bims-mevinf 2023-06-25 papers

Crit Rev Microbiol. 2023 Jun 22. 1-25

Interplay between lipid metabolism, lipid droplets and RNA virus replication.

Mónica A Farías, Benjamín Diethelm-Varela, Alexis M Kalergis, Pablo A González.

Lipids play essential roles in the cell as components of cellular membranes, signaling molecules, and energy storage sources. Lipid droplets are cellular organelles composed of neutral lipids, such as triglycerides and cholesterol esters, and are also considered as cellular energy reserves, yet new functions have been recently associated with these structures, such as regulators of oxidative stress and cellular lipotoxicity, as well as modulators of pathogen infection through immune regulation. Lipid metabolism and lipid droplets participate in the infection process of many RNA viruses and control their replication and assembly, among others. Here, we review and discuss the contribution of lipid metabolism and lipid droplets over the replication cycle of RNA viruses, altogether pointing out potentially new pharmacological antiviral targets associated with lipid metabolism.

Keywords: RNA virus infections; lipid droplets; lipid metabolism; neutral lipids

DOI: https://doi.org/10.1080/1040841X.2023.2224424

Int Immunopharmacol. 2023 Jun 19. pii: S1567-5769(23)00835-4. [Epub ahead of print]121 110512

Metformin restrains ZIKV replication and alleviates virus-induced inflammatory responses in microglia.

Xiaofang Wang, Hui Wang, Panpan Yi, Coleman Baker, Gonzales Casey, Xuping Xie, Huanle Luo, Jiyang Cai, Xuegong Fan, Lynn Soong, Haitao Hu, Pei-Yong Shi, Yuejin Liang, Jiaren Sun.

The re-emergence of Zika virus (ZIKV) remains a major public health threat that has raised worldwide attention. Accumulating evidence suggests that ZIKV can cause serious pathological changes to the human nervous system, including microcephaly in newborns. Recent studies suggest that metformin, an established treatment for diabetes may play a role in viral infection; however, little is known about the interactions between ZIKV infection and metformin administration. Using fluorescent ZIKV by flow cytometry and immunofluorescence imaging, we found that ZIKV can infect microglia in a dose-dependent manner. Metformin diminished ZIKV replication without the alteration of viral entry and phagocytosis. Our study demonstrated that metformin downregulated ZIKV-induced inflammatory response in microglia in a time- and dose-dependent manner. Our RNA-Seq and qRT-PCR analysis found that type I and III interferons (IFN), such as IFNα2, IFNβ1 and IFNλ3 were upregulated in ZIKV-infected cells by metformin treatment, accompanied with the downregulation of GBP4, OAS1, MX1 and ISG15. Together, our results suggest that metformin-mediated modulation in multiple pathways may attribute to restraining ZIKV infection in microglia, which may provide a potential tool to consider for use in unique clinical circumstances.

Keywords: Inflammation; Interferon; Metformin; Microglia; Viral infection; ZIKV

DOI: https://doi.org/10.1016/j.intimp.2023.110512

J Cell Biochem. 2023 Jun 19.

Zika virus: Critical crosstalk between pathogenesis, cytopathic effects, and macroautophagy.

Lucas Coêlho Bernardo-Menezes, Almerinda Agrelli, Ana Sofia Lima Estevão de Oliveira, Elisa de Almeida Neves Azevedo, Clarice Neuenschwander Lins de Morais.

Zika virus (ZIKV) is a re-emerging positive-sense RNA arbovirus. Its genome encodes a polyprotein that is cleaved by proteases into three structural proteins (Envelope, pre-Membrane, and Capsid) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). These proteins have essential functions in viral replication cycle, cytopathic effects, and host cellular response. When infected by ZIKV, host cells promote macroautophagy, which is believed to favor virus entry. Although several authors have attempted to understand this link between macroautophagy and viral infection, little is known. Herein, we performed a narrative review of the molecular connection between macroautophagy and ZIKV infection while focusing on the roles of the structural and nonstructural proteins. We concluded that ZIKV proteins are major virulence factors that modulate host-cell machinery to its advantage by disrupting and/or blocking specific cellular systems and organelles' function, such as endoplasmic reticulum stress and mitochondrial dysfunction.

