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Unique Tropism and Entry Mechanism of Mumps Virus.

ABSTRACT: Mumps virus (MuV) is an important human pathogen that causes parotitis, orchitis, oophoritis, meningitis, encephalitis, and sensorineural hearing loss. Although mumps is a vaccine-preventable disease, sporadic outbreaks have occurred worldwide, even in highly vaccinated populations. MuV not only causes systemic infection but also has a unique tropism to glandular tissues and the central nervous system. In general, tropism can be defined by multiple factors in the viral life cycle, including its entry, interaction with host factors, and host-cell immune responses. Although the underlying mechanisms of MuV tropism remain to be fully understood, recent studies on virus-host interactions have provided insights into viral pathogenesis. This review was aimed at summarizing the entry process of MuV by focusing on the glycan receptors, particularly the recently identified receptors with a trisaccharide core motif, and their interactions with the viral attachment proteins. Here, we describe the receptor structures, their distribution in the human body, and the recently identified host factors for MuV and analyze their relationship with MuV tropism.

SUBMITTER: Kubota M

PROVIDER: S-EPMC8471308 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Unique Tropism and Entry Mechanism of Mumps Virus.

Kubota Marie M Hashiguchi Takao T

Viruses 20210901 9

Mumps virus (MuV) is an important human pathogen that causes parotitis, orchitis, oophoritis, meningitis, encephalitis, and sensorineural hearing loss. Although mumps is a vaccine-preventable disease, sporadic outbreaks have occurred worldwide, even in highly vaccinated populations. MuV not only causes systemic infection but also has a unique tropism to glandular tissues and the central nervous system. In general, tropism can be defined by multiple factors in the viral life cycle, including its ...[more]

PMID: 34578327

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Project description:AbstractBackgroundHIV-1 entry into cells is mediated by sequential binding of target cell CD4 and CCR5 or CXCR4 to the metastable envelope (Env) trimer of gp120-gp41 heterodimers (Figure 1). We determined that MF275, a single diastereomer of the small molecule entry inhibitor PF-68742, is necessary and sufficient to inhibit entry of a subset of HIV-1 strains. We investigated the mechanism of MF275.MethodsRecombinant luciferase-expressing HIV-1 pseudotyped by wild-type or mutant HIV-1 Envs was incubated with MF275, other entry inhibitors, and/or antibodies. The virus-inhibitor mixture was added to CD4+ CCR5+ or CD4? CCR5+ target cells and luciferase activity measured.ResultsUnlike other entry inhibitors, MF275 not only reversibly inhibited the infection of CD4+ CCR5+ cells by some HIV-1 strains, but also irreversibly enhanced the infection of CD4? CCR5+ cells by others. In both cases, the strain susceptibility profiles were unique from those of CD4-mimetics, BMS-378806, and maraviroc. Furthermore, MF275 activity was not affected by mutations conferring resistance to other entry inhibitors and vice versa. In line with its activating activity, MF275 sensitized susceptible Envs to neutralization by a variety of broadly neutralizing antibodies against different epitopes. Changes in the gp120 C5 and gp41 FP regions conferred resistance to MF275 inhibition but not activation. Furthermore, sensitivity to other entry inhibitors in the presence of MF275 indicated that inhibition and activation target different conformational intermediates along the entry pathway, with the former targeting the prehairpin intermediate.ConclusionMF275 is unique among HIV-1 entry inhibitors. Depending on the conformation of the target Env, which appears related to the gp120-gp41 interface, MF275 mediates inhibition or activation via distinct mechanisms (Figure 2). Further characterization of the MF275 mechanisms and binding site/s will advance understanding of the HIV-1 entry pathway as well as assist optimization of its clinical utility as an antiretroviral in multi-class drug resistance and potentially as an adjunct to vaccines. Disclosures All authors: No reported disclosures.

