Rinderpest Virus Blocks Type I and Type II Interferon Action: Role of Structural and Nonstructural Proteins

Abstract

Rinderpest virus (RPV) is a paramyxovirus closely related to the human pathogen Measles virus. It causes severe disease in cattle, buffalo, and some wild animals; although it can infect humans, it does not cause disease. Here, we demonstrate that RPV blocks the action of both type I (␣) and type II (␥) interferons (IFNs) by blocking the phosphorylation and nuclear translocation of STAT1 and STAT2 and that this block is not related to species specificity. In addition, both wild-type virulent and vaccine strains of the virus blocked IFN action. Unlike the case with some other paramyxoviruses, neither STAT1 nor STAT2 is degraded upon virus infection. STAT1 is bound by both the viral structural protein P, and thereby recruited to concentrations of viral protein in the cell, and the nonstructural protein V. Although both P and V proteins bind to STAT1 and can block IFN action when expressed in transfected cells, the IFN antagonist activity of the P protein is weaker than that of the V protein. The viral C protein also seems to weakly block IFN-induced activation of STAT1 in transfection experiments. However, studies with knockout viruses showed that the viral V protein appears to be the dominant inhibitor of IFN signaling in the context of virus infection, since prevention of viral V expression restored the IFN sensitivity of infected cells. Although a change in the distribution pattern of STAT2 was observed in virus-infected cells, STAT2 was not bound by any viral protein.

Paramyxovirus evasion of innate immunity: Diverse strategies for common targets

“…MeV V protein does not degrade STATs [104] , but has been reported by different laboratories to use several distinct mechanisms, including inhibition of STAT nuclear translocation without affecting STAT phosphorylation [103][104][105] , and inhibition of STAT1 and STAT2 phosphorylation due to interaction of its N-terminal domain with JAK1 [106,107] . Canine distemper virus (CDV) and RPV V proteins also inhibit IFN-activated STAT1/STAT2 nuclear import [108,109] , with RPV V protein, but not that of CDV, inhibiting STAT1/2 phosphorylation.…”

Two Domains of the V Protein of Virulent Canine Distemper Virus Selectively Inhibit STAT1 and STAT2 Nuclear Import

“…We then investigated at which step the CDV-V protein was able to affect the IFN-␣/␤-mediated signaling pathway. However, conclusions drawn from singleprotein overexpression experiments may differ from results obtained with the same protein in the context of a viral infection (25). In order to overcome this problem, we generated 30 min with IFN-␣/␤ and subsequently fixed, permeabilized, and stained for STAT1 localization using an anti-STAT1 antibody.…”

“…For instance, the V proteins of rubulaviruses are responsible for a direct degradation of the pool of STAT molecules in the cytoplasm, whereas the V proteins of MV (depending on the viral strain) and RPV inhibit the phosphorylation of STAT1 and STAT2 upon IFN treatment (5,8,25,30,42). In line with these results, we next examined by immunoblotting whether the CDV-V-mediated inhibition of the IFN-␣/␤-mediated signaling pathway was due to either STAT degradation or inhibition of STAT phosphorylation.…”

“…Upon IFN-␣/␤ treatment, accumulation of STAT1 and STAT2 in the cytoplasm rather than in the nucleus was reported to occur in cells infected with measles and rinderpest morbilliviruses (MV and RPV, respectively) (8,25,28). Thus, taking advantage of our newly generated recombinant viruses, we next assessed by immunofluorescence analysis whether the nuclear accumulation of STAT1 and STAT2 was modulated by these viruses.…”

“…In addition, recent work done with C-and V-deficient recombinant measles virus (MV) and rinderpest virus (RPV) indicated that V and, to some extent, P contribute to the final control of the IFN-␣/␤-mediated signaling pathway. However, to analyze the functions of the P gene products, these recombinant viruses were based on the genetic background of vaccine strains (8,25). Nevertheless, the paramyxovirus V protein has been identified as the main inhibitor of the IFN-induced antiviral state though various molecular mechanisms were unraveled (12,14,15).…”