RESUMEN
Viruses enter the host cell, and various strategies are employed to evade the host immune system. These include overcoming the various components of the immune system, including modulation of the physical and chemical barriers, non-specific innate response and specific adaptive immune response. Morbilliviruses impose immune modulation by utilizing various approaches including hindering antigen presentation to T-Helper (TH) cells, hematopoiesis and suppression of effector molecule activities. These viruses can also impede the early stages of T cell activation. Despite the availability of effective vaccines, morbilliviruses are still a significant threat to mankind. After infection, they also induce a state of immune suppression in the host. The molecular mechanisms employed by morbilliviruses to induce the state of immune suppression in the infected host are still being investigated. This review is an attempt to summarize insights into some of the strategies adopted by morbilliviruses to mediate immune modulation in the host.
RESUMEN
Peste des petits ruminants (PPR), a disease of socioeconomic importance has been a serious threat to small ruminants. The causative agent of this disease is PPR virus (PPRV) which belongs to the genus Morbillivirus. Hemagglutinin (H) is a PPRV coded transmembrane protein embedded in the viral envelope and plays a vital role in mediating the entry of virion particle into the cell. The infected host mounts an effective humoral response against H protein which is important for host to overcome the infection. In the present study, we have investigated structural, physiological and functional properties of hemagglutinin protein using various computational tools. The sequence analysis and structure prediction analysis show that hemagglutinin protein comprises of beta sheets as the predominant secondary structure, and may lack neuraminidase activity. PPRV-H consists of several important domains and motifs that form an essential scaffold which impart various critical roles to the protein. Comparative modeling predicted the protein to exist as a homo-tetramer that binds to its cognate cellular receptors. Certain amino acid substitutions identified by multiple sequence alignment were found to alter the predicted structure of the protein. PPRV-H through its predicted interaction with TLR-2 molecule may drive the expression of CD150 which could further propagate the virus into the host. Together, our study provides new insights into PPRV-H protein structure and its predicted functions.
RESUMEN
Peste des petits ruminants virus (PPRV) is known to induce transient immunosuppression in infected small ruminants by modulating several cellular pathways involved in the antiviral immune response. Our study shows that the PPRV-coded non-structural proteins C and V can interact with the cellular NF-κB p65 subunit. The PPRV-C protein interacts with the transactivation domain (TAD) while PPRV-V interacts with the Rel homology domain (RHD) of the NF-κB p65 subunit. Both viral proteins can suppress the NF-κB transcriptional activity and NF-κB-mediated transcription of cellular genes. PPRV-V protein expression can significantly inhibit the nuclear translocation of NF-κB p65 upon TNF-α stimulation, whereas PPRV-C does not affect it. The NF-κB-mediated pro-inflammatory cytokine gene expression is significantly downregulated in cells expressing PPRV-C or PPRV-V protein. Our study provides evidence suggesting a role of PPRV non-structural proteins V and C in the modulation of NF-κB signalling through interaction with the NF-κB p65 subunit.
Asunto(s)
Peste de los Pequeños Rumiantes , Virus de la Peste de los Pequeños Rumiantes , Animales , Humanos , Virus de la Peste de los Pequeños Rumiantes/genética , Peste de los Pequeños Rumiantes/metabolismo , Citocinas/genética , Citocinas/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Virales/genética , Proteínas Virales/metabolismo , Rumiantes , Expresión Génica , Cabras/genéticaRESUMEN
Autophagy is an essential and highly conserved catabolic process in cells, which is important in the battle against intracellular pathogens. Viruses have evolved several ways to alter the host defense mechanisms. PPRV infection is known to modulate the components of a host cell's defense system, resulting in enhanced autophagy. In this study, we demonstrate that the N protein of PPRV interacts with the core components of the class III phosphatidylinositol-3-kinase (PI3K) complex-I and results in the induction of autophagy in the host cell over, thereby expressing this viral protein. Our data shows the interaction between PPRV-N protein and different core components of the autophagy pathway, i.e., VPS34, VPS15, BECN1 and ATG14L. The PPRV-N protein can specifically interact with VPS34 of the PI3K complex-I and colocalize with the proteins of PI3K complex-I in the same sub-cellular compartment, that is, in the cytoplasm. These interactions do not affect the intracellular localization of the different host proteins. The autophagy-related genes were transcriptionally modulated in PPRV-N-expressing cells. The expression of LC3B and SQSTM1/p62 was also modulated in PPRV-N-expressing cells, indicating the induction of autophagic activity. The formation of typical autophagosomes with double membranes was visualized by transmission electron microscopy in PPRV-N-expressing cells. Taken together, our findings provide evidence for the critical role of the N protein of the PPR virus in the induction of autophagy, which is likely to be mediated by PI3K complex-I of the host.