Antiviral responses of ATG13 to the infection of peste des petits ruminants virus through activation of interferon response.

Not only are autophagy-related (ATG) proteins the essential orchestrators of the autophagy machinery, but also they regulate many other cellular pathways. Here, we demonstrated that ATG13 exerted an obviously antiviral activity against the infection of peste des petits ruminants virus (PPRV) in cell culture model. We found that PPRV infection or the treatment with interferon (IFN) against PPRV infection significantly induced ATG13 expression. Mechanistically, ATG13 stimulated interferon expression and the subsequent activation of the JAK-STAT cascade. These activations triggered the transcription of interferon-stimulated genes (ISGs) to exert antiviral activity. Conversely, the loss of ATG13 significantly attenuated the potency of RIG-IN in activating IFN responses. In summary, we have demonstrated that basal ATG13 was involved in host antiviral activities against PPRV infection and the over-expression of ATG13 activated IFN production to inhibit PPRV replication in an unconventional fashion.

Basal interferon signaling and therapeutic use of interferons in controlling peste des petits ruminants virus infection.

Peste des petits ruminants virus (PPRV) is a morbillivirus which causes severe disease in ruminants. Since interferons (IFNs) serve as the important defense line against viral infection, we have investigated the roles of types I and III IFNs in PPRV infection in vitro. Upon PPRV infection, IFN-λ3 was strongly induced, while IFN-ß and IFN-λ2 were moderately induced at transcriptional level in human embryonic kidney 293 T (HEK293T) cells. Although the transcription of type I and III IFNs were triggered, the production of functional IFN products was not detected. Importantly, the replication of PPRV was strongly inhibited in HEK293T cells treated by the exogenous IFNs (IFN-α-2b, IFN-ß and IFN-λ3). Consistently, these IFNs significantly activate a panel of IFN-stimulated genes (ISGs). The inhibition of JAK-STAT pathway by JAK I inhibitor can abrogate the anti-PPRV activity of IFNs. Thus, our study shall contribute to better understanding of the complex PPRV-host interactions and provide rationale for therapeutic development of IFN-based treatment against PPRV infection.

The IMPDH inhibitors, ribavirin and mycophenolic acid, inhibit peste des petits ruminants virus infection.

Peste des petits ruminants virus (PPRV) causes highly contagious diseases in domestic and particular wild small ruminants, leading to substantial economic loss. The development of effective and cheap antiviral medications shall help to circumvent this emerging burden. In this study, we found that ribavirin, a competitive inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor, significantly inhibits the replication of PPRV. As IMPDH is a key enzyme in purine nucleotide synthesis, supplementation of exogenous guanosine attenuate the anti-PPRV effect of ribavirin. Interestingly, an uncompetitive IMPDH inhibitor, mycophenolic acid (MPA), exerted more potent antiviral effect again PPRV. Similarly, this effect was largely restored upon supplementation of guanosine. Thus, we have demonstrated that the IMPDH inhibitors ribavirin and MPA combat PPRV infection through purine nucleotide depletion. Because both regimens have been widely used in the clinic for treating viral infection or organ rejection in transplantation patients for decades, respectively, repurposing these existing safe and cheap medications may provide a new avenue for combating PPRV infection.

Peste des petits ruminants virus infection of small ruminants: a comprehensive review.

Peste des petits ruminants (PPR) is caused by a Morbillivirus that belongs to the family Paramyxoviridae. PPR is an acute, highly contagious and fatal disease primarily affecting goats and sheep, whereas cattle undergo sub-clinical infection. With morbidity and mortality rates that can be as high as 90%, PPR is classified as an OIE (Office International des Epizooties)-listed disease. Considering the importance of sheep and goats in the livelihood of the poor and marginal farmers in Africa and South Asia, PPR is an important concern for food security and poverty alleviation. PPR virus (PPRV) and rinderpest virus (RPV) are closely related Morbilliviruses. Rinderpest has been globally eradicated by mass vaccination. Though a live attenuated vaccine is available against PPR for immunoprophylaxis, due to its instability in subtropical climate (thermo-sensitivity), unavailability of required doses and insufficient coverage (herd immunity), the disease control program has not been a great success. Further, emerging evidence of poor cross neutralization between vaccine strain and PPRV strains currently circulating in the field has raised concerns about the protective efficacy of the existing PPR vaccines. This review summarizes the recent advancement in PPRV replication, its pathogenesis, immune response to vaccine and disease control. Attempts have also been made to highlight the current trends in understanding the host susceptibility and resistance to PPR.

RNA interference against animal viruses: how morbilliviruses generate extended diversity to escape small interfering RNA control.

Viruses are serious threats to human and animal health. Vaccines can prevent viral diseases, but few antiviral treatments are available to control evolving infections. Among new antiviral therapies, RNA interference (RNAi) has been the focus of intensive research. However, along with the development of efficient RNAi-based therapeutics comes the risk of emergence of resistant viruses. In this study, we challenged the in vitro propensity of a morbillivirus (peste des petits ruminants virus), a stable RNA virus, to escape the inhibition conferred by single or multiple small interfering RNAs (siRNAs) against conserved regions of the N gene. Except with the combination of three different siRNAs, the virus systematically escaped RNAi after 3 to 20 consecutive passages. The genetic modifications involved consisted of single or multiple point nucleotide mutations and a deletion of a stretch of six nucleotides, illustrating that this virus has an unusual genomic malleability.

Synthesis and antiviral activity of 4,4'-(arylmethylene)bis(1H-pyrazol-5-ols) against peste des petits ruminant virus (PPRV).

An efficient and eco-friendly method for the synthesis of 4,4'-(arylmethylene)bis(1H-pyrazol-5-ols) has been accomplished by tandem Knoevenagel-Michael reaction of two equivalents of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one with various aromatic aldehydes catalyzed by ceric ammonium nitrate (CAN) in water. All the synthesized compounds 3a-j were evaluated for in vitro antiviral activity against peste des petits ruminant virus (PPRV). Compound 3i emerged as the most interesting compound in this series exhibiting excellent antiviral activity against PPRV and found to be more potent than the standard drug ribavirin used.