インサイト - Evolutionary Computation - # Coevolution of Vertebrate Immune Receptors and 5'ppp-RNA Viruses

Evolutionary Arms Race Between Vertebrates and 5'ppp-RNA Viruses: The Role of MDA5 in Compensating for RIG-I Deficiency

Q: How might the evolutionary loss of RIG-I in vertebrates have influenced the overall diversity and complexity of their immune systems?

The evolutionary loss of RIG-I in vertebrates has likely had a significant impact on the overall diversity and complexity of their immune systems. RIG-I is a crucial component of the innate immune system, responsible for detecting viral RNA and initiating antiviral responses. Its loss in multiple vertebrate species suggests a dynamic evolutionary process shaped by the constant interaction between hosts and viruses. The absence of RIG-I in certain vertebrates has necessitated the evolution of alternative mechanisms to recognize and respond to viral infections. This loss has likely led to the diversification of immune receptors and pathways in these species. For example, the observed adaptations in MDA5, a homolog of RIG-I, demonstrate how vertebrates have evolved alternative receptors to compensate for the absence of RIG-I. This evolutionary process has likely contributed to the complexity and adaptability of the immune systems in these species, allowing them to effectively combat viral infections despite the loss of a key immune receptor.

Q: What other potential immune receptors or pathways could vertebrates have evolved to compensate for the loss of RIG-I, beyond the observed MDA5 adaptations?

In addition to the adaptations in MDA5 observed in response to the loss of RIG-I, vertebrates could have potentially evolved other immune receptors or pathways to compensate for this loss. One potential compensatory mechanism could involve the upregulation or modification of other pattern recognition receptors (PRRs) that can recognize viral components and initiate immune responses. For example, Toll-like receptors (TLRs) or cytosolic DNA sensors such as cGAS-STING pathway could be upregulated or modified to enhance antiviral immunity in the absence of RIG-I. Furthermore, vertebrates may have evolved novel signaling pathways or immune regulatory mechanisms to compensate for the loss of RIG-I. This could involve the activation of alternative downstream signaling cascades or the modulation of existing immune pathways to enhance antiviral responses. The evolution of these compensatory mechanisms would contribute to the overall resilience and effectiveness of the immune system in combating viral infections in the absence of RIG-I.

Q: Given the central role of m6A modifications in host-virus coevolution, are there any therapeutic strategies that could target these epigenetic mechanisms to enhance antiviral immunity?

The central role of m6A modifications in host-virus coevolution highlights the potential for targeting these epigenetic mechanisms as a therapeutic strategy to enhance antiviral immunity. One possible therapeutic approach could involve modulating the activity of m6A writers, erasers, or readers to manipulate the host immune response to viral infections. For example, targeting m6A writers such as METTL3 and METTL14 could potentially enhance the stability of antiviral immune factors like MDA5, leading to a more robust immune response against viral pathogens. Additionally, inhibiting m6A readers such as YTHDF proteins could prevent the degradation of m6A-modified antiviral transcripts, thereby increasing the expression of key immune factors involved in antiviral defense. By targeting specific components of the m6A machinery, it may be possible to fine-tune the host immune response to better combat viral infections and enhance overall antiviral immunity. Further research into the precise mechanisms of m6A regulation in the context of viral infections could uncover novel therapeutic targets for enhancing host immunity against a wide range of viral pathogens.

核心概念

In the absence of RIG-I, vertebrates have evolved MDA5 to recognize 5'ppp-RNA viruses, while viruses have developed m6A-mediated strategies to degrade MDA5 and evade host immunity.

