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19 pages, 4398 KiB

Open AccessArticle

Dengue and Zika Virus Capsid Proteins Contain a Common PEX19-Binding Motif

by Mafalda A. Farelo, Despoina Korrou-Karava, Katrina F. Brooks, Tiffany A. Russell, Kevin Maringer and Peter U. Mayerhofer

Viruses 2022, 14(2), 253; https://doi.org/10.3390/v14020253 - 27 Jan 2022

Cited by 5 | Viewed by 3576

Abstract

Flaviviruses such as dengue virus (DENV) and Zika virus (ZIKV) have evolved sophisticated mechanisms to suppress the host immune system. For instance, flavivirus infections were found to sabotage peroxisomes, organelles with an important role in innate immunity. The current model suggests that the [...] Read more.

Flaviviruses such as dengue virus (DENV) and Zika virus (ZIKV) have evolved sophisticated mechanisms to suppress the host immune system. For instance, flavivirus infections were found to sabotage peroxisomes, organelles with an important role in innate immunity. The current model suggests that the capsid (C) proteins of DENV and ZIKV downregulate peroxisomes, ultimately resulting in reduced production of interferons by interacting with the host protein PEX19, a crucial chaperone in peroxisomal biogenesis. Here, we aimed to explore the importance of peroxisomes and the role of C interaction with PEX19 in the flavivirus life cycle. By infecting cells lacking peroxisomes we show that this organelle is required for optimal DENV replication. Moreover, we demonstrate that DENV and ZIKV C bind PEX19 through a conserved PEX19-binding motif, which is also commonly found in cellular peroxisomal membrane proteins (PMPs). However, in contrast to PMPs, this interaction does not result in the targeting of C to peroxisomes. Furthermore, we show that the presence of C results in peroxisome loss due to impaired peroxisomal biogenesis, which appears to occur by a PEX19-independent mechanism. Hence, these findings challenge the current model of how flavivirus C might downregulate peroxisomal abundance and suggest a yet unknown role of peroxisomes in flavivirus biology. Full article

(This article belongs to the Special Issue Host Factors in Viral Infections)

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13 pages, 2029 KiB

Open AccessArticle

Function of Host Protein Staufen1 in Rabies Virus Replication

by Gaowen Liu, Congjie Chen, Ruixian Xu, Ming Yang, Qinqin Han, Binghui Wang, Yuzhu Song, Xueshan Xia and Jinyang Zhang

Viruses 2021, 13(8), 1426; https://doi.org/10.3390/v13081426 - 22 Jul 2021

Cited by 7 | Viewed by 2416

Abstract

Rabies virus is a highly neurophilic negative-strand RNA virus with high lethality and remains a huge public health problem in developing countries to date. The double-stranded RNA-binding protein Staufen1 (STAU1) has multiple functions in RNA virus replication, transcription, and translation. However, its function [...] Read more.

Rabies virus is a highly neurophilic negative-strand RNA virus with high lethality and remains a huge public health problem in developing countries to date. The double-stranded RNA-binding protein Staufen1 (STAU1) has multiple functions in RNA virus replication, transcription, and translation. However, its function in RABV infection and its mechanism of action are not clear. In this study, we investigated the role of host factor STAU1 in RABV infection of SH-SY-5Y cells. Immunofluorescence, TCID₅₀ titers, confocal microscopy, quantitative real-time PCR and Western blotting were carried out to determine the molecular function and subcellular distribution of STAU1 in these cell lines. Expression of STAU1 in SH-SY-5Y cells was down-regulated by RNA interference or up-regulated by transfection of eukaryotic expression vectors. The results showed that N proficiently colocalized with STAU1 in SH-SY-5Y at 36 h post-infection, and the expression level of STAU1 was also proportional to the time of infection. Down-regulation of STAU1 expression increased the number of Negri body-like structures, enhanced viral replication, and a caused 10-fold increase in viral titers. Meanwhile, N protein and G protein mRNA levels also accumulated gradually with increasing infection time, which implied that STAU1 inhibited rabies virus infection of SH-SY-5Y cells in vitro. In conclusion, our results provide important clues for the detailed replication mechanism of rabies virus and the discovery of therapeutic targets. Full article

(This article belongs to the Special Issue Host Factors in Viral Infections)

