What is Viruses?

Viruses are pathogens which have harmful effects on bodies. The body has different methods to eliminate them from the body. But some viruses have evasion mechanisms through which they can counteract the effects of the body. They can suppress the effects of the body and survive and propagate in the body.

Viruses interact with eukaryotic cells which causes the selection of genes which can block viral replication and propagation. Some viruses suppress apoptotic and necroptotic pathways. Some of them have Caspase8 inhibitors which inhibit the T cell proliferation.

Viral spread depends on the fate of infected cells. The interactions between viruses and eukaryotic cells have led to selection of eukaryotic genes that propagate cell death upon infection to block viral multiplication, while some viruses encode suppressors of cell death to counteract these protective mechanisms. Viruses suppress not only the apoptotic pathway but also the necroptotic pathway, demonstrating that both programmed cell death mechanisms are crucial for host defense. Caspase-8 is essential for T cell proliferation after antigen stimulation and for CD4+ and CD8+ T cell-mediated antiviral responses. Interestingly, viruses have evolved into having many specific caspase-8 inhibitors, such as cytokine response modifier A (CrmA), viral inhibitor of caspase activation (v-ICA), and viral FLICE-like inhibitory proteins (FLIPs). (Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity, 38(2), 209-223.).

Research has shown that Caspase8 inhibition, FLIPL and FADD suppress necroptosis by cleaving RIPK1, RIPK3 and CYLD. Caspase-8 inhibition is only a way to prevent induction of apoptosis to allow the virus to propagate in the infected cell. However, recently it became clear that caspase-8, FLIPL, and FADD negatively control necroptosis induction, probably by cleaving RIPK1, RIPK3, and CYLD or some other target(s) downstream of RIP3 kinase. This would mean that on the one hand inhibition of caspase-8 prevents apoptosis induction while on the other hand the cell would be sensitized to necroptosis induction. (Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity, 38(2), 209-223.). Inhibitor of caspase-8 and a RIPK3 are encoded by MCMV which helps it evade certain death pathways. Inhibitor Some viruses (e.g., MCMV) have evolved strategies to counteract several death pathways. MCMV encodes both an inhibitor of caspase-8 and a RIPK3 inhibitor, and so it can efficiently block both apoptosis and necroptosis. (Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity, 38(2), 209-223.) Cytomelagovirus induced RIPK3- dependent necrosis can be blocked by viral RIPK3 inhibitor, M45. The RHIM domain helps it to bind to RIPK3 nad block necroptosis. MCMV-induced RIPK3-dependent programmed necrosis is a major host defense pathway that can be effectively blocked by the viral RIPK3 inhibitor, M45.

This protein possesses a homotypic interaction domain RHIM, which enables it to bind RIPK3. Consequently, MCMV can efficiently block necroptosis, but strains lacking M45 or containing a mutation in its RHIM domain induce regulated necrosis that is dependent on RIPK3 but not on RIPK1. (Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity, 38(2), 209-223.) Cytomegaloviruses encode an array of cell-death suppressors to counter apoptotic cell-death pathways that may dominate in different cell and tissue settings. MCMV encodes three genes that target core components of the apoptotic machinery: viral mitochondrial inhibitor of apoptosis, vMIA, viral inhibitor of Bak oligomerization, vIBO, and viral inhibitor of caspase-8 activation, vICA. Together, these functions antagonize caspase-dependent death pathways that would otherwise compromise viral replication. (Upton, J. W., Kaiser, W. J., & Mocarski, E. S. (2010). Virus inhibition of RIP3-dependent necrosis. Cell host & microbe, 7(4), 302-313.) Expression of M45 was found to be important for ZBP1- and RIPK3-dependent necroptosis. MCMV contains both a viral inhibitor of caspase activation (vICA) and a viral inhibitor of RHIM activation (vIRA)15. vICA blocks apoptosis, but is a double-edged sword for the virus, as it also blocks caspase-8 activity and sensitizes to necroptosis. However, vIRA contains its own RHIM domain which interferes with the interaction of RIPK3 with DAI, a RHIM containing protein shown to be important in controlling herpesvirus infection through induction of necroptosis. HCMV seems to have evolved a different strategy to counteract necroptosis, as it does not encode a RHIM domain containing protein like vIRA, but can still block necroptosis downstream of RIPK3 via an unknown mechanism. (Brault, M. R. (2018). Engagement of programmed cell death by nucleic acid sensing (Doctoral dissertation).
(MCMV) infection: MCMV prevents ZBP1- and RIPK3-dependent necroptosis by expression of M45. (Maelfait, J., Liverpool, L., Bridgeman, A., Ragan, K. B., Upton, J. W., & Rehwinkel, J. (2017).

Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. The EMBO journal, 36(17), 2529-2543.) During M45-RHIM-mutant MCMV infection, the viral M36 protein—also known as viral inhibitor of caspase-8-induced apoptosis (vICA)—is believed to predispose cells to necroptosis by blocking caspase-8. (Maelfait, J., Liverpool, L., Bridgeman, A., Ragan, K. B., Upton, J. W., & Rehwinkel, J. (2017). Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. The EMBO journal, 36(17), 2529-2543.) Viruses in turn suppress necroptosis. A well-studied example is mouse cytomegalovirus. Expression of wild-type ZBP1 but not ZBP1-Za1a2mut protected Zbp1/ MEFs or NIH3T3 cells against MCMVM45mutRHIM-induced cytopathic effects 5 days post-infection. Furthermore, replication of the virus genome was blunted by wild-type but not by mutant ZBP1. These observations show that ZBP1 defended cells against MCMV and that intact ZBP1 ZBDs were required for this. (Maelfait, J., Liverpool, L., Bridgeman, A., Ragan, K. B., Upton, J. W., & Rehwinkel, J. (2017). Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. The EMBO journal, 36(17), 2529-2543.)
The dramatic differences in behavior of viruses expressing WT or RHIM-deficient form of vIRA, assayed in vitro and in vivo, demonstrate this cell-death suppressor is critical for MCMV replication and pathogenesis. (Upton, J. W., Kaiser, W. J., & Mocarski, E. S. (2010). Virus inhibition of RIP3-dependent necrosis. Cell host & microbe, 7(4), 302-313.) MCMV shows high evasion towards necroptosis but there are other viruses like HIV-1, HSV etc induce necrotic- like cell death. Several other viruses, including WNV, HIV type 1 (HIV-1), and herpes simplex virus (HSV), have been shown to induce necrotic-like cell death. (Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity, 38(2), 209-223.) MCMV can suppress IFN- activation. RIP3 partner DAI has the capacity to trigger RHIM and RIP3-dependent IFN activation in mouse and human cells, although neither NF-kB nor IFN contributes to virus-induced necrosis. DAI-dependent IFN activation can be suppressed by MCMV-encoded Vira. (Livingston-Rosanoff, J. W. U., & Lisa, P. (2014). True Grit: Programmed Necrosis in Antiviral. J Immunol, 192, 2019-2026.)

RIPK3 is required for protection against VV. The ones deficient in RIPK3, necroptosis is every evident. Infection of WT mice with VV induces tissue necroptosis and infiltration of neutrophils into visceral fat pads, but these events are significantly decreased in RIPK3-deficient animals. This reduced inflammation correlated with increased viral titers in the organs of RIPK3-deficient mice, and consequently, these mice were more vulnerable to the infection. This indicates that RIPK3 is required for protection against VV. (Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity, 38(2), 209-223.) The body produces high levels of TNF and IL-6 upon infection with dengue. Elevated levels of the proinflammatory cytokines TNF and IL-6 were observed upon infection of dengue. (Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity, 38(2), 209-223.) Evaluation of RIP3K-deficient mice has shown that necroptosis plays an important role in the control of vaccinia virus (VV) but is dispensable for the control of WT murine cytomegalovirus (MCMV), mouse hepatitis virus, and lymphocytic choriomeningitis virus (LCMV), arguing for case-specific strategies in host-virus immune responses. (Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity, 38(2), 209-223.) Recent reports showing the critical role of RIP1 and RIP3 in DR-induced necroptosis, together with previous evidence that vIRA physically interacts efficiently with RIP3 as well as RIP, suggest that vIRA may interact with RIP3 and/ or RIP1 to suppress cell death in sensitive cell types. (Upton, J. W., Kaiser, W. J., & Mocarski, E. S. (2010). Virus inhibition of RIP3-dependent necrosis. Cell host & microbe, 7(4), 302-313.)

