International Journal of Molecular Sciences

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18 pages, 3135 KiB

Open AccessArticle

Sustained Microglial Activation Promotes Synaptic Loss and Neuronal Dysfunction after Recovery from ZIKV Infection

by Nahyun Kim, Hanul Choi, Uijin Kim, Suyeon Kim, Young Bong Kim and Ha Youn Shin

Int. J. Mol. Sci. 2024, 25(17), 9451; https://doi.org/10.3390/ijms25179451 - 30 Aug 2024

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Abstract

Zika virus (ZIKV), transmitted by Aedes mosquitoes, has been a global health concern since 2007. It primarily causes fetal microcephaly and neuronal defects through maternal transmission and induces neurological complications in adults. Recent studies report elevated proinflammatory cytokines and persistent neurological alterations post [...] Read more.

Zika virus (ZIKV), transmitted by Aedes mosquitoes, has been a global health concern since 2007. It primarily causes fetal microcephaly and neuronal defects through maternal transmission and induces neurological complications in adults. Recent studies report elevated proinflammatory cytokines and persistent neurological alterations post recovery, but the in vivo mechanisms remain unclear. In our study, viral RNA loads in the brains of mice infected with ZIKV peaked at 7 days post infection and returned to baseline by day 21, indicating recovery. RNA sequencing of the cerebral cortex at 7 and 21 days revealed upregulated genes related to neuroinflammation and microglial activation. Histological analyses indicated neuronal cell death and altered neurite morphology owing to severe neuroinflammation. Additionally, sustained microglial activation was associated with increased phospho-Tau levels, constituting a marker of neurodegeneration. These findings highlight how persistent microglial activation leads to neuronal dysfunction post ZIKV recovery, providing insights into the molecular pathogenesis of ZIKV-induced brain abnormalities. Full article

(This article belongs to the Special Issue Virus Infection and Infectious Diseases: Unraveling Mechanisms, Innovations, and Therapeutic Strategies)

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19 pages, 6280 KiB

Open AccessArticle

Shedding Light on Viral Shedding: Novel Insights into Nuclear Assembly, Cytoplasmic Transformation and Extracellular Vesicle Release of the BK Virus

by Daniela Gerges, Karim Abd El-Ghany, Zsofia Hevesi, Monika Aiad, Haris Omic, Clemens Baumgartner, Wolfgang Winnicki, Michael Eder, Alice Schmidt, Farsad Eskandary and Ludwig Wagner

Int. J. Mol. Sci. 2024, 25(16), 9130; https://doi.org/10.3390/ijms25169130 - 22 Aug 2024

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Abstract

Despite the high prevalence of BK polyomavirus (BKPyV) and the associated risk for BKPyV-associated nephropathy (BKPyVAN) in kidney transplant (KTX) recipients, many details on viral processes such as replication, maturation, assembly and virion release from host cells have not been fully elucidated. VP1 [...] Read more.

Despite the high prevalence of BK polyomavirus (BKPyV) and the associated risk for BKPyV-associated nephropathy (BKPyVAN) in kidney transplant (KTX) recipients, many details on viral processes such as replication, maturation, assembly and virion release from host cells have not been fully elucidated. VP1 is a polyomavirus-specific protein that is expressed in the late phase of its replicative cycle with important functions in virion assembly and infectious particle release. This study investigated the localization and time-dependent changes in the distribution of VP1-positive viral particles and their association within the spectrum of differing cell morphologies that are observed in the urine of KTX patients upon active BKPyV infection. We found highly differing recognition patterns of two anti-VP1 antibodies with respect to intracellular and extracellular VP1 localization, pointing towards independent binding sites that were seemingly associated with differing stages of virion maturation. Cells originating from single clones were stably cultured out of the urine sediment of KTX recipients with suspected BKPyVAN. The cell morphology, polyploidy, virus replication and protein production were investigated by confocal microscopy using both a monoclonal (mAb 4942) and a polyclonal rabbit anti-VP1-specific antibody (RantiVP1 Ab). Immunoblotting was performed to investigate changes in the VP1 protein. Both antibodies visualized VP1 and the mAb 4942 recognized VP1 in cytoplasmic vesicles exhibiting idiomorphic sizes when released from the cells. In contrast, the polyclonal antibody detected VP1 within the nucleus and in cytoplasm in colocalization with the endoplasmic reticulum marker CNX. At the nuclear rim, VP1 was recognized by both antibodies. Immunoblotting revealed two smaller versions of VP1 in urinary decoy cell extracts, potentially from different translation start sites as evaluated by in silico analysis. Oxford Nanopore sequencing showed integration of BKPyV DNA in chromosomes 3, 4 and 7 in one of the five tested primary cell lines which produced high viral copies throughout four passages before transcending into senescence. The different staining with two VP1-specific antibodies emphasizes the modification of VP1 during the process of virus maturation and cellular exit. The integration of BKPyV into the human genome leads to high virus production; however, this alone does not transform the cell line into a permanently cycling and indefinitely replicating one. Full article

