Differential Features of Fusion Activation Within the Paramyxoviridae
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viruses Review Differential Features of Fusion Activation within the Paramyxoviridae Kristopher D. Azarm and Benhur Lee * Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-212-241-2552 Received: 17 December 2019; Accepted: 29 January 2020; Published: 30 January 2020 Abstract: Paramyxovirus (PMV) entry requires the coordinated action of two envelope glycoproteins, the receptor binding protein (RBP) and fusion protein (F). The sequence of events that occurs during the PMV entry process is tightly regulated. This regulation ensures entry will only initiate when the virion is in the vicinity of a target cell membrane. Here, we review recent structural and mechanistic studies to delineate the entry features that are shared and distinct amongst the Paramyxoviridae. In general, we observe overarching distinctions between the protein-using RBPs and the sialic acid- (SA-) using RBPs, including how their stalk domains differentially trigger F. Moreover, through sequence comparisons, we identify greater structural and functional conservation amongst the PMV fusion proteins, as compared to the RBPs. When examining the relative contributions to sequence conservation of the globular head versus stalk domains of the RBP, we observe that, for the protein-using PMVs, the stalk domains exhibit higher conservation and find the opposite trend is true for SA-using PMVs. A better understanding of conserved and distinct features that govern the entry of protein-using versus SA-using PMVs will inform the rational design of broader spectrum therapeutics that impede this process. Keywords: paramyxovirus; viral envelope proteins; type I fusion protein; henipavirus; virus entry; viral transmission; structure; rubulavirus; parainfluenza virus 1. Introduction The family Paramyxoviridae (Order: Mononegavirales, Class: Monjiviricetes, Subphylum: Haploviricotina, Phylum: Negarnaviricotina, Realm: Riboviria) comprises of enveloped, non-segmented negative-sense RNA viruses that have a vast host range, ranging from mammals and birds to reptiles and fish [1]. The most recent classification of Paramyxoviridae by the International Committee on Taxonomy of Viruses (ICTV) includes four subfamilies, 14 genera, and 72 recognized species (Figure1). Paramyxoviruses (PMVs) belonging to divergent genera such as measles virus (Morbillivirus), mumps virus (Orthorubulavirus), the human parainfluenza viruses (Orthorubulavirus, Respirovirus), and Nipah and Hendra viruses (Henipavirus) are major human-tropic pathogens of global biomedical importance. Human-to-human transmission of measles, mumps and the parainfluenza viruses likely occurs through airborne routes or fomites [2], while direct contact with infectious bodily fluids (respiratory secretions, saliva, urine) is required for transmission of henipaviruses (HNVs) [3–5]. HNVs, including the zoonotic Hendra and Nipah viruses (HeV and NiV), are highly pathogenic in humans and domestic animals when spillover occurs from their natural chiropteran (bat) hosts. While HeV outbreaks appear confined to northeastern Australia, NiV outbreaks occur with alarming regularity in South/Southeast Asia and result in mortality rates upward of 90% [5–7]. More recently, sampling of bat reservoirs in parts of South America and Africa—areas distinct from what was thought to be the normal geographical distribution for extant HNVs [8–10]—has not only shown evidence for divergent HNV species, but has also revealed that bats host PMVs from major genera (e.g., morbilliviruses, respiroviruses, orthorubulaviruses and Viruses 2020, 12, 161; doi:10.3390/v12020161 www.mdpi.com/journal/viruses Viruses 2020, 12, 161 2 of 28 Viruses 2020, 12, 161 2 of 28 pararubulaviruses) that comprise of species pathogenic to humans or domestic animals. Furthermore, species pathogenic to humans or domestic animals. Furthermore, serological evidence suggests the serological evidence suggests the divergent HNVs in Africa have previously spilled over into the divergent HNVs in Africa have previously spilled over into the human population [11]. Thus, both human population [11]. Thus, both extant and emerging PMVs pose a threat to global health. extant and emerging PMVs pose a threat to global health. Figure 1. Phylogenetic tree of the family Paramyxoviridae. L protein sequences from representative Figurespecies 1. Phylogenetic of the 14 genera— tree ofMetaavulavirus the family Paramyxoviridae(APMV-2-L,. YP_009513219.1),L protein sequencesOrthoavulavirus from representative(NDV-L, speciesAAS67167.1), of the 14Paraavulavirus genera—Metaavulavirus(APMV-3-L, (APMV-2-L, YP_009094217.1), YP_009513219.1),Orthorubulavirus Orthoavulavirus(MuV-L, NP_054714.1), (NDV-L, AAS67167.1),Pararubulavirus