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Nucleocapsids of muscaviruses have regularly spaced braided, bead-like surface projections and virion particles that are more stable than those of glossinaviruses (Kariithi et al., 2010, Kariithi et al., 2017a). Members of the genus Muscavirus infect and cause only symptomatic salivary gland hypertrophy syndrome (SGH) in houseflies; the virus induces rapid cellular and nuclear hypertrophy in the SGs within 2–3 days post-infection (Lietze et al., 2012). Topical exposure or injection of members of the genus Muscavirus into adult houseflies results in overt SGH and total shutdown of oogenesis. There is no evidence for vertical transmission of this virus (Kariithi et al., 2017b, Lietze et al., 2007). Members of the genus Muscavirus are globally distributed within populations of the synanthropic housefly (Prompiboon et al., 2010), and can infect other muscids (Geden et al., 2011a). The virus induces total shutdown of vitellogenesis and sterility in viremic females, which refuse to copulate when paired with healthy males (Kariithi et al., 2017b).
The elongated, enveloped rod-shaped muscavirus virion measures 65×550 nm, contains a unique braided, bead-like surface topography, and has rounded ends (Garcia-Maruniak et al., 2008).
Muscavirus particles sediment at a density of 1.153 g cm-3 when subjected to 10–60% Nycodenz gradient centrifugation (Coler et al., 1993), and are more stable, potentially accounting for the higher infectivity of muscaviruses compared to glossinaviruses (Kariithi et al., 2017a).
The muscavirus genome is a circular dsDNA molecule of 124,279 bp encoding 108 non-overlapping ORFs that are evenly distributed over the two DNA strands and arranged in unidirectional clusters; 101 ORFs have been validated to be transcriptionally active (Garcia-Maruniak et al., 2009, Garcia-Maruniak et al., 2008, Salem et al., 2009). Several pairs of transcripts distributed across the muscavirus genome overlap (in unidirectional, convergent, or divergent pattern), some of which are transcribed in tandem. The 3′-ends of 95 of the 108 ORFs contain polyadenylation signals (Salem et al., 2009). Similar to other circular dsDNA viruses of invertebrates, the muscavirus genome contains multiple regions with tandem repeats.
Of the 108 ORFs in the muscavirus genome, 29 encode structural proteins (Garcia-Maruniak et al., 2008). Amongst the key viral proteins are proteins involved in the replication of the virus genome (i.e. DNA polymerase and helicase) and six homologs to the baculovirus core conserved proteins involved in per os infection (P74, PIF-1, PIF-2, PIF-3, ODV-e66 and Ac150) (Garcia-Maruniak et al., 2008). Also notable of the muscavirus proteins are those which display homology to proteins involved in the disruption of peritrophic matrix (zinc-dependent matrix metalloproteinase), in nucleotide transport/metabolism (dUTP pyrophosphatase), inhibition of apoptosis, synthesis of DNA precursors and replication and cell division (thymidylate synthase and dihydrofolate reductase), or are homologs of several cellular proteins (Garcia-Maruniak et al., 2008).
The circular dsDNA genome of muscavirus is 124,279 bp with a G+C content of 43.5% and encodes 108 putative methionine-initiated ORFs. Only 30 of these ORFs encode proteins homologous to known proteins (Garcia-Maruniak et al., 2008). These homologs include several proteins reported in baculoviruses and nudiviruses (P74, PIF-1, -2, -3, ODV-E66, RR1, RR2, IAP, dUTPase, MP, Ac81-like, and LEFs 4, 5, 8, 9), seven proteins described in nudiviruses (MCP, DHFR, TS, TK, and three unknown proteins), and several cellular proteins (Garcia-Maruniak et al., 2008). The muscavirus genome contains 18 direct repeats covering approximately 1.7% of the genome; seven of these repeats are located inside putative coding sequences (Garcia-Maruniak et al., 2009).
Replication of viral DNA and production of nucleocapsids occurs in the virogenic stroma of the infected SG nuclei, after which they migrate and align to the nuclear membranes and exit the nucleus via the nuclear pore complex into the cytoplasm (Boucias et al., 2013a). The nucleocapsids acquire their envelope within the cytoplasm in areas adjacent to the nuclear membranes and from peptides associated with the ribosomes (Boucias et al., 2013a, Lietze et al., 2011a). The mature virions migrate to and bud out of the plasmalemma bordering the salivary gland lumens (Lietze et al., 2011a).