(This article belongs to the Special Issue Virus Infection and Infectious Diseases: Unraveling Mechanisms, Innovations, and Therapeutic Strategies)

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17 pages, 4440 KiB

Open AccessArticle

Reactive Oxygen Species Induction by Hepatitis B Virus: Implications for Viral Replication in p53-Positive Human Hepatoma Cells

by Yuna Jeong, Jiwoo Han and Kyung Lib Jang

Int. J. Mol. Sci. 2024, 25(12), 6606; https://doi.org/10.3390/ijms25126606 - 15 Jun 2024

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Abstract

Hepatitis B virus (HBV) infects approximately 300 million people worldwide, causing chronic infections. The HBV X protein (HBx) is crucial for viral replication and induces reactive oxygen species (ROS), leading to cellular damage. This study explores the relationship between HBx-induced ROS, p53 activation, [...] Read more.

Hepatitis B virus (HBV) infects approximately 300 million people worldwide, causing chronic infections. The HBV X protein (HBx) is crucial for viral replication and induces reactive oxygen species (ROS), leading to cellular damage. This study explores the relationship between HBx-induced ROS, p53 activation, and HBV replication. Using HepG2 and Hep3B cell lines that express the HBV receptor NTCP, we compared ROS generation and HBV replication relative to p53 status. Results indicated that HBV infection significantly increased ROS levels in p53-positive HepG2-NTCP cells compared to p53-deficient Hep3B-NTCP cells. Knockdown of p53 reduced ROS levels and enhanced HBV replication in HepG2-NTCP cells, whereas p53 overexpression increased ROS and inhibited HBV replication in Hep3B-NTCP cells. The ROS scavenger N-acetyl-L-cysteine (NAC) reversed these effects. The study also found that ROS-induced degradation of the HBx is mediated by the E3 ligase Siah-1, which is activated by p53. Mutations in p53 or inhibition of its transcriptional activity prevented ROS-mediated HBx degradation and HBV inhibition. These findings reveal a p53-dependent negative feedback loop where HBx-induced ROS increases p53 levels, leading to Siah-1-mediated HBx degradation and HBV replication inhibition. This study offers insights into the molecular mechanisms of HBV replication and identifies potential therapeutic targets involving ROS and p53 pathways. Full article

(This article belongs to the Special Issue Virus Infection and Infectious Diseases: Unraveling Mechanisms, Innovations, and Therapeutic Strategies)

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17 pages, 2760 KiB

Open AccessArticle

T Cell Homeostasis Disturbances in a Cohort of Long-Term Elite Controllers of HIV Infection

by José M. Benito, Daniel Jiménez-Carretero, Clara Restrepo, José M. Ligos, Jaime Valentín-Quiroga, Ignacio Mahillo, Alfonso Cabello, Eduardo López-Collazo, Fátima Sánchez-Cabo, Miguel Górgolas, Vicente Estrada and Norma Rallón

Int. J. Mol. Sci. 2024, 25(11), 5937; https://doi.org/10.3390/ijms25115937 - 29 May 2024

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Abstract

Elite controllers (ECs) are people living with HIV (PLWH) able to control HIV replication without antiretroviral therapy and have been proposed as a model of a functional HIV cure. Much evidence suggests that this spontaneous control of HIV has a cost in terms [...] Read more.

Elite controllers (ECs) are people living with HIV (PLWH) able to control HIV replication without antiretroviral therapy and have been proposed as a model of a functional HIV cure. Much evidence suggests that this spontaneous control of HIV has a cost in terms of T cell homeostasis alterations. We performed a deep phenotypic study to obtain insight into T cell homeostasis disturbances in ECs maintaining long-term virologic and immunologic control of HIV (long-term elite controllers; LTECs). Forty-seven PLWH were included: 22 LTECs, 15 non-controllers under successful antiretroviral therapy (onART), and 10 non-controllers not receiving ART (offART). Twenty uninfected participants (UCs) were included as a reference. T cell homeostasis was analyzed by spectral flow cytometry and data were analyzed using dimensionality reduction and clustering using R software v3.3.2. Dimensionality reduction and clustering yielded 57 and 54 different CD4 and CD8 T cell clusters, respectively. The offART group showed the highest perturbation of T cell homeostasis, with 18 CD4 clusters and 15 CD8 clusters significantly different from those of UCs. Most of these alterations were reverted in the onART group. Interestingly, LTECs presented several disturbances of T cell homeostasis with 15 CD4 clusters and 13 CD8 clusters different from UC. Moreover, there was a specific profile of T cell homeostasis alterations associated with LTECs, characterized by increases in clusters of naïve T cells, increases in clusters of non-senescent effector CD8 cells, and increases in clusters of central memory CD4 cells. These results demonstrate that, compared to ART-mediated control of HIV, the spontaneous control of HIV is associated with several disturbances in CD4 and CD8 T cell homeostasis. These alterations could be related to the existence of a potent and efficient virus-specific T cell response, and to the ability to halt disease progression by maintaining an adequate pool of CD4 T cells. Full article

