The Roseoloviruses Downregulate the Protein Tyrosine Phosphatase PTPRC (CD45)

Abstract

Like all herpesviruses, the roseoloviruses (HHV6A, -6B, and -7) establish lifelong infection within their host, requiring these viruses to evade host anti-viral responses. One common host-evasion strategy is the downregulation of host-encoded, surface-expressed glycoproteins. Roseoloviruses have been shown to evade the host immune response by downregulating NK-activating ligands, class I MHC, and the TCR/CD3 complex. To more globally identify glycoproteins that are differentially expressed on the surface of HHV6A-infected cells, we performed cell surface capture of N-linked glycoproteins present on the surface of T cells infected with HHV6A, and compared these to proteins present on the surface of uninfected T cells. We found that the protein tyrosine phosphatase CD45 is downregulated in T cells infected with HHV6A. We also demonstrated that CD45 is similarly downregulated in cells infected with HHV7. CD45 is essential for signaling through the T cell receptor and as such, is necessary for developing a fully functional immune response. Interestingly, the closely related β-herpesviruses human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) have also separately evolved unique mechanisms to target CD45. While HCMV and MCMV target CD45 signaling and trafficking, HHV6A acts to downregulate CD45 transcripts. Importance Human herpesviruses-6 and -7 infect essentially 100% of the world's population before the age of 5 and then remain latent or persistent in their host throughout life. As such, these viruses are among the most pervasive and stealthy of all viruses. Host immune cells rely on the presence of surface-expressed proteins to identify and target virus-infected cells. Here, we investigated the changes that occur to proteins expressed on the cell surface of T cells after infection with human herpesvirus-6A. We discovered that HHV-6A infection results in a reduction of CD45 on the surface of infected T cells and impaired activation in response to T cell receptor stimulation.

Evaluation of Inactivation Methods for Rift Valley Fever Virus in Mouse Microglia

“…In contrast, CD45 and CD11b are expressed on the surface of uninfected microglia [ 27 ] and their expression is downregulated upon ZH501, but not MP-12, infection. Infection with viruses from several families of DNA viruses including Herpesviruses [ 28 , 29 ] and Adenoviruses [ 30 ] has been shown to cause downregulation and/or modulation of CD45 activity most notably in T cells, resulting in decreased T cell activity and thus promoting viral persistence. In these cases, the modulation of CD45 activity is dependent on the specific binding of a viral protein to the CD45 protein [ 31 ].…”

Enforced dimerization of CD45 by the adenovirus E3/49K protein inhibits T cell receptor signaling

“…Interestingly, other viruses also have been reported to target CD45, yet appear to use different strategies. The T-cell-tropic roseoloviruses downregulate CD45 transcripts and the MCMV m42 protein induces CD45 degradation in lysosomes in infected cells (Thiel et al, 2016; Whyte et al, 2021). The m42 protein is a tail-anchored membrane protein with a cytosolic N-terminal domain lacking a significant extracellular part (Thiel et al, 2016).…”

“…One of these proteins, the HCMV UL11 protein, was also shown to bind to CD45 to reduce T cell signaling and proliferation and to increase IL-10 secretion as a recombinant Fc fusion protein (Gabaev et al, 2011; Osanyinlusi et al, 2022; Zischke et al, 2017). Conspicuously, CD45 is also targeted in infected cells by the m42 protein of murine cytomegalovirus (MCMV) that down-regulates cell surface expression of CD45 in RAW264.7 macrophages by triggering its lysosomal degradation (Thiel et al, 2016) and by the T-cell-tropic roseoloviruses which downregulate CD45 transcripts (Whyte et al, 2021).…”

High Prevalence of Common Human Viruses in Thyroid Tissue

“…Among herpesviruses, Epstein-Barr virus (EBV) has been associated with GD (17)(18)(19), while human herpes virus 6 (HHV-6) and cytomegalovirus (CMV) may be associated with both HT and GD (20)(21)(22)(23)(24). The aforementioned viruses may produce subclinical disease and persistent infection at any age (25)(26)(27)(28)(29).…”