T Cell Inactivation by Poxviral B22 Family Proteins Increases Viral Virulence

Abstract

Infections with monkeypox, cowpox and weaponized variola virus remain a threat to the increasingly unvaccinated human population, but little is known about their mechanisms of virulence and immune evasion. We now demonstrate that B22 proteins, encoded by the largest genes of these viruses, render human T cells unresponsive to stimulation of the T cell receptor by MHC-dependent antigen presentation or by MHC-independent stimulation. In contrast, stimuli that bypass TCR-signaling are not inhibited. In a non-human primate model of monkeypox, virus lacking the B22R homologue (MPXVΔ197) caused only mild disease with lower viremia and cutaneous pox lesions compared to wild type MPXV which caused high viremia, morbidity and mortality. Since MPXVΔ197-infected animals displayed accelerated T cell responses and less T cell dysregulation than MPXV US2003, we conclude that B22 family proteins cause viral virulence by suppressing T cell control of viral dissemination.

Characterization of a large, proteolytically processed cowpox virus membrane glycoprotein conserved in most chordopoxviruses

“…We considered that other CPXV genes might make the role of CPXV219 partially redundant or that the activity of CPXV219 is fine-tuned for its natural rodent host and is nonfunctional in mice. Both ideas are consistent with the recent report by Alzhanova and coworkers (Alzhanova et al, 2014). While searching for a MPXV gene product that renders T-cells non-responsive they identified MPX197, a homolog of CPXV219.…”

“…In a recent study Alzhanova and coworkers (Alzhanova et al, 2014) analyzed the monkeypox virus (MPXV) homolog of CPXV219. Their study and ours were consistent in providing evidence for proteolytic cleavage of the full-length protein and cell surface expression of the C-terminal fragment, despite methodological differences.…”

“…Their study and ours were consistent in providing evidence for proteolytic cleavage of the full-length protein and cell surface expression of the C-terminal fragment, despite methodological differences. In contrast to our approach, which involved construction of recombinant CPXV containing epitope tags at both the N- and C-termini, Alzhanova and co-workers (Alzhanova et al, 2014) relied on transient expression by plasmids in uninfected cells or by adenovirus vectors. Because the majority of their studies were carried out with only a C-terminal epitope tag, they did not demonstrate the formation of a stable N-terminal fragment.…”

Sequence of Pathogenic Events in Cynomolgus Macaques Infected with Aerosolized Monkeypox Virus

“…Larger animal group sizes, however, are needed in order to confirm this statistically. Nevertheless, this could be indicative of immunosuppression, as the immunomodulatory effect of monkeypox virus has been previously observed by others (2,31,32). The rises in lymphocytes, in particular CD8 ϩ T cells, observed later in monkeypox infection, are likely to be the result of the host raising an adaptive immune response to the viral infection.…”

A homolog of the variola virus B22 membrane protein contributes to ectromelia virus pathogenicity in the mouse footpad model

“…The protein is expressed early in infection, has a signal peptide and transits the secretory pathway where extensive glycosylation and proteolytic cleavage occur prior to insertion into the plasma membrane (Reynolds and Moss, 2015). The MPXV homolog (MPXV197) has similar properties (Alzhanova et al, 2014). The roles of CPX219 and MPXV197 have been studied in mice and rhesus macaques, respectively.…”