(This article belongs to the Special Issue Virus Infection and Infectious Diseases: Unraveling Mechanisms, Innovations, and Therapeutic Strategies)

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12 pages, 1341 KiB

Open AccessArticle

The Diverse Nature of the Molecular Interactions That Govern the COV-2 Variants’ Cell Receptor Affinity Ranking and Its Experimental Variability

by Fredy Sussman and Daniel S. Villaverde

Int. J. Mol. Sci. 2024, 25(5), 2585; https://doi.org/10.3390/ijms25052585 - 23 Feb 2024

Cited by 1 | Viewed by 884

Abstract

A critical determinant of infectivity and virulence of the most infectious and or lethal variants of concern (VOCs): Wild Type, Delta and Omicron is related to the binding interactions between the receptor-binding domain of the spike and its host receptor, the initial step [...] Read more.

A critical determinant of infectivity and virulence of the most infectious and or lethal variants of concern (VOCs): Wild Type, Delta and Omicron is related to the binding interactions between the receptor-binding domain of the spike and its host receptor, the initial step in cell infection. It is of the utmost importance to understand how mutations of a viral strain, especially those that are in the viral spike, affect the resulting infectivity of the emerging VOC, knowledge that could help us understand the variant virulence and inform the therapies applied or the vaccines developed. For this sake, we have applied a battery of computational protocols of increasing complexity to the calculation of the spike binding affinity for three variants of concern to the ACE2 cell receptor. The results clearly illustrate that the attachment of the spikes of the Delta and Omicron variants to the receptor originates through different molecular interaction mechanisms. All our protocols unanimously predict that the Delta variant has the highest receptor-binding affinity, while the Omicron variant displays a substantial variability in the binding affinity of the spike that relates to the structural plasticity of the Omicron spike–receptor complex. We suggest that the latter result could explain (at least in part) the variability of the in vitro binding results for this VOC and has led us to suggest a reason for the lower virulence of the Omicron variant as compared to earlier strains. Several hypotheses have been developed around this subject. Full article

(This article belongs to the Special Issue Virus Infection and Infectious Diseases: Unraveling Mechanisms, Innovations, and Therapeutic Strategies)

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24 pages, 3582 KiB

Open AccessArticle

The African Swine Fever Virus Virulence Determinant DP96R Suppresses Type I IFN Production Targeting IRF3

by Niranjan Dodantenna, Ji-Won Cha, Kiramage Chathuranga, W. A. Gayan Chathuranga, Asela Weerawardhana, Lakmal Ranathunga, Yongkwan Kim, Weonhwa Jheong and Jong-Soo Lee

Int. J. Mol. Sci. 2024, 25(4), 2099; https://doi.org/10.3390/ijms25042099 - 8 Feb 2024

Cited by 6 | Viewed by 1921

Abstract

DP96R of African swine fever virus (ASFV), also known as uridine kinase (UK), encodes a virulence-associated protein. Previous studies have examined DP96R along with other genes in an effort to create live attenuated vaccines. While experiments in pigs have explored the [...] Read more.

DP96R of African swine fever virus (ASFV), also known as uridine kinase (UK), encodes a virulence-associated protein. Previous studies have examined DP96R along with other genes in an effort to create live attenuated vaccines. While experiments in pigs have explored the impact of DP96R on the pathogenicity of ASFV, the precise molecular mechanism underlying this phenomenon remains unknown. Here, we describe a novel molecular mechanism by which DP96R suppresses interferon regulator factor-3 (IRF3)-mediated antiviral immune responses. DP96R interacts with a crucial karyopherin (KPNA) binding site within IRF3, disrupting the KPNA-IRF3 interaction and consequently impeding the translocation of IRF3 to the nucleus. Under this mechanistic basis, the ectopic expression of DP96R enhances the replication of DNA and RNA viruses by inhibiting the production of IFNs, whereas DP96R knock-down resulted in higher IFNs and IFN-stimulated gene (ISG) transcription during ASFV infection. Collectively, these findings underscore the pivotal role of DP96R in inhibiting IFN responses and increase our understanding of the relationship between DP96R and the virulence of ASFV. Full article