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15 pages, 3201 KiB

Open AccessArticle

Bovine Parainfluenza Virus Type 3 (BPIV3) Enters HeLa Cells via Clathrin-Mediated Endocytosis in a Cholesterol- and Dynamin-Dependent Manner

by Wei Pan, Hui Nie, Hongmei Wang and Hongbin He

Viruses 2021, 13(6), 1035; https://doi.org/10.3390/v13061035 - 31 May 2021

Cited by 7 | Viewed by 2897

Abstract

Bovine parainfluenza virus 3 (BPIV3) is a crucial causative agent of respiratory disease in young and adult cattle. No specific therapies are available for BPIV3 infection. Understanding the internalization pathway of the virus will provide a new strategy for the development of antiviral [...] Read more.

Bovine parainfluenza virus 3 (BPIV3) is a crucial causative agent of respiratory disease in young and adult cattle. No specific therapies are available for BPIV3 infection. Understanding the internalization pathway of the virus will provide a new strategy for the development of antiviral therapy. Here, the mechanism of BPIV3 entry into HeLa cells was analyzed using RNA silencing and pharmacological inhibitors. Treatment of HeLa cells with hypertonic medium prevented BPIV3 internalization. These results indicated that BPIV3 entered HeLa cells via receptor-mediated endocytosis. Moreover, removing cell membrane cholesterol through MβCD treatment hampered viral penetration but not viral replication. In addition, BPIV3 infection was inhibited by pretreatment with dynasore or chlorpromazine (CPZ) or knockdown of dynamin II or clathrin heavy chain. However, virus entry was unaffected by nystatin, EIPA, wortmannin, or cytochalasin D treatment or caveolin-1 knockdown. These data demonstrated that the entry of BPIV3 into HeLa cells was dependent on clathrin-mediated endocytosis but not on caveolae-mediated endocytosis or the macropinocytosis pathway. Many viruses are transported to endosomes, which provide an acidic environment and release their genome upon separation from primary endocytic vesicles. However, we found that BPIV3 infection required endosomal cathepsins, but not a low pH. In summary, we show, for the first time, that BPIV3 enters HeLa cells through the clathrin-mediated endocytosis pathway, presenting novel insights into the invasion mechanism of Paramyxoviridae. Full article

(This article belongs to the Special Issue Host Factors in Viral Infections)

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11 pages, 2701 KiB

Open AccessArticle

Liver-Derived Cell Transfection Model Efficacy for HBV Genotype B Replication/Transcription Is Determined by Complex Host Transcription Factor Network

by Roxanne Hui-Heng Chong, Atefeh Khakpoor, Theresa May-Chin Tan, Seng-Gee Lim and Guan-Huei Lee

Viruses 2021, 13(3), 524; https://doi.org/10.3390/v13030524 - 22 Mar 2021

Viewed by 1973

Abstract

Background: Interaction between host transcription factors (TFs) and the viral genome is fundamental for hepatitis B virus (HBV) gene expression regulation. Additionally, the distinct interaction of the TFs’ network with the HBV genome determines the regulatory effect outcome. Hence, different HBV genotypes and [...] Read more.

Background: Interaction between host transcription factors (TFs) and the viral genome is fundamental for hepatitis B virus (HBV) gene expression regulation. Additionally, the distinct interaction of the TFs’ network with the HBV genome determines the regulatory effect outcome. Hence, different HBV genotypes and their variants may display different viral replication/transcription regulation. Due to the lack of an efficient infection model suitable for all HBV genotypes, the hepatoma cell transfection model is primarily used in studies involving non-D HBV genotypes and variants. Methods: We explored the transcriptome profile of host TFs with a regulatory effect on HBV in eight liver-derived cell lines in comparison with primary human hepatocytes (PHH). We further analyzed the suitability of these models in supporting HBV genotype B replication/transcription. Results: Among studied models, HC-04, as a result of the close similarity of TFs transcriptome profile to PHH and the interaction of specific TFs including HNF4α and PPARα, showed the highest efficiency in regard to viral replication and antigen production. The absence of TFs expression in L02 transfection model resulted in its inefficiency in HBV replication/transcription. Conclusion: These observations help to better design studies on regulatory mechanisms involving non-D HBV genotypes and variants’ gene expression and the development of more efficient therapeutical approaches. Full article

