, hydroxykynurenine increased by 7 dpi, whereas the levels of indole-3-acetic acid and nicotinamide riboside decreased.
CONCLUSIONS: Our data may facilitate understanding the molecular mechanisms of host responses to IAV infection and provide a basis for discovering potential new mechanistic, diagnostic, and prognostic biomarkers and therapeutic targets for IAV infection.

Keywords: Amino acids; Immunometabolism; Infection; Influenza; Influenza A virus; Metabolites; Neurotoxicity; Tryptophan pathway

DOI: https://doi.org/10.1186/s12985-023-02239-0

FEBS Lett. 2023 Nov 20.

HIV-1 replication requires optimal activation of the unfolded protein response.

Anjali Tripathi, Kruthika Iyer, Debashis Mitra.

Several human diseases including viral infections activate the unfolded protein response (UPR) due to abnormal accumulation of unfolded/misfolded proteins. However, UPR modulation and its functional relevance in HIV-1 infection lack comprehensive elucidation. This study reveals that HIV-1 activates IRE1, PERK, and ATF6 signaling pathways of UPR. The knockdown of PERK and ATF6 reduces HIV-1 long terminal repeat (LTR)-driven gene expression, whereas the endoplasmic reticulum (ER) chaperone HSPA5 prevents proteasomal degradation of HIV-1 p24 through its chaperone activity. Interestingly, overstimulation of UPR by a chemical inducer leads to anti-HIV activity through an enhanced type-1 interferon response. Also, treatment with a chemical ER stress inhibitor reduces HIV-1 replication. These findings suggest that an optimal UPR activation is crucial for effective viral replication, as either overstimulating UPR or inhibiting ER stress leads to viral suppression.

Keywords: ATF6; ER stress; HIV-1; HSPA5; PERK; unfolded protein response

DOI: https://doi.org/10.1002/1873-3468.14772