TIM-1 Augments Cellular Entry of Ebola Virus Species and Mutants, Which Is Blocked by Recombinant TIM-1 Protein

Zhang, Min; Wang, Xinwei; Hu, Linhan; Zhang, Yuting; Zheng, Hang; H, Wu; Wang, Jing; Luo, Longlong; He, X. T.; Qiao, Chun‐Feng; Li, Xinying; Huang, Weijin; Wang, Youchun; Feng, Jie; Chen, Guojiang

doi:10.1128/spectrum.02212-21

Cited by 8 publications

(6 citation statements)

References 57 publications

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“…hTIM-1 expressed on the cell membrane is cleaved by a matrix metalloproteinase upstream of the transmembrane domain, resulting in the production of the soluble form of hTIM-1 [ 32 , 33 ]. Soluble forms of hTIM-1 are reported to inhibit some viral infections and are expected to be therapeutic candidates [ 13 , 15 , 34 , 35 , 36 ]. To further assess the effects of SNV substitutions on viral entry, purified soluble hTIM-1 proteins containing each representative SNV substitution were produced and their neutralizing activities against VSIVΔG*-EBOV were compared ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

Single Nucleotide Variants of the Human TIM-1 IgV Domain with Reduced Ability to Promote Viral Entry into Cells

Hattori

Saito

Miyamoto

et al. 2022

Viruses

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Human T-cell immunoglobulin mucin 1 (hTIM-1) is known to promote cellular entry of enveloped viruses. Previous studies suggested that the polymorphisms of hTIM-1 affected its function. Here, we analyzed single nucleotide variants (SNVs) of hTIM-1 to determine their ability to promote cellular entry of viruses using pseudotyped vesicular stomatitis Indiana virus (VSIV). We obtained hTIM-1 sequences from a public database (Ensembl genome browser) and identified 35 missense SNVs in 3 loops of the hTIM-1 immunoglobulin variable (IgV) domain, which had been reported to interact with the Ebola virus glycoprotein (GP) and phosphatidylserine (PS) in the viral envelope. HEK293T cells transiently expressing wildtype hTIM-1 or its SNV mutants were infected with VSIVs pseudotyped with filovirus or arenavirus GPs, and their infectivities were compared. Eleven of the thirty-five SNV substitutions reduced the efficiency of hTIM-1-mediated entry of pseudotyped VSIVs. These SNV substitutions were found not only around the PS-binding pocket but also in other regions of the molecule. Taken together, our findings suggest that some SNVs of the hTIM-1 IgV domain have impaired ability to interact with PS and/or viral GPs in the viral envelope, which may affect the hTIM-1 function to promote viral entry into cells.

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Section: Resultsmentioning

confidence: 99%

Single Nucleotide Variants of the Human TIM-1 IgV Domain with Reduced Ability to Promote Viral Entry into Cells

Hattori

Saito

Miyamoto

et al. 2022

Viruses

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“…Additionally, hTIM-1 deficiency decreases viral tissue load and pathogenicity in immunocompetent mice [ 37 ]. Recombinant TIM-1 ECD protein represents a potential therapeutic avenue for Ebola virus and its mutated species [ 43 ]. Thus, hTIM-1 is a promising target for antiviral development.…”

Section: Discussionmentioning

confidence: 99%

Interaction between hTIM-1 and Envelope Protein Is Important for JEV Infection

Liang

Pan

Xie

et al. 2023

Viruses

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Japanese encephalitis virus (JEV), a mosquito-borne zoonotic virus, is one of the most important causes of human viral encephalitis. JEV relies on various attachment or entry co-factors to enter host cells. Among these co-factors, hTIM-1 has been identified as an attachment factor to promote JEV infection through interacting with phosphatidylserine (PS) on the viral envelope. However, the reasons why JEV prefers to use hTIM-1 over other PS binding receptors are unknown. Here, we demonstrated that hTIM-1 can directly interact with JEV E protein. The interaction between hTIM-1 and JEV relies on specific binding sites, respectively, ND114115 in the hTIM-1 IgV domain and K38 of the E protein. Furthermore, during the early stage of infection, hTIM-1 and JEV are co-internalized into cells and transported into early and late endosomes. Additionally, we found that the hTIM-1 soluble ectodomain protein effectively inhibits JEV infection in vitro. Moreover, hTIM-1-specific antibodies have been shown to downregulate JEV infectivity in cells. Taken together, these findings suggested that hTIM-1 protein directly interacts with JEV E protein and mediates JEV infection, in addition to the PS-TIM-1 interaction.

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“…This is important in determining the T-cell response and contribution to disease phenotype. Therapeutic strategies used may vary and the differential role of TIM-1 in T-cell signalling is still being clarified 125 . Recent suggestions are that EBOV is dependent on phosphosphatidylserine with caspase-dependent scramblases (XK-related protein (Xkr)) utilised further elucidating EBOV intracellular pathways 126 .…”

Section: Discussionmentioning

confidence: 99%

Filoviridae: Insights into Immune Responses to Ebolavirus

Brown

2023

Preprint

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Ebola virus is a zoonotic virus comprised of 6 different species designated within the family Filoviridae and genus Ebolavirus. The first recorded outbreak of an Ebola virus (EBOV) was in Yambuku, Zaire (ZEBOV) in 1976, followed by Sudan Ebola virus (SUBOV) later that year. Outbreaks have been increasing throughout the 21st century, and mortality rates can reach up to 90%. Such extraordinary virulence is evidenced with few pathogens, similarly with Marburg virus (MARV) that originated in Uganda and was first detected in Germany in 1967. The virulent nature of filovirus disease has established these related viruses as a formidable global concern. There are currently four types of Ebolaviridae species known to infect humans, with two more recently identified in other animals that are genomically different with respect to cellular pathogenesis or aetiology of disease. Recent advances into understanding the pathogenesis of filovirus disease infections have been remarkable, yet the immunological response to filovirus infection remains unknown. Scientific analysis of cellular mechanisms can provide insight into virulence factors utilised by other pathogenic viruses that also cause febrile illness with occasional haemorrhagic fever in humans. In this review, we aim to provide a brief summary of EBOV proteins and the role of innate and adaptive immune cells known since 2000. We will consider the relevance and implications of immunological proteins measured by CD marker, alongside cytokine, chemokine and other biologically relevant pathways, as well as genetic research. Thorough understanding of immunological correlates affecting host responses to Ebola viruses will facilitate both clinical and applied research knowledge, contributing towards protection against potential public health threats.

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TIM-1 Augments Cellular Entry of Ebola Virus Species and Mutants, Which Is Blocked by Recombinant TIM-1 Protein

Cited by 8 publications

References 57 publications

Single Nucleotide Variants of the Human TIM-1 IgV Domain with Reduced Ability to Promote Viral Entry into Cells

Single Nucleotide Variants of the Human TIM-1 IgV Domain with Reduced Ability to Promote Viral Entry into Cells

Interaction between hTIM-1 and Envelope Protein Is Important for JEV Infection

Filoviridae: Insights into Immune Responses to Ebolavirus

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