(This article belongs to the Special Issue Virus Infection and Infectious Diseases: Unraveling Mechanisms, Innovations, and Therapeutic Strategies)

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13 pages, 5571 KiB

Open AccessArticle

Chicken Interferon-Alpha and -Lambda Exhibit Antiviral Effects against Fowl Adenovirus Serotype 4 in Leghorn Male Hepatocellular Cells

by Jinyu Lai, Xingchen He, Rongjie Zhang, Limei Zhang, Libin Chen, Fengping He, Lei Li, Liangyu Yang, Tao Ren and Bin Xiang

Int. J. Mol. Sci. 2024, 25(3), 1681; https://doi.org/10.3390/ijms25031681 - 30 Jan 2024

Cited by 2 | Viewed by 1473

Abstract

Hydropericardium hepatitis syndrome (HHS) is primarily caused by fowl adenovirus serotype 4 (FAdV-4), causing high mortality in chickens. Although vaccination strategies against FAdV-4 have been adopted, HHS still occurs sporadically. Furthermore, no effective drugs are available for controlling FAdV-4 infection. However, type I [...] Read more.

Hydropericardium hepatitis syndrome (HHS) is primarily caused by fowl adenovirus serotype 4 (FAdV-4), causing high mortality in chickens. Although vaccination strategies against FAdV-4 have been adopted, HHS still occurs sporadically. Furthermore, no effective drugs are available for controlling FAdV-4 infection. However, type I and III interferon (IFN) are crucial therapeutic agents against viral infection. The following experiments were conducted to investigate the inhibitory effect of chicken IFN against FadV-4. We expressed recombinant chicken type I IFN-α (ChIFN-α) and type III IFN-λ (ChIFN-λ) in Escherichia coli and systemically investigated their antiviral activity against FAdV-4 infection in Leghorn male hepatocellular (LMH) cells. ChIFN-α and ChIFN-λ dose dependently inhibited FAdV-4 replication in LMH cells. Compared with ChIFN-λ, ChIFN-α more significantly inhibited viral genome transcription but less significantly suppressed FAdV-4 release. ChIFN-α- and ChIFN-λ-induced IFN-stimulated gene (ISG) expression, such as PKR, ZAP, IRF7, MX1, Viperin, IFIT5, OASL, and IFI6, in LMH cells; however, ChIFN-α induced a stronger expression level than ChIFN-λ. Thus, our data revealed that ChIFN-α and ChIFN-λ might trigger different ISG expression levels, inhibiting FAdV-4 replication via different steps of the FAdV-4 lifecycle, which furthers the potential applications of IFN antiviral drugs in chickens. Full article

(This article belongs to the Special Issue Virus Infection and Infectious Diseases: Unraveling Mechanisms, Innovations, and Therapeutic Strategies)

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Review

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16 pages, 329 KiB

Open AccessReview

Applications of Biological Therapy for Latent Infections: Benefits and Risks

by Yuan Zong, Koju Kamoi, Miki Miyagaki, Jing Zhang, Mingming Yang, Yaru Zou and Kyoko Ohno-Matsui

Int. J. Mol. Sci. 2024, 25(17), 9184; https://doi.org/10.3390/ijms25179184 - 24 Aug 2024

Viewed by 1128

Abstract

Biological therapies have revolutionized medical treatment by targeting the key mediators or receptors involved in inflammatory responses, thereby effectively suppressing inflammation and achieving beneficial outcomes. They are more advanced than conventional therapies using corticosteroids and immunosuppressants, offering effective solutions for autoimmune diseases, cancer, [...] Read more.

Biological therapies have revolutionized medical treatment by targeting the key mediators or receptors involved in inflammatory responses, thereby effectively suppressing inflammation and achieving beneficial outcomes. They are more advanced than conventional therapies using corticosteroids and immunosuppressants, offering effective solutions for autoimmune diseases, cancer, transplant rejection, and various infectious diseases, including coronavirus disease 2019. Although they exert low immunosuppressive effects, biological therapies can reactivate specific biological targets associated with infections. This review summarizes the currently available biological therapies and discusses their immunosuppressive mechanisms and clinical applications, highlighting the variations in the types and frequencies of infection recurrence induced by different biological agents. Additionally, this review describes the risk factors associated with various biological agents, thus aiding clinicians in selecting the most appropriate biological therapy. Full article

(This article belongs to the Special Issue Virus Infection and Infectious Diseases: Unraveling Mechanisms, Innovations, and Therapeutic Strategies)

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