Bovine Herpesvirus 1 Counteracts Immune Responses and Immune-Surveillance to Enhance Pathogenesis and Virus Transmission

Abstract

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.

Keywords: VP8; abortion; bovine herpesvirus 1 (BoHV-1); bovine respiratory disease complex; immune evasion; infected cells protein 0 (bICP0).

Figure 1

BoHV-1 encoded immune-evasion genes that promote productive infection. Cellular mechanisms leading to innate immune antiviral signaling pathways are denoted in blue. Red lettering denotes viral genes that counteract antiviral signaling pathways. It is well-established that two protein kinases (IKK-ε +TBK1) activate the transcription factors (IRF3 and IRF7), which are required for activating the IFN-β promoter (–98). The JNK protein kinase (c-Jun N-terminal kinases) activates the AP1 (activating protein 1) and ATF2 (activating transcription factor 2), which are also required for activating the IFN-β promoter (–98). For further details, see the text.