要約

This study provides insights into the evolutionary arms race between vertebrates and 5'ppp-RNA viruses. The key findings are:

RIG-I, a crucial pattern recognition receptor for detecting 5'ppp-RNA, has been lost multiple times independently in vertebrate evolution, including in mammals, birds, and fish.
In the absence of RIG-I, vertebrates like the miiuy croaker (Miichthys miiuy) and chicken (Gallus gallus) have evolved their MDA5 receptor to recognize 5'ppp-RNA, compensating for the loss of RIG-I function.
The 5'ppp-RNA viruses, such as the siniperca cheer rhabdovirus (SCRV) and vesicular stomatitis virus (VSV), can utilize the m6A methylation mechanism to degrade the MDA5 receptor, weakening the host's antiviral immune response and promoting their own replication and immune evasion.
The recognition of 5'ppp-RNA by MDA5 depends on its C-terminal regulatory (RD) domain, similar to the function of the RD domain in RIG-I.
MDA5 can interact with the STING protein to facilitate signal transduction in the antiviral response, compensating for the loss of the RIG-I-STING interaction.
The evolutionary acquisition of 5'ppp-RNA recognition ability by MDA5 likely led to the functional redundancy and gradual loss of RIG-I in vertebrates.

Overall, this study provides a comprehensive understanding of the coevolutionary dynamics between vertebrate immune receptors and 5'ppp-RNA viruses, highlighting the adaptive strategies employed by both hosts and pathogens.

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biorxiv.org

統計

The loss of RIG-I in vertebrates can be traced back to approximately 330 million years ago.
MDA5 overexpression significantly inhibits SCRV viral replication, while MDA5 knockdown promotes it.
SCRV infection increases the m6A modification and expression levels of MDA5 in host cells.
METTL3 and METTL14 (m6A writers) can degrade MDA5 mRNA stability and expression, thereby suppressing the antiviral abilities of MDA5.
YTHDF2 and YTHDF3 (m6A readers) can recognize m6A-modified MDA5 and accelerate its degradation, while FTO (m6A eraser) can reverse this effect.

引用

"The incessant arms race between viruses and hosts has led to numerous evolutionary innovations that shape life's evolution."
"Viruses are constantly co-evolving with hosts. Our available data suggested that the vertebrate has evolved MDA5 with alternative functions to recognize and resist 5'ppp-RNA virus in the absence of RIG-I. As a response, virus has also evolved to use the m6A mechanism to evade the host immune response."
"By utilizing these m6A-related enzymes in the host, viruses can not only use m6A modification to hide themselves and avoid recognition by host receptors but also manipulate host gene expression to enable immune evasion."

抽出されたキーインサイト

An arms race between 5’ppp-RNA virus and its alternative recognition receptor MDA5 in RIG-I-lost teleost fish

by Geng,S., Lv,... 場所 www.biorxiv.org 01-11-2024

https://www.biorxiv.org/content/10.1101/2024.01.10.575132v2

深掘り質問

How might the evolutionary loss of RIG-I in vertebrates have influenced the overall diversity and complexity of their immune systems?

The evolutionary loss of RIG-I in vertebrates has likely had a significant impact on the overall diversity and complexity of their immune systems. RIG-I is a crucial component of the innate immune system, responsible for detecting viral RNA and initiating antiviral responses. Its loss in multiple vertebrate species suggests a dynamic evolutionary process shaped by the constant interaction between hosts and viruses.
The absence of RIG-I in certain vertebrates has necessitated the evolution of alternative mechanisms to recognize and respond to viral infections. This loss has likely led to the diversification of immune receptors and pathways in these species. For example, the observed adaptations in MDA5, a homolog of RIG-I, demonstrate how vertebrates have evolved alternative receptors to compensate for the absence of RIG-I. This evolutionary process has likely contributed to the complexity and adaptability of the immune systems in these species, allowing them to effectively combat viral infections despite the loss of a key immune receptor.

What other potential immune receptors or pathways could vertebrates have evolved to compensate for the loss of RIG-I, beyond the observed MDA5 adaptations?

In addition to the adaptations in MDA5 observed in response to the loss of RIG-I, vertebrates could have potentially evolved other immune receptors or pathways