Infection of cattle by bovine herpesvirus 1 (BoHV-1) can culminate in upper respiratory tract disorders, conjunctivitis, or genital disorders. Infection also consistently leads to transient immune-suppression. BoHV-1 is the number one infectious agent in cattle that is associated with abortions in cattle. BoHV-1, as other α-herpesvirinae subfamily members, establishes latency in sensory neurons. Stressful stimuli, mimicked by the synthetic corticosteroid dexamethasone, consistently induce reactivation from latency in latently infected calves and rabbits. Increased corticosteroid levels due to stress have a two-pronged effect on reactivation from latency by: (1) directly stimulating viral gene expression and replication, and (2) impairing antiviral immune responses, thus enhancing virus spread and transmission. BoHV-1 encodes several proteins, bICP0, bICP27, gG, UL49.5, and VP8, which interfere with key antiviral innate immune responses in the absence of other viral genes. Furthermore, the ability of BoHV-1 to infect lymphocytes and induce apoptosis, in particular CD4+ T cells, has negative impacts on immune responses during acute infection. BoHV-1 induced immune-suppression can initiate the poly-microbial disorder known as bovine respiratory disease complex, which costs the US cattle industry more than one billion dollars annually. Furthermore, interfering with antiviral responses may promote viral spread to ovaries and the developing fetus, thus enhancing reproductive issues associated with BoHV-1 infection of cows or pregnant cows. The focus of this review is to describe the known mechanisms, direct and indirect, by which BoHV-1 interferes with antiviral immune responses during the course of infection.

Bovine alphaherpesvirus 1 (BoHV-1) is a persistent and recurring disease that affects cattle worldwide. It is a major contributor to bovine respiratory disease and reproductive failure in the US. A major complication of BoHV-1 arises from the lifelong latent infection established in the sensory ganglia of the peripheral nervous system following acute infection. Lifelong latency is marked by periodic reactivation from latency that leads to virus transmission and transient immunosuppression. Physiological and environmental stress, along with hormone fluctuations, can drive virus reactivation from latency, allowing the virus to spread rapidly. This review discusses the mechanisms of the latency/reactivation cycle, with particular emphasis on how different hormones directly regulate BoHV-1 gene expression and productive infection. Glucocorticoids, including the synthetic corticosteroid dexamethasone, are major effectors of the stress response. Stress directly regulates BoHV-1 gene expression through multiple pathways, including β-catenin dependent Wnt signaling, and the glucocorticoid receptor. Related type 1 nuclear hormone receptors, the androgen and progesterone receptors, also drive BoHV-1 gene expression and productive infection. These receptors form feed-forward transcription loops with the stress-induced Krüppel-like transcription factors KLF4 and KLF15. Understanding these molecular pathways is critical for developing novel therapeutics designed to block reactivation and reduce virus spread and disease.

Macrophages are crucial members of the mononuclear phagocyte system essential to protect the host from invading pathogens and are central to the inflammatory response with their ability to acquire specialized phenotypes of inflammatory (M1) and anti-inflammatory (M2) and to produce a pool of inflammatory mediators. Equipped with a broad range of receptors, such as Toll-like receptor 4 (TLR4), CD14, and Fc gamma receptors (FcγRs), macrophages can efficiently recognize and phagocytize invading pathogens and secrete cytokines by triggering various secondary signaling pathways. Phospholipase C (PLC) is a family of enzymes that hydrolyze phospholipids, the most significant of which is phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Cleavage at the internal phosphate ester generates two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), both of which mediate in diverse cellular functions including the inflammatory response. Recent studies have shown that some PLC isoforms are involved in multiple stages in TLR4-, CD14-, and FcγRs-mediated activation of nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and interferon regulatory factors (IRFs), all of which are associated with the regulation of the inflammatory response. Therefore, secondary signaling by PLC is implicated in the pathogenesis of numerous inflammatory diseases. This review provides an overview of our current knowledge on how PLC signaling regulates the macrophage-mediated inflammatory response.

Bovine herpesvirus 1 (BoHV-1), an important bovine pathogen, establishes lifelong latency in sensory neurons. Latently infected calves consistently reactivate from latency following a single intravenous injection of the synthetic corticosteroid dexamethasone. The immediate early transcription unit 1 (IEtu1) promoter, which drives bovine ICP0 (bICP0) and bICP4 expression, is stimulated by dexamethasone because it contains two glucocorticoid receptor (GR) response elements (GREs). Several Krüppel-like transcription factors (KLF), including KLF15, are induced during reactivation from latency, and they stimulate certain viral promoters and productive infection. In this study, we demonstrate that the GR and KLF15 were frequently expressed in the same trigeminal ganglion (TG) neuron during reactivation and cooperatively stimulated productive infection and IEtu1 GREs in mouse neuroblastoma cells (Neuro-2A). We further hypothesized that additional regions in the BoHV-1 genome are transactivated by the GR or stress-induced transcription factors. To test this hypothesis, BoHV-1 DNA fragments (less than 400 bp) containing potential GR and KLF binding sites were identified and examined for transcriptional activation by stress-induced transcription factors. Intergenic regions within the unique long 52 gene (UL52; a component of the DNA primase/helicase complex), bICP4, IEtu2, and the unique short region were stimulated by KLF15 and the GR. Chromatin immunoprecipitation studies revealed that the GR and KLF15 interacted with sequences within IEtu1 GREs and the UL52 fragment. Coimmunoprecipitation studies demonstrated that KLF15 and the GR were associated with each other in transfected cells. Since the GR stimulates KLF15 expression, we suggest that these two transcription factors form a feed-forward loop that stimulates viral gene expression and productive infection following stressful stimuli.IMPORTANCEBovine herpesvirus 1 (BoHV-1) is an important viral pathogen that causes respiratory disease and suppresses immune responses in cattle; consequently, life-threatening bacterial pneumonia can occur. Following acute infection, BoHV-1 establishes lifelong latency in sensory neurons. Reactivation from latency is initiated by the synthetic corticosteroid dexamethasone. Dexamethasone stimulates lytic cycle viral gene expression in sensory neurons of calves latently infected with BoHV-1, culminating in virus shedding and transmission. Two stress-induced cellular transcription factors, Krüppel-like transcription factor 15 (KLF15) and the glucocorticoid receptor (GR), cooperate to stimulate productive infection and viral transcription. Additional studies demonstrated that KLF15 and the GR form a stable complex and that these stress-induced transcription factors bind to viral DNA sequences, which correlates with transcriptional activation. The ability of the GR and KLF15 to synergistically stimulate viral gene expression and productive infection may be critical for the ability of BoHV-1 to reactivate from latency following stressful stimuli.