Project description:In the 21st century, several human and swine coronaviruses (CoVs) have emerged suddenly and caused great damage to people's lives and property. The porcine epidemic diarrhea virus (PEDV), leading to enormous economic losses to the pork industry and remains a large challenge. PEDV showed extensive cell tropism, and we cannot ignore the potential risk of cross-species transmission. However, the mechanism of adaptation and cell tropism of PEDV remains largely unknown and in vitro isolation of PEDV remains a huge challenge, which seriously impedes the development of vaccines. In this study, we confirmed that the spike (S) protein determines the adaptability of PEDV to monkey Vero cells and LLC-PK1 porcine cells, and isolated exchange of S1 and S2 subunits of adaptive strains did not make PEDV adapt to cells. Further, we found that the cellular adaptability of rCH/SX/2016-SHNXP depends on S1 and the first half of S2 (S3), and the 803L and 976H of the S2 subunit are critical for rCH/SX/2016-S1HNXP+S3HNXP adaptation to Vero cells. These findings highlight the decisive role of PEDV S protein in cell tropism and the potential role of coronaviruses S protein in cross-species transmissibility. Besides, our work also provides some different insight into finding PEDV receptors and developing PEDV and other coronaviruses vaccines. IMPORTANCE CoVs can spill from an animal reservoir into a naive host to cause diseases in humans or domestic animals. PEDV results in high mortality in piglets, which has caused immense economic losses in the pork industry. Virus isolation is the first step in studying viral pathogenesis and developing effective vaccines. However, the molecular mechanism of PEDV cell tropism is largely unknown, and isolation of endemic PEDV strains remains a major challenge. This study confirmed that the S gene is the decisive gene of PEDV adaptability to monkey Vero cells and porcine LLC-PK1 cells by the PEDV reverse genetics system. Isolated exchange of S1 and S2 of adaptive strains did not make PEDV adapt to cells, and the 803L and 976H of S2 subunit are critical for rCH/SX/2016-S1HNXP+S3HNXP adaptation to Vero cells. These results illustrate the decisive role of PEDV S protein in cell tropism and highlight the potential role of coronaviruses S protein in cross-species transmissibility. Besides, our finding also provides some unique insight into identifying PEDV functional receptors and has guiding significance for developing PEDV and other coronavirus vaccines.

Project description:Mumps virus (MuV) is an important aerosol-transmitted human pathogen causing epidemic parotitis, meningitis, encephalitis, and deafness. MuV preferentially uses a trisaccharide containing α2,3-linked sialic acid as a receptor. However, given the MuV tropism toward glandular tissues and the central nervous system, an additional glycan motif(s) may also serve as a receptor. Here, we performed a large-scale glycan array screen with MuV hemagglutinin-neuraminidase (MuV-HN) attachment proteins by using 600 types of glycans from The Consortium for Functional Glycomics Protein-Glycan Interaction Core in an effort to find new glycan receptor motif(s). According to the results of the glycan array, we successfully determined the crystal structures of MuV-HN proteins bound to newly identified glycan motifs, sialyl LewisX (SLeX) and the oligosaccharide portion of the GM2 ganglioside (GM2-glycan). Interestingly, the complex structures showed that SLeX and GM2-glycan share the same configuration with the reported trisaccharide motif, 3'-sialyllactose (3'-SL), at the binding site of MuV-HN, while SLeX and GM2-glycan have several unique interactions compared with those of 3'-SL. Thus, MuV-HN protein can allow an additional spatial modification in GM2-glycan and SLeX at the second and third carbohydrates from the nonreducing terminus of the core trisaccharide structure, respectively. Importantly, MuV entry was efficiently inhibited in the presence of 3'-SL, SLeX, or GM2-glycan derivatives, which indicates that these motifs can serve as MuV receptors. The α2,3-sialylated oligosaccharides, such as SLeX and 3'-sialyllactosamine, are broadly expressed in various tissues, and GM2 exists mainly in neural tissues and the adrenal gland. The distribution of these glycan motifs in human tissues/organs may have bearing on MuV tropism.IMPORTANCE Mumps virus (MuV) infection is characterized by parotid gland swelling and can cause pancreatitis, orchitis, meningitis, and encephalitis. MuV-related hearing loss is also a serious complication because it is usually irreversible. MuV outbreaks have been reported in many countries, even in high-vaccine-coverage areas. MuV has tropism toward glandular tissues and the central nervous system. To understand the unique MuV tropism, revealing the mechanism of receptor recognition by MuV is very important. Here, using a large-scale glycan array and X-ray crystallography, we show that MuV recognizes sialyl LewisX and GM2 ganglioside as receptors, in addition to a previously reported MuV receptor, a trisaccharide containing an α2,3-linked sialic acid. The flexible recognition of these glycan receptors by MuV may explain the unique tropism and pathogenesis of MuV. Structures will also provide a template for the development of effective entry inhibitors targeting the receptor-binding site of MuV.

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Unique Tropism and Entry Mechanism of Mumps Virus.

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Unique Tropism and Entry Mechanism of Mumps Virus.

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