Keywords: cytopathic effects; endoplasmic reticulum stress; host cellular response; replication cycle; virulence factors

DOI: https://doi.org/10.1002/jcb.30438

J Virol. 2023 Jun 20. e0018023

The Early Secretory Pathway Is Crucial for Multiple Aspects of the Hepatitis C Virus Life Cycle.

Kiran Avula, Bharati Singh, Subhashish Samantaray, Gulam Hussain Syed.

Although most of the early events of the hepatitis C virus (HCV) life cycle are well characterized, our understanding of HCV egress is still unclear. Some reports implicate the conventional endoplasmic reticulum (ER)-Golgi route, while some propose noncanonical secretory routes. Initially, the envelopment of HCV nucleocapsid occurs by budding into the ER lumen. Subsequently, the HCV particle exit from the ER is assumed to be mediated by coat protein complex II (COPII) vesicles. COPII vesicle biogenesis also involves the recruitment of cargo to the site of vesicle biogenesis via interaction with COPII inner coat proteins. We investigated the modulation and the specific role of the individual components of the early secretory pathway in HCV egress. We observed that HCV inhibits cellular protein secretion and triggers the reorganization of the ER exit sites and ER-Golgi intermediate compartments (ERGIC). Gene-specific knockdown of the components of this pathway such as SEC16A, TFG, ERGIC-53, and COPII coat proteins demonstrated the functional significance of these components and the distinct role played by these proteins in various aspects of the HCV life cycle. SEC16A is essential for multiple steps in the HCV life cycle, whereas TFG is specifically involved in HCV egress and ERGIC-53 is crucial for HCV entry. Overall, our study establishes that the components of the early secretory pathway are essential for HCV propagation and emphasize the importance of the ER-Golgi secretory route in this process. Surprisingly, these components are also required for the early stages of the HCV life cycle due to their role in overall intracellular trafficking and homeostasis of the cellular endomembrane system. IMPORTANCE The virus life cycle involves entry into the host, replication of the genome, assembly of infectious progeny, and their subsequent release. Different aspects of the HCV life cycle, including entry, genome replication, and assembly, are well characterized; however, our understanding of the HCV release is still not clear and subject to debate due to varied findings. Here, we attempted to address this controversy and enhance our understanding of HCV egress by evaluating the role of the different components of the early secretory pathway in the HCV life cycle. To our surprise, we found that the components of the early secretory pathway are not only essential for HCV release but also contribute to many other earlier events of the HCV life cycle. This study emphasizes the importance of the early secretory pathway for the establishment of productive HCV infection in hepatocytes.

Keywords: COPII vesicle; ERGIC-53; HCV entry; HCV secretion; SEC16A; TFG; TRK-fused gene; early secretory pathway; endoplasmic reticulum exit sites; hepatitis C virus

DOI: https://doi.org/10.1128/jvi.00180-23

Trends Mol Med. 2023 Jun 07. pii: S1471-4914(23)00115-6. [Epub ahead of print]

SARS-CoV-2 targets the liver and manipulates glucose metabolism.

Carlos J Pirola, Silvia Sookoian.

A recent publication by Barreto and colleagues showed that SARS-CoV-2 directly triggers hyperglycemia by infecting hepatocytes and inducing phosphoenolpyruvate carboxykinase (PEPCK)-dependent gluconeogenesis. Here, we discuss the biological importance of these findings, including the hepatic tropism of SARS-CoV-2. We also comment on the clinical implications of the bidirectional connection between COVID-19 and noncommunicable diseases.

Keywords: SARS-CoV-2; glucose metabolism; liver

DOI: https://doi.org/10.1016/j.molmed.2023.06.001