The transcriptional profile of
H. zea gut epithelial tissue was analyzed by DNA microarray 24 h following viral infection and compared to that of uninfected tissues. The gut epithelium is a tissue that, by virtue of its function, undergoes dynamic changes in transcription during different life stages, diet and feeding conditions, and exposure to environmental hazards such as pathogens or toxins [
41,
42,
43]. It is generally accepted that the gut is the site of primary baculovirus infection, and our analyses reveal a rapidly evolving reaction by the host to respond offensively to the virus, as well as virus manipulation of the host defense and cellular machinery to propagate itself at the expense of the insect [
44,
45,
46]. These findings are supported by those seen by Breitenbach
et al. [
20] and Nguyen
et al. [
27], where both analyzed
Heliothis virescens or
H. zea transcriptional responses to similar baculoviruses, HzSNPV or
Helicoverpa armigera nucleopolyhedrovirus (HearNPV), respectively. Importantly, as well as being the first report on
H. zea gut global transcription in response to baculovirus infection, these data complement those of the other groups, who focused on hemocytes in
H. virescens or cell line cultures of
H. zea, and careful comparison may provide insights into how these vastly different tissues both respond to, and are exploited by, the replicating virus.
In agreement with extensive research in baculovirus-mediated suppression of the insect’s apoptotic pathway(s), our results likewise demonstrate the extent and magnitude of the effect of baculovirus inhibitors of apoptosis [
19,
47,
48,
49,
50]. Over half of the apoptotic genes analyzed were suppressed; some genes related to apoptosis, however, were up-regulated. Most notably, in the gut epithelium (
Table 2) short class caspase, initiator caspase (DREDD), and effector caspase were all repressed in response to viral infection. Baculoviruses, including HzSNPV, inhibit the efficacy of the caspase, which are enzymes that promote the apoptotic program of planned cell death. Survivin (
Table 2) works in tandem with viral-encoded apoptotic inhibitors as it acts as an inhibitor of apoptosis proteins (iaps) [
51,
52]. While the vast majority of the genes in this group for the gut epithelium were repressed, we detected a number that were up-regulated, such as DAXX-like protein. While it remains incompletely characterized, this protein is thought to play a crucial role in cell survival signaling [
53,
54,
55]. Therefore, the higher expression levels of DAXX-like protein observed in this study suggests the stimulation of the anti-apoptosis regulation, which in turn, prolongs the infectivity of HzSNPV throughout its infection cycles. The observation of a number of up-regulated genes related to apoptosis likely points to the relatively early 24 h time point at which these tissues were harvested; the general outcome and hallmark of lethal infection is a global suppression of the apoptotic response, allowing the virus to disseminate within and without the hemoceol by later times post infection. Our work also reinforces the extent to which the virus modulates the life cycle and development of the insect during its natural history of infection, demonstrating hormone suppression, specifically found in phenol UDP-glucosyltransferase (
Table 2 and
Table S1), that functions to suppress ecdysteroids [
56,
57]. This functionally slows, or stops the progression of molting/pupating, thus allowing the virus to prolong infection and produce more environmentally stable polyhedra. Other notable genes involved in viral exploitation of host function include DEAD Box RNA helicase genes, which aid in viral replication [
58,
59]. HzSNPV, as well as other baculoviruses, alter eukaryotic initiation factors in the cells they manipulate [
60,
61]. Also of significance was the observation of a generalized inhibition of several key metabolic pathways that function in energy storage and utilization. Whereas healthy larvae move metabolites and digestive products efficiently from the midgut into the hemocel for storage in the fat body, the nearly global inhibition of these processes, including glucose and other sugar utilization, fatty acid metabolism, and amino acid trafficking offer additional insights as to the degree to which baculoviruses alter host behavior at the molecular level to promote their replication and spread at the expense of the host.
Endogenous retrotransposon and retrovirus-like genes were detected in this microarray study. These genes are related to the evolutionary histories of insects and retroviral elements that have been assimilated into the host genome [
62,
63]. These genes generally code for gag-pol repeat proteins, as well those identified as retroelement polypeptides and reverse transcriptase, findings that agree with previous analysis of other tissues in infected HzSNPV [
20]. It remains poorly understood how baculovirus infection stimulates retroviral reactivation and/or retrotransposon activity; given the large number of transposable elements found in these and other insects, it is quite likely that a combination of direct stimulation by baculovirus transcriptional transactivators and cellular transactivators in the infected cells both play a role in mobilizing these otherwise quiescent elements [
64].
Taken together, these results demonstrate the degree to which lethal HzSNPV infection modulates the gut epithelium of its natural host, and adds to an evolving picture of virus-mediated transcriptional regulation during the natural history of infection by baculoviruses. Our real-time qRT-PCR results confirm the validity of a sampling of those genes that were identified in our microarray, and further analysis of baculovirus transcriptional targets may provide new insights as to how this and closely related baculoviruses have evolved to exploit host machinery, as well as identify cellular pathways and effector molecules that may suppress replication and allow for host escape from mortal infection.