Paraavulavirus(SoRV-L, YP_009094034.1), (APMV-3-L, YP_009094217.1),Synodonvirus (WTLPV-L, Orthorubulavirus AVM87369.1), (MuV-L,Aquaparamyxovirus NP_054714.1), Pararubulavirus(ASPMV-L, YP_009094152.1), (SoRV-L, RespirovirusYP_009094034.1),(HPIV3-L, Synodonvirus ABY47607.1), Ferlavirus(WTLPV-L,(FDLV-L, AVM87369.1), NP_899661.1), AquaparamyxovirusSalemvirus (SalV-L, (ASPMV-L, YP_009094339.1), YP_009094152.1),Henipavirus Respirovirus(NiV-L, (HPIV3-L, NP_112028.1), ABY47607.1),Jeilongvirus Ferlavirus(BeiV-L, (FDLV-L,YP_512254.1), NP_899661.1),Narmovirus Salemvirus(MossV-L, (SalV-L, NP_958055.1), YP_009094339.1), and Morbillivirus Henipavirus(MeV-L, (NiV-L, NP_056924.1)—were NP_112028.1), Jeilongvirusaligned by (BeiV-L, ClustalW YP_512254.1), and a neighbor-joining Narmovirus tree (MossV-L, was generated NP_958055.1), using Geneious and Morbillivirus Prime 2019.2. (MeV-L, Scale bar NP_056924.1)—wereof the resultant neighbor-joining aligned by ClustalW tree indicates and a 0.2neighb aminoor-joining acid substitutions tree was gene perrated site. For using clarity, Geneious only the Primeparent 2019.2. genus Scale of the bar representative of the resultant species neighbor-joi is indicated.ning Members tree indicates in each 0.2 subfamily amino acid cluster substitutions are shaded in perblue site. (subfamily For clarity,Avulavirinae only the pare), greennt genus (subfamily of the representativeRubulavirinae), spec yellowies is (subfamily indicated.Metaparamyxovirinae Members in each ) subfamilyand red cluster (subfamily are shadedOrthoparamyxovirinae in blue (subfamily), respectively. Avulavirinae), green (subfamily Rubulavirinae), yellow (subfamily Metaparamyxovirinae) and red (subfamily Orthoparamyxovirinae), respectively. Paramyxovirus (PMV) entry occurs via pH-independent fusion of the viral envelope with the hostParamyxovirus cell membrane. (PMV) For the entry majority occurs of via PMVs, pH-independ this processent involves fusion theof the concerted viral envelope actions ofwith two the viral hostglycoproteins: cell membrane. the For receptor-binding the majority of proteinPMVs, this (RBP) process and fusioninvolves protein the concerted (F). There actions are various of two flavorsviral glycoproteins:of RBP [12–15 the]. HN,receptor-binding hemagglutinin-neuraminidase, protein (RBP) and fusion proteins protein bind (F). sialic There acid are (SA) various on red flavors blood cellsof RBP(RBCs) [12–15]. and HN, cause hemagglutinin-neuraminidase, them to aggregate (hemagglutination proteins activity), bind sialic in additionacid (SA) to on being red ableblood to cells cleave (RBCs)SA (neuraminidase and cause them activity) to aggregate to facilitate (hemagglutination virion release activity), from the infectedin addition cell to [16 being–21]. able Hemagglutinin to cleave SA(H) (neuraminidase proteins of the activity) genus Morbillivirus to facilitate virionsolely haverelease hemagglutination from the infected activity, cell [16–21]. aggregating Hemagglutinin RBCs from (H)certain proteins primates, of the genus but not Morbillivirus humans, bysolely binding have hemagglutination to CD46 [22]. For activity, systemic aggregating spread and RBCs respiratory from certaintransmission primates, in but humans, not humans, MeV-RBP by uses binding the physiologically to CD46 [22]. relevantFor systemic SLAM spread (or CD150) and respiratory and Nectin-4 transmissionproteins, respectively in humans,[ MeV-RBP23–27]. Finally, uses the remaining physiologically members relevant of the OrthoparamyxovirinaeSLAM (or CD150) and, thatNectin-4 do not proteins,express respectively HN or H proteins, [23–27]. possess Finally, G proteinsremaining that members are either of experimentally the Orthoparamyxovirinae confirmed, or that predicted do not to expressbind proteinaceousHN or H proteins, receptors possess [28 G–33 proteins]. More that recently, are either the RBP experimentally from members confirmed of the Pararubulavirus or predicted to generabind proteinaceous (e.g., Sosuga recept virus),ors presumed [28–33]. More to contain recently, HN the activity, RBP from has beenmembers shown of the to notPararubulavirus use SA-based generareceptors (e.g. [, 34Sosuga] (Figure virus),2 and presumed below for moreto contain detailed HN discussion). activity, has The been RBP shown binds theto not host use receptor SA-based on the receptorstarget cell. [34] Following (Figure 2 and receptor below binding, for more the detailed RBP undergoes discussion). a conformational The RBP binds change the host that receptor allosterically on thetriggers target thecell. metastable Following fusion receptor protein, binding, which th thene RBP undergoes undergoes its owna conformational conformational change cascade that that allostericallyeventually