(This article belongs to the Special Issue Host Factors in Viral Infections)

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15 pages, 2527 KiB

Open AccessArticle

Th1-Polarized, Dengue Virus-Activated Human Mast Cells Induce Endothelial Transcriptional Activation and Permeability

by Ayesa Syenina, Wilfried A. A. Saron, Cyril J. Jagaraj, Siham Bibi, Michel Arock, Duane J. Gubler, Abhay P. S. Rathore, Soman N. Abraham and Ashley L. St. John

Viruses 2020, 12(12), 1379; https://doi.org/10.3390/v12121379 - 02 Dec 2020

Cited by 7 | Viewed by 3283

Abstract

Dengue virus (DENV), an arbovirus, strongly activates mast cells (MCs), which are key immune cells for pathogen immune surveillance. In animal models, MCs promote clearance of local peripheral DENV infections but, conversely, also promote pathological vascular leakage when widely activated during systemic DENV [...] Read more.

Dengue virus (DENV), an arbovirus, strongly activates mast cells (MCs), which are key immune cells for pathogen immune surveillance. In animal models, MCs promote clearance of local peripheral DENV infections but, conversely, also promote pathological vascular leakage when widely activated during systemic DENV infection. Since DENV is a human pathogen, we sought to ascertain whether a similar phenomenon could occur in humans by characterizing the products released by human MCs (huMCs) upon direct (antibody-independent) DENV exposure, using the phenotypically mature huMC line, ROSA. DENV did not productively infect huMCs but prompted huMC release of proteases and eicosanoids and induced a Th1-polarized transcriptional profile. In co-culture and trans-well systems, huMC products activated human microvascular endothelial cells, involving transcription of vasoactive mediators and increased monolayer permeability. This permeability was blocked by MC-stabilizing drugs, or limited by drugs targeting certain MC products. Thus, MC stabilizers are a viable strategy to limit MC-promoted vascular leakage during DENV infection in humans. Full article

(This article belongs to the Special Issue Host Factors in Viral Infections)

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16 pages, 890 KiB

Open AccessArticle

Polymorphisms in Processing and Antigen Presentation-Related Genes and Their Association with Host Susceptibility to Influenza A/H1N1 2009 Pandemic in a Mexican Mestizo Population

by Marco Antonio Ponce-Gallegos, Aseneth Ruiz-Celis, Enrique Ambrocio-Ortiz, Gloria Pérez-Rubio, Alejandra Ramírez-Venegas, Nora E. Bautista-Félix and Ramcés Falfán-Valencia

Viruses 2020, 12(11), 1224; https://doi.org/10.3390/v12111224 - 29 Oct 2020

Cited by 3 | Viewed by 2354

Abstract

(1) Background: The influenza A/H1N1 pdm09 virus rapidly spread throughout the world. Despite the inflammatory and virus-degradation pathways described in the pathogenesis of influenza A virus (IAV) infection, little is known about the role of the single nucleotide polymorphisms (SNPs) in the genes [...] Read more.

(1) Background: The influenza A/H1N1 pdm09 virus rapidly spread throughout the world. Despite the inflammatory and virus-degradation pathways described in the pathogenesis of influenza A virus (IAV) infection, little is known about the role of the single nucleotide polymorphisms (SNPs) in the genes involved in the processing and antigenic presentation-related mechanisms. (2) Methods: In this case-control study, we evaluated 17 SNPs in five genes (TAP1, TAP2, TAPBP, PSMB8, and PSMB9). One hundred and twenty-eight patients with influenza A/H1N1 infection (INF-P) and 111 healthy contacts (HC) were included; all of them are Mexican mestizo. (3) Results: In allele and genotype comparison, the rs241433/C allele (TAP2), as well as AG haplotype (rs3763365 and rs4148882), are associated with reduced risk for influenza A/H1N1 infection (p < 0.05). On the other hand, the rs2071888G allele (TAPBP) and GG haplotype (rs3763365 and rs9276810) are associated with a higher risk for influenza A/H1N1 infection. In addition, after adjustment for covariates, the association to a reduced risk for influenza A/H1N1 infection remains with rs241433/C allele (p < 0.0001, OR = 0.24, 95% CI = 0.13–0.43), and the association with TAPBP is also maintained with the G allele (p = 0.0095, OR = 1.89, 95% CI = 1.17–3.06) and GG genotype models (p < 0.05, OR = 2.18, 95% CI = 1.27–3.74). (4) Conclusion: The rs241433/C allele and AC genotype (TAP2) and the AG haplotype are associated with a reduced risk for influenza A/H1N1 infection. In addition, the rs2071888/G allele and GG genotype (TAPBP) and the GG haplotype are associated with a higher risk for developing influenza A/H1N1 infection in a Mexican mestizo population. Full article

