bims-mevinf 2024-02-18 papers

Issue of 2024‒02‒18
six papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

FEBS Lett. 2024 Feb 13.

Intracellular pathogens rely on host metabolic networks for multiplication. Enveloped viruses need lipids for formation of the viral envelope and positive sense RNA viruses that replicate in membranous inclusions require lipids for formation of the replication compartments. In addition, all intracellular pathogens need energy for their replicative cycle. As triglycerides in lipid droplets are the main energy storage unit of cells and major source of membrane lipids, it is not surprising that viruses have evolved various strategies to exploit different aspects of lipid droplet biology.

Keywords: assembly; lipid droplet; metabolism; replication organelles; viruses

DOI: https://doi.org/10.1002/1873-3468.14819

J Chem Ecol. 2024 Feb 14.

Viral Infection Induces Changes to the Metabolome, Immune Response and Development of a Generalist Insect Herbivore.

Marilia Elias Gallon, Nadya Dougherty Muchoney, Angela Marie Smilanich.

Host plant consumption and pathogen infection commonly influence insect traits related to development and immunity, which are ultimately reflected in the behavior and physiology of the insect. Herein, we explored changes in the metabolome of a generalist insect herbivore, Vanessa cardui (Lepidoptera: Nymphalidae), in response to both dietary variation and pathogen infection in order to gain insight into tritrophic interactions for insect metabolism and immunity. Caterpillars were reared on two different host plants, Plantago lanceolata (Plantaginaceae) and Taraxacum officinale (Asteraceae) and subjected to a viral infection by Junonia coenia densovirus (JcDV), along with assays to determine the insect immune response and development. Richness and diversity of plant and caterpillar metabolites were evaluated using a liquid chromatography-mass spectrometry approach and showed that viral infection induced changes to the chemical content of V. cardui hemolymph and frass dependent upon host plant consumption. Overall, the immune response as measured by phenoloxidase (PO) enzymatic activity was higher in individuals feeding on P. lanceolata compared with those feeding on T. officinale. Additionally, infection with JcDV caused suppression of PO activity, which was not host plant dependent. We conclude that viral infection combined with host plant consumption creates a unique chemical environment, particularly within the insect hemolymph. Whether and how these metabolites contribute to defense against viral infection is an open question in chemical ecology.

Keywords: Chemical diversity; Junonia coenia densovirus; LC-MS; Plantago lanceolata; Taraxacum officinale; Vanessa cardui

DOI: https://doi.org/10.1007/s10886-024-01472-3

Front Cell Infect Microbiol. 2024 ;14 1349221

The host mannose-6-phosphate pathway and viral infection.

Qincheng Liu, Weiqi Wang, Liwei Xu, Qisheng Zhang, Hongna Wang.

Viruses, despite their simple structural composition, engage in intricate and complex interactions with their hosts due to their parasitic nature. A notable demonstration of viral behavior lies in their exploitation of lysosomes, specialized organelles responsible for the breakdown of biomolecules and clearance of foreign substances, to bolster their own replication. The man-nose-6-phosphate (M6P) pathway, crucial for facilitating the proper transport of hydrolases into lysosomes and promoting lysosome maturation, is frequently exploited for viral manipulation in support of replication. Recently, the discovery of lysosomal enzyme trafficking factor (LYSET) as a pivotal regulator within the lysosomal M6P pathway has introduced a fresh perspective on the intricate interplay between viral entry and host factors. This groundbreaking revelation illuminates unexplored dimensions of these interactions. In this review, we endeavor to provide a thorough overview of the M6P pathway and its intricate interplay with viral factors during infection. By consolidating the current understanding in this field, our objective is to establish a valuable reference for the development of antiviral drugs that selectively target the M6P pathway.

Keywords: GNPT; LYSET; M6P; M6PR; cathepsin; infectious diseases; lysosome; virus

DOI: https://doi.org/10.3389/fcimb.2024.1349221

Nat Commun. 2024 Feb 16. 15(1): 1442

Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus.