A major envelope protein (MdHV96) of muscaviruses has been identified as immunogenic in mice/rabbit (Boucias et al., 2013a).
Members of the genus Muscavirus specifically induce symptomatic infections (SGH) in the common housefly, which is highly susceptible to the virus; injection of ~100 viral particles results in SGH in all injected flies (Lietze et al., 2007). This virus can infect other muscids, including the stable fly Stomoxys calcitrans (Geden et al., 2011a), but without induction of overt SGH symptoms. Different geographical muscavirus strains have similar molecular and biological properties, with the prevalence of virus-infected flies varying spatially and temporally (0–40%) amongst housefly populations (Prompiboon et al., 2010). There is no available cell culture system capable of supporting muscavirus replication (Arif and Pavlik 2013).
The common housefly (Musca domestica) is the natural host for members of this genus, in which infection is symptomatic (overt SGH) (Lietze et al., 2012, Lietze et al., 2011b). Under experimental conditions, members of the genus Muscavirus can infect other muscids (e.g. lesser housefly, face fly, stable fly and tsetse fly), but without induction of diagnostic SGH (Geden et al., 2011b). However, muscavirus-challenged stable flies (Stomoxys calcitrans) and black dump flies (Hydrotaea aenescens) produce significantly fewer eggs (Geden et al., 2011a, Geden et al., 2011b).
The transmission of muscaviruses is primarily horizontal, either orally among adult flies co-feeding on virus-contaminated food substrates, or via holding flies in virus-contaminated fly cages (Geden et al., 2008, Lietze et al., 2009). Mechanical transmission (trans-cuticular via wounds) has been suggested (Vallejo et al., 2013). There is no evidence of vertical (mother-to-progeny) transmission.
Members of the genus Muscavirus have a global distribution, being found in North America, Europe, Africa, Asia, the Caribbean, and the southwestern Pacific, corresponding to those areas that are infested by the cosmopolitan pest, the common housefly Musca domestica (Prompiboon et al., 2010).
Muscavirus infection induces extensive nuclear and cellular hypertrophy of the salivary glands (SG), thereby causing non-lytic increase in individual cell sizes (without an increase in cell numbers), and ultimately, the SGs are hypertrophic (i.e. enlarged cells incapable of dividing) (Figure 4A.Hytrosaviridae and 4B.Hytrosaviridae) (Kariithi et al., 2017a, Lietze et al., 2011c, Lietze et al., 2011a). Infection by muscavirus induces overt SGH symptoms in 100% of flies (i.e. the virus does not infect asymptomatically) within 3 days post-infection (Lietze et al., 2007). However, adult flies develop resistance to oral infection within hours after eclosion, potentially due to the maturation of the peritrophic membrane (Lietze et al., 2011b, Boucias et al., 2015). Post-challenge, the virus replicates rapidly and completely shuts down vitellogenesis, potentially via blocking production of sesquiterpenoids (Kariithi et al., 2017b, Lietze et al., 2007). Infection by muscavirus alters housefly mating behaviors; viremic females refuse to copulate when paired with healthy males, while viremic males show reduced avidity to initiate courtship with healthy females (Kariithi et al., 2017b, Lietze et al., 2007). Females infected at a previtellogenic stage neither mate nor develop eggs, while those infected at postvitellogenic stage deposit their current egg batches only. However, the infected flies do not exhibit any external disease signs (Lietze et al., 2007). The mechanism underlying the cytopathology exhibited by the infected SGs cells is unknown, and the majority of the 108 muscavirus genes have no known homologs (Salem et al., 2009). However, ORF78 encodes a homolog of the baculovirus inhibitor of apoptosis (iap), which may be involved in the prevention of programmed cell death, thus allowing the persistence of non-lytic SGH throughout the adult housefly lifespan serving as a foci for production of progeny virus (Lietze et al., 2011c).
Species demarcation criteria have not been defined yet since Musca hytrovirus is the only species in the genus Muscavirus. Up to 16 different muscavirus isolates have been reported from several ecogeographical regions (Prompiboon et al., 2010, Geden et al., 2011b), but they have not been characterized.
Merodon equestris salivary gland hypertrophy virus1
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