Lepidopteran insects are the only known hosts for tetraviruses. A systematic survey of approximately a thousand diseased insects from different orders showed tetravirus hosts were confined largely to noctuid, saturniid and lymacodid moths of the Heterocera suborder of the Lepidoptera. Tetraviruses appear to differ in the breadth of the range of species they are able to infect. HaSV appears unable to infect species outside the subfamily Heliothinae, while Tricoplusia ni virus (TnV) and Dasychira pudibunda virus (DpV) are able to infect insects outside the family of their nominal host. Closely related viruses may have very distinct host ranges, as exemplified by NwV and HaSV. The former is able to infect a saturniid host, yet is unable to infect the noctuid heliothine host of the latter, despite having a high degree of relationship (>90% for the replicase).
No replication in other animals has been detected. Numerous animals injected with high titres of tetraviruses for antibody production have failed to show any abnormal response or disease symptoms. A detailed pathological study of mice injected with TaV showed no evidence that the virus was in any observable way harmful to them. Transfection of vertebrate cell lines with HaSV genomic RNA also showed no activity. However, studies on serological reactions by vertebrates (including humans) towards particles of tetraviruses, done in the 1970s, suggested that tetravirus specificity was more broad as positive reactions were noted. However, these reactions are believed to be nonspecific, owing to the type of serological test involved and indications that the reaction is not due to replication. Further work is required to consolidate these findings, especially in view of the large body of evidence showing the specificity of tetraviruses for insects and their potential widespread use in agriculture (see below).
Horizontal transmission via ingestion by larvae has been demonstrated for several tetraviruses. Interestingly, the range of symptoms from this means of transmission varies greatly. Few or no symptoms (only slight growth retardation at high doses) can be seen upon infection of several hosts by TnV. On the other hand, N/?V displays a marked pathological effect upon larvae 7-9 days postinfection, with infected larvae in all stages ceasing to feed, becoming moribund, discolored and flaccid, and, upon death, remaining hanging by their prolegs. The cadavers are distinct from those infected with baculoviruses because an internal liquefaction occurs which leaves the integument intact. A dependence upon the larval life-stage can also be seen. HaSV is highly active against neonate larvae, with as little as 5000 particles causing them to cease feeding within a day and to die within 4 days. Surprisingly, HaSV infection of later instar larvae shows little effect. It has not been clearly demonstrated whether adults or pupae are capable of being infected by tetraviruses, although N/JV was reported to be isolated from these stages.
Vertical transmission of tetraviruses is also believed to occur. It has been impossible to remove HaSV from a laboratory-bred colony of its host despite stringent sanitation procedures. Evidence from studies of HaSV pathology in early instar larvae show subpathogenic, low-level infections exist for this virus, which is highly virulent at higher doses. TnV appears to be vertically transmitted under artificial conditions and there is evidence for vertical transmission of the more virulent DpV. Symptoms of infection from this route are difficult to detect, with the most obvious being slow-growing larvae. The
TETRAVIRUSES (TH77MMRKME) 1771
evidence for vertical transmission, however, remains undefinitive and further work needs to be done to establish it. The most likely mechanism for vertical transmission, should it occur, is transovum, as tetraviruses appear to infect only midgut cells (see below).
All the available evidence points to the larval midgut as the exclusive site of infection of tetraviruses. Examinations by light and electron microscopy for several viruses have shown their particles only in midgut tissues. In a definitive experiment showing this phenomenon, Northern blots of RNA extracted from infected larvae showed the presence of HaSV RNA only in midgut tissue, even after infection by injection into the hemocele. This experiment also shows that the tissue tropism of HaSV is not due to the lack of exposure to the virus by other host tissues. The marked tropism of HaSV which prevents its culture in continuous cell lines appears to be a function of both the abilities of the particles to bind and enter cells and a restriction on the activity of the replicase in cells other than those of the midgut. Binding studies using the histochemical detection of HaSV particles on cross-sections of larval midguts show exclusive binding to outer cell membranes, particularly the goblet cell apical membrane. However, even when cellular uptake mechanisms for particle entry are bypassed in cultured cells (including those of the cotton bollworm host, Helicoverpa armigera) by transfection of HaSV genomic RNA, no replication activity is seen.
In the most detailed pathology study for a tetra-virus, HaSV was seen to infect all three major cell types of the lepidopteran midgut: goblet, columnar and regenerative stem cells. Infected cells showed crystalline arrays of particles, which were associated with a massive increase in the rate of cells detaching from the basal membrane and shedding into the lumen. Cells were shed to the extent that few, if any, remained in midguts of insects with advanced infections; this phenomenon was correlated to an increased rate of apoptosis. Hence the rapid loss of infected gut cells may be a cellularly mediated defense that protects the insect against more extensive viral infection.
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