Quanyuan Wan, Leah Tavakoli, Ting-Yu Wang, Andrew J Tucker, Ruiting Zhou, Qizhi Liu, Shu Feng, Dongwon Choi, Zhiheng He, Michaela U Gack, Jun Zhao.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and multiple types of B cell malignancies. Emerging evidence demonstrates that KSHV reprograms host-cell central carbon metabolic pathways, which contributes to viral persistence and tumorigenesis. However, the mechanisms underlying KSHV-mediated metabolic reprogramming remain poorly understood. Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) is a key enzyme of the de novo pyrimidine synthesis, and was recently identified to deamidate the NF-κB subunit RelA to promote aerobic glycolysis and cell proliferation. Here we report that KSHV infection exploits CAD for nucleotide synthesis and glycolysis. Mechanistically, KSHV vCyclin binds to and hijacks cyclin-dependent kinase CDK6 to phosphorylate Ser-1900 on CAD, thereby activating CAD-mediated pyrimidine synthesis and RelA-deamidation-mediated glycolytic reprogramming. Correspondingly, genetic depletion or pharmacological inhibition of CDK6 and CAD potently impeded KSHV lytic replication and thwarted tumorigenesis of primary effusion lymphoma (PEL) cells in vitro and in vivo. Altogether, our work defines a viral metabolic reprogramming mechanism underpinning KSHV oncogenesis, which may spur the development of new strategies to treat KSHV-associated malignancies and other diseases.

DOI: https://doi.org/10.1038/s41467-024-45852-5

Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2315653121

Monkeypox virus infection of human astrocytes causes gasdermin B cleavage and pyroptosis.

Hajar Miranzadeh Mahabadi, Y C James Lin, Natacha S Ogando, Eman W Moussa, Nazanin Mohammadzadeh, Oliver Julien, Neal M Alto, Ryan S Noyce, David H Evans, Christopher Power.

Monkeypox virus (MPXV) infections in humans cause neurological disorders while studies of MPXV-infected animals indicate that the virus penetrates the brain. Pyroptosis is an inflammatory type of regulated cell death, resulting from plasma membrane rupture (PMR) due to oligomerization of cleaved gasdermins to cause membrane pore formation. Herein, we investigated the human neural cell tropism of MPXV compared to another orthopoxvirus, vaccinia virus (VACV), as well as its effects on immune responses and cell death. Astrocytes were most permissive to MPXV (and VACV) infections, followed by microglia and oligodendrocytes, with minimal infection of neurons based on plaque assays. Aberrant morphological changes were evident in MPXV-infected astrocytes that were accompanied with viral protein (I3) immunolabelling and detection of over 125 MPXV-encoded proteins in cell lysates by mass spectrometry. MPXV- and VACV-infected astrocytes showed increased expression of immune gene transcripts (IL12, IRF3, IL1B, TNFA, CASP1, and GSDMB). However, MPXV infection of astrocytes specifically induced proteolytic cleavage of gasdermin B (GSDMB) (50 kDa), evident by the appearance of cleaved N-terminal-GSDMB (30 kDa) and C-terminal- GSDMB (18 kDa) fragments. GSDMB cleavage was associated with release of lactate dehydrogenase and increased cellular nucleic acid staining, indicative of PMR. Pre-treatment with dimethyl fumarate reduced cleavage of GSDMB and associated PMR in MPXV-infected astrocytes. Human astrocytes support productive MPXV infection, resulting in inflammatory gene induction with accompanying GSDMB-mediated pyroptosis. These findings clarify the recently recognized neuropathogenic effects of MPXV in humans while also offering potential therapeutic options.

Keywords: Monkeypox virus; dimethyl fumarate; gasdermin B; neurotropism; neurovirulence

DOI: https://doi.org/10.1073/pnas.2315653121

Autophagy. 2024 Feb 15. 1-3

The role of SARS-CoV-2 ORF7a in autophagy flux disruption: implications for viral infection and pathogenesis.

Shun Li, Hao Zhang, Weichen Li, Jingbo Zhai, Xiaobo Li, Chunfu Zheng.

Although alterations in the autophagy-lysosome pathway have been observed in the SARS-CoV-2 infection and invasion process since the outbreak of the coronavirus disease in 2019, the in-depth mechanism of autophagic and lysosomal reprogramming by SARS-CoV-2 has yet to be well identified. Our recent study unveiled a pivotal role played by the open reading frame 7a (ORF7a) protein in the SARS-CoV-2 genome, particularly in the modulation of macroautophagy/autophagy flux and function during viral infection and pathogenesis. Our study elucidated the underlying molecular mechanisms by which SARS-CoV-2 ORF7a intercepts autophagic flux, evades host autophagy-lysosome degradation, and accelerates viral infection and progeny germination. Furthermore, our study highlights that ORF7a can be a therapeutic target, and glecaprevir may hold potential as a drug against SARS-CoV-2 by targeting ORF7a. The key observations revealed in this study also contribute to a growing understanding of the function of SARS-CoV-2 ORF7a and the mechanisms underlying COVID-2019 treatment.

Keywords: Autophagy; COVID-19; ORF7a; SARS-CoV-2; lysosome

DOI: https://doi.org/10.1080/15548627.2024.2312787