(This article belongs to the Special Issue Host Factors in Viral Infections)

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Review

Jump to: Research

16 pages, 1108 KiB

Open AccessReview

Host Factors That Control Mosquito-Borne Viral Infections in Humans and Their Vector

by Chasity E. Trammell and Alan G. Goodman

Viruses 2021, 13(5), 748; https://doi.org/10.3390/v13050748 - 24 Apr 2021

Cited by 4 | Viewed by 3109

Abstract

Mosquito-borne viral infections are responsible for a significant degree of morbidity and mortality across the globe due to the severe diseases these infections cause, and they continue to increase each year. These viruses are dependent on the mosquito vector as the primary means [...] Read more.

Mosquito-borne viral infections are responsible for a significant degree of morbidity and mortality across the globe due to the severe diseases these infections cause, and they continue to increase each year. These viruses are dependent on the mosquito vector as the primary means of transmission to new vertebrate hosts including avian, livestock, and human populations. Due to the dynamic host environments that mosquito-borne viruses pass through as they are transmitted between vector and vertebrate hosts, there are various host factors that control the response to infection over the course of the pathogen’s life cycle. In this review, we discuss these host factors that are present in either vector or vertebrate models during infection, how they vary or are conserved between hosts, and their implications in future research pertaining to disease prevention and treatment. Full article

(This article belongs to the Special Issue Host Factors in Viral Infections)

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21 pages, 3050 KiB

Open AccessReview

Role of the Host Genetic Susceptibility to 2009 Pandemic Influenza A H1N1

by Gloria Pérez-Rubio, Marco Antonio Ponce-Gallegos, Bruno André Domínguez-Mazzocco, Jaime Ponce-Gallegos, Román Alejandro García-Ramírez and Ramcés Falfán-Valencia

Viruses 2021, 13(2), 344; https://doi.org/10.3390/v13020344 - 22 Feb 2021

Cited by 8 | Viewed by 3973

Abstract

Influenza A virus (IAV) is the most common infectious agent in humans, and infects approximately 10–20% of the world’s population, resulting in 3–5 million hospitalizations per year. A scientific literature search was performed using the PubMed database and the Medical Subject Headings (MeSH) [...] Read more.

Influenza A virus (IAV) is the most common infectious agent in humans, and infects approximately 10–20% of the world’s population, resulting in 3–5 million hospitalizations per year. A scientific literature search was performed using the PubMed database and the Medical Subject Headings (MeSH) “Influenza A H1N1” and “Genetic susceptibility”. Due to the amount of information and evidence about genetic susceptibility generated from the studies carried out in the last influenza A H1N1 pandemic, studies published between January 2009 to May 2020 were considered; 119 papers were found. Several pathways are involved in the host defense against IAV infection (innate immune response, pro-inflammatory cytokines, chemokines, complement activation, and HLA molecules participating in viral antigen presentation). On the other hand, single nucleotide polymorphisms (SNPs) are a type of variation involving the change of a single base pair that can mean that encoded proteins do not carry out their functions properly, allowing higher viral replication and abnormal host response to infection, such as a cytokine storm. Some of the most studied SNPs associated with IAV infection genetic susceptibility are located in the FCGR2A, C1QBP, CD55, and RPAIN genes, affecting host immune responses through abnormal complement activation. Also, SNPs in IFITM3 (which participates in endosomes and lysosomes fusion) represent some of the most critical polymorphisms associated with IAV infection, suggesting an ineffective virus clearance. Regarding inflammatory response genes, single nucleotide variants in IL1B, TNF, LTA IL17A, IL8, IL6, IRAK2, PIK3CG, and HLA complex are associated with altered phenotype in pro-inflammatory molecules, participating in IAV infection and the severest form of the disease. Full article

(This article belongs to the Special Issue Host Factors in Viral Infections)

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