bims-mevinf 2023-02-19 papers

J Virol. 2023 Feb 16. e0001623

Newcastle Disease Virus Manipulates Mitochondrial MTHFD2-Mediated Nucleotide Metabolism for Virus Replication.

Ning Tang, Pingyi Chen, Changrun Zhao, Panrao Liu, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Xiufan Liu, Tingrong Luo, Yingjie Sun, Chan Ding.

Viruses require host cell metabolic reprogramming to satisfy their replication demands; however, the mechanism by which the Newcastle disease virus (NDV) remodels nucleotide metabolism to support self-replication remains unknown. In this study, we demonstrate that NDV relies on the oxidative pentose phosphate pathway (oxPPP) and the folate-mediated one-carbon metabolic pathway to support replication. In concert with [1,2-13C2] glucose metabolic flow, NDV used oxPPP to promote pentose phosphate synthesis and to increase antioxidant NADPH production. Metabolic flux experiments using [2,3,3-2H] serine revealed that NDV increased one-carbon (1C) unit synthesis flux through the mitochondrial 1C pathway. Interestingly, methylenetetrahydrofolate dehydrogenase (MTHFD2) was upregulated as a compensatory mechanism for insufficient serine availability. Unexpectedly, direct knockdown of enzymes in the one-carbon metabolic pathway, except for cytosolic MTHFD1, significantly inhibited NDV replication. Specific complementation rescue experiments on small interfering RNA (siRNA)-mediated knockdown further revealed that only a knockdown of MTHFD2 strongly restrained NDV replication and was rescued by formate and extracellular nucleotides. These findings indicated that NDV replication relies on MTHFD2 to maintain nucleotide availability. Notably, nuclear MTHFD2 expression was increased during NDV infection and could represent a pathway by which NDV steals nucleotides from the nucleus. Collectively, these data reveal that NDV replication is regulated by the c-Myc-mediated 1C metabolic pathway and that the mechanism of nucleotide synthesis for viral replication is regulated by MTHFD2. IMPORTANCE Newcastle disease virus (NDV) is a dominant vector for vaccine and gene therapy that accommodates foreign genes well but can only infect mammalian cells that have undergone cancerous transformation. Understanding the remodeling of nucleotide metabolic pathways in host cells by NDV proliferation provides a new perspective for the precise use of NDV as a vector or in antiviral research. In this study, we demonstrated that NDV replication is strictly dependent on pathways involved in redox homeostasis in the nucleotide synthesis pathway, including the oxPPP and the mitochondrial one-carbon pathway. Further investigation revealed the potential involvement of NDV replication-dependent nucleotide availability in promoting MTHFD2 nuclear localization. Our findings highlight the differential dependence of NDV on enzymes for one-carbon metabolism, and the unique mechanism of action of MTHFD2 in viral replication, thereby providing a novel target for antiviral or oncolytic virus therapy.

Keywords: MTHFD2; Newcastle disease virus; c-Myc; mitochondrial 1C metabolism; oxPPP

DOI: https://doi.org/10.1128/jvi.00016-23

J Cell Physiol. 2023 Feb 15.

Targeting first trimester trophoblast cell metabolism modulates its susceptibility to Zika virus infection.

Diego Kafer, Agostina Marquez, Fátima Merech, Vanesa Hauk, Daniel Paparini, Rosanna Ramhorst, Claudia Pérez Leirós, Cybele Garcia, Daiana Vota.

In the last 15 years Zika virus (ZIKV) caused several outbreaks of increasing scale in Micronesia, South Pacific islands, and more recently in the Caribbean and South America. The severity of the clinical presentation in neonates from pregnant women infected with ZIKV during the last outbreak supports the relevance of unraveling the mechanism of infection and viral persistence in the placenta with local viral isolates. Here, we investigated the relevance of trophoblast metabolic rewiring for viral multiplication and the role of the vasoactive intestinal peptide (VIP) as an endogenous factor associated with placental restriction to ZIKV infection at early pregnancy. Our in vitro model demonstrated that ZIKV triggers metabolic rewiring in first trimester cytotrophoblast-derived cells by increasing glucose utilization as fuel to sustain its replication, decreasing long-chain polyunsaturated fatty acid uptake, and promoting lipid droplets accumulation to favor its multiplication. Of note, variations in nutrient availability modulated viral spread in trophoblast cultures. The presence of VIP during trophoblast infection impaired ZIKV infective particle production and viral replication, restoring cell migration and metabolism. Moreover, the blockade of endogenous VIP signaling increased viral particle production and the viral entry receptor AXL expression. These results highlight the potential role of VIP as an endogenous antiviral factor related to trophoblast cell permissiveness to ZIKV infection at early pregnancy.

Keywords: Zika virus; metabolism; placenta; trophoblast; vasoactive intestinal peptide

DOI: https://doi.org/10.1002/jcp.30970

bioRxiv. 2023 Jan 30. pii: 2023.01.29.526157. [Epub ahead of print]

Influenza A virus modulation of Streptococcus pneumoniae infection using ex vivo transcriptomics in a human primary lung epithelial cell model reveals differential host glycoconjugate uptake and metabolism.

Adonis D'Mello, Jessica R Lane, Jennifer L Tipper, Eriel Martínez, Holly N Roussey, Kevin S Harrod, Carlos J Orihuela, Hervé Tettelin.

Background: Streptococcus pneumoniae (Spn) is typically an asymptomatic colonizer of the nasopharynx but it also causes pneumonia and disseminated disease affecting various host anatomical sites. Transition from colonization to invasive disease is not well understood. Studies have shown that such a transition can occur as result of influenza A virus coinfection.
Methods: We investigated the pneumococcal (serotype 19F, strain EF3030) and host transcriptomes with and without influenza A virus (A/California/07 2009 pH1N1) infection at this transition. This was done using primary, differentiated Human Bronchial Epithelial Cells (nHBEC) in a transwell monolayer model at an Air-Liquid Interface (ALI), with multispecies deep RNA-seq.
Results: Distinct pneumococcal gene expression profiles were observed in the presence and absence of influenza. Influenza coinfection allowed for significantly greater pneumococcal growth and triggered the differential expression of bacterial genes corresponding to multiple metabolic pathways; in totality suggesting a fundamentally altered bacterial metabolic state and greater nutrient availability when coinfecting with influenza. Surprisingly, nHBEC transcriptomes were only modestly perturbed by infection with EF3030 alone in comparison to that resulting from Influenza A infection or coinfection, which had drastic alterations in thousands of genes. Influenza infected host transcriptomes suggest significant loss of ciliary function in host nHBEC cells.
Conclusions: Influenza A virus infection of nHBEC promotes pneumococcal infection. One reason for this is an altered metabolic state by the bacterium, presumably due to host components made available as result of viral infection. Influenza infection had a far greater impact on the host response than did bacterial infection alone, and this included down regulation of genes involved in expressing cilia. We conclude that influenza infection promotes a pneumococcal metabolic shift allowing for transition from colonization to disseminated disease.
Author summary: Secondary Streptococcus pneumoniae bacterial infections typically occur after influenza A virus respiratory infection. Such coinfections often lead to invasive pneumococcal disease. The mechanisms involved in this process are not well understood. Here, using an ex vivo human lung bronchial epithelial cell model, we investigated the biological processes of the host and pneumococcus occurring at this niche, during coinfection with multi-species transcriptomics techniques, and in vivo mouse model experimentation. We observed stark differences in global pneumococcal metabolism in different infection states, as well as viral induced epithelial cell changes in ciliary function, potentially aiding pneumococcal dissemination. Overall, this study identified broad and targeted biological processes involved in this host-pathogen interaction.

DOI: https://doi.org/10.1101/2023.01.29.526157

Expert Rev Endocrinol Metab. 2023 Feb 16. 1-13

COVID-19 and diabetes mellitus: a review of the incidence, pathophysiology and management of diabetes during the pandemic.

Jordana Faruqi, Ashok Balasubramanyam.

INTRODUCTION: The COVID-19 pandemic has changed the landscape of modern medicine on a global scale. An emerging concern is the recognition of a bidirectional relationship between COVID-19 and diabetes. Diabetes is a risk factor for severe COVID-19 illness. Intriguingly, recent epidemiological and in vitro studies suggest that infection with SARS-CoV-2, the causative viral agent of COVID-19, is associated with new-onset diabetes and worsening diabetes control. These factors have affected the management of diabetes.
AREAS COVERED: This review provides an overview of our current understanding of the incidence and prevalence of diabetes in relation to the COVID-19 pandemic, highlights studies evaluating SARS-CoV-2's beta cell tropism and its effects on insulin secretion and sensitivity and evaluates the impact of the pandemic on diabetes management and metabolic control.
EXPERT OPINION: Epidemiological studies have noted an increase in the incidence of new-onset diabetes associated with COVID-19 in patients with phenotypes of type 1 diabetes, type 2 diabetes and Ketosis-Prone Diabetes. Prospective studies are needed to fully elucidate the association between COVID-19 and diabetes and to characterize persons at risk of developing diabetes after SARS-CoV-2 infection, identify those who should be screened for diabetes, and determine the natural histories of different forms of diabetes associated with COVID-19.

Keywords: COVID-19; DKA; Diabetes; Ketosis-Prone diabetes; SARS-CoV-2; glycemic control; insulin; telemedicine; type 1 diabetes; type 2 diabetes

DOI: https://doi.org/10.1080/17446651.2023.2176300