The necrosome is a complex consisting of RIP1, RIP3, and Fas-associated protein with death domain leading to activation of the pseudokinase mixed lineage kinase like followed by a rapid plasma membrane rupture and inflammatory response through the release of damage-associated molecular patterns and cytokines. It was observed that even a necrosome could suppress apoptosis but the mechanism hasn’t been found yet. Necrosome also suppresses apoptosis but the underlying mechanism has not been described yet. ( Wu, X. N., Yang, Z. H., Wang, X. K., Zhang, Y., Wan, H., Song, Y., … & Han, J. (2014). Distinct roles of RIP1–RIP3 hetero-and RIP3–RIP3 homo-interaction in mediating necroptosis. Cell death and differentiation, 21(11), 1709.)

Inflammatory gene expression and cell death is one of the host mechanisms to evade pathogens. Cellular sensing of viral pathogens by the host activates inflammatory gene expression and triggers cell death. These distinct cell-intrinsic response pathways directly control viral spread from the portal of entry and influence the quality of pathogen-specific adaptive immunity. (Upton, J. W., Kaiser, W. J., & Mocarski, E. S. (2010). Virus inhibition of RIP3-dependent necrosis. Cell host & microbe, 7(4), 302-313.) The importance of death has been reinforced by the widespread existence of apoptotic cell-death suppressors, including those that viruses employ to subvert intrinsic clearance. These include caspase inhibitors, such as baculovirus p35, viral inhibitors of apoptosis, poxvirus crmA, and viral FLICE (caspase-8) inhibitory proteins, as well as mitochondrial cell-death suppressors such as viral Bcl-2 homologs and other proteins encoded by large DNA viruses that block cytochrome release from mitochondria. (Upton, J. W., Kaiser, W. J., & Mocarski, E. S. (2010). Virus inhibition of RIP3-dependent necrosis. Cell host & microbe, 7(4), 302-313.) Pathogen recognition receptors trigger NF-kB and IRF3/IRF7, activating production of IFN and other cytokines. These sensors regulate alternate activation of cytokines or cell death in a manner analogous to TNF family death receptor signaling, subject to modulation by virus-encoded cell death suppressors. ( Livingston-Rosanoff, J. W. U., & Lisa, P. (2014). True Grit: Programmed Necrosis in Antiviral. J Immunol, 192, 2019-2026.) TNF-induced necroptosis makes a striking contribution to host defense against the poxvirus and vaccinia in mice where a virus-encoded inhibitor related to CrmA likely unleashes the pathway. (Livingston-Rosanoff, J. W. U., & Lisa, P. (2014). True Grit: Programmed Necrosis in Antiviral. J Immunol, 192, 2019-2026.) The ability of TCR to trigger RIP3 necrosis indicates that the CARMA1–BCL10–MALT1 complex that normally activates NF-kB also in?uences the core “Ripoptosome” complex or, alternatively, contributes to increased production of TNF, followed by TNFR1-induced necroptosis. (Livingston-Rosanoff, J. W. U., & Lisa, P. (2014). True Grit: Programmed Necrosis in Antiviral. J Immunol, 192, 2019-2026.)

While caspase-8 suppression is the most well characterized “trapdoor” for pathogens, it seems probable that there are other cellular perturbations that lead to RIPK3 activation and necroptosis. What these cellular changes are and how they lead to RIPK3 activation remains to be explored. (Brault, M. R. (2018). Engagement of programmed cell death by nucleic acid sensing (Doctoral dissertation).

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