Peste des petits ruminants virus (PPRV) causes a fatal disease in small ruminants. V protein of PPRV plays a pivotal role in interfering with host innate immunity by blocking IFNs signaling through interacting with STAT1 and STAT2. In the present study, the results demonstrated that PPRV V protein blocks IFN actions in a dose dependent manner and restrains the translocation of STAT1/2 proteins. We speculate that the translocation inhibition might be caused by the interfering of the downstream of STAT protein. Mutagenesis defines that Cys cluster and Trp motif of PPRV V protein are essential for STAT-mediated IFN signaling. These findings give a new sight for the further studies to understand the delicate mechanism of PPRV to escape the IFN signaling.
Peste des petits ruminants virus (PPRV) is the etiological agent of peste des petits ruminants, causing acute immunosuppression in its natural hosts. However, the molecular mechanisms by which PPRV antagonizes the host immune responses have not been fully characterized. In particular, how PPRV suppresses the activation of the host RIG-I-like receptor (RLR) pathway has yet to be clarified. In this study, we demonstrated that PPRV infection significantly suppresses RLR pathway activation and type I interferon (IFN) production and identified PPRV N protein as an extremely important antagonistic viral factor that suppresses beta interferon (IFN-β) and IFN-stimulated gene (ISG) expression. A detailed analysis showed that PPRV N protein inhibited type I IFN production by targeting interferon regulatory factor 3 (IRF3), a key molecule in the RLR pathway required for type I IFN induction. PPRV N protein interacted with IRF3 (but not with other components of the RLR pathway, including MDA5, RIG-I, VISA, TBK1, and MITA) and abrogated the phosphorylation of IRF3. As expected, PPRV N protein also considerably impaired the nuclear translocation of IRF3. The TBK1-IRF3 interaction was involved significantly in IRF3 phosphorylation, and we showed that PPRV N protein inhibits the association between TBK1 and IRF3, which in turn inhibits IRF3 phosphorylation. The amino acid region 106 to 210 of PPRV N protein was determined to be essential for suppressing the nuclear translocation of IRF3 and IFN-β production, and the 140 to 400 region of IRF3 was identified as the crucial region for the N-IRF3 interaction. Together, our findings demonstrate a new mechanism evolved by PPRV to inhibit type I IFN production and provide structural insights into the immunosuppression caused by PPRV.
IMPORTANCE Peste des petits ruminants is a highly contagious animal disease affecting small ruminants, which threatens both small livestock and endangered susceptible wildlife populations in many countries. The causative agent, peste des petits ruminants virus (PPRV), often causes acute immunosuppression in its natural hosts during infection. Here, for the first time, we demonstrate that N protein, the most abundant protein of PPRV, plays an extremely important role in suppression of interferon regulatory factor 3 (IRF3) function and type I interferon (IFN) production by interfering with the formation of the TBK1-IRF3 complex. This study explored a novel antagonistic mechanism of PPRV.
Inflammation refers to the response of the immune system to viral, bacterial, and fungal infections, or other foreign particles in the body, which can involve the production of a wide array of soluble inflammatory mediators. It is important for the development of many RNA virus-infected diseases. The primary factors through which the infection becomes inflammation involve inflammasome. Inflammasomes are proteins complex that the activation is responsive to specific pathogens, host cell damage, and other environmental stimuli. Inflammasomes bring about the maturation of various pro-inflammatory cytokines such as IL-18 and IL-1β in order to mediate the innate immune defense mechanisms. Many RNA viruses and their components, such as encephalomyocarditis virus (EMCV) 2B viroporin, the viral RNA of hepatitis C virus, the influenza virus M2 viroporin, the respiratory syncytial virus (RSV) small hydrophobic (SH) viroporin, and the human rhinovirus (HRV) 2B viroporin can activate the Nod-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome to influence the inflammatory response. On the other hand, several viruses use virus-encoded proteins to suppress inflammation activation, such as the influenza virus NS1 protein and the measles virus (MV) V protein. In this review, we summarize how RNA virus infection leads to the activation or inhibition of the NLRP3 inflammasome.
Peste des petits ruminants virus (PPRV) is a Morbillivirus that causes highly contagious and severe disease in various ruminants. PPRV infection leads to a severe inhibition of host antiviral immune response. Our previous study demonstrated that PPRV V protein blocks IFN response by targeting STAT proteins. In the current study, we identified the phosphoprotein (P) as a novel antagonistic factor of PPRV to counteract host antiviral innate immune response. PPRV P protein significantly suppressed RIG-Ilike receptor pathway signaling and impaired IFN-b and ISGs expression by targeting IFN regulatory factor (IRF)3 in both human embryonic kidney 293T cells and primary goat fibroblasts. The 1-102 region of P protein was critical for the antagonistic function of P protein. P protein interacted with IRF association domain (IAD) of IRF3 to block the interaction between TBK1 and IRF3. The interaction between TBK1 and the IAD of IRF3 is responsible for triggering the phosphorylation of IRF3. P protein competed with TBK1 to bind to the IAD of IRF3 that contributed to the decreased phosphorylation of IRF3, which, in turn, interfered with the dimerization of IRF3 and blocked IRF3 nuclear transportation. Besides, we also found that P protein interacted with IRF5 and IRF8. However, the involved mechanism remains unknown. Taken together, our results reveal a novel mechanism by which PPRV P protein antagonizes host antiviral innate immune response by interacting with the transcription factor IRF3, thereby inhibiting the type I IFN production and promoting viral replication.
Inflammation refers to the response of the immune system to viral, bacterial, and fungal infections or other foreign particles in the body, which can involve the production of a wide array of soluble inflammatory mediators. The NLRP3 inflammasome is one of the best-characterized inflammasome leading to IL-1β production and maturation.
The tapeworm Taenia solium is an important human zoonotic parasite that causes great economic loss and also endangers public health. At present, an effective vaccine that will prevent infection and chemotherapy without any side effect remains to be developed. In this study, codon usage patterns in the T. solium genome were examined through 8,484 protein-coding genes. Neutrality analysis showed that T. solium had a narrow GC distribution, and a significant correlation was observed between GC12 and GC3. Examination of an NC (ENC vs GC3s)-plot showed a few genes on or close to the expected curve, but the majority of points with low-ENC (the effective number of codons) values were detected below the expected curve, suggesting that mutational bias plays a major role in shaping codon usage. The Parity Rule 2 plot (PR2) analysis showed that GC and AT were not used proportionally. We also identified 26 optimal codons in the T. solium genome, all of which ended with either a G or C residue. These optimal codons in the T. solium genome are likely consistent with tRNAs that are highly expressed in the cell, suggesting that mutational and translational selection forces are probably driving factors of codon usage bias in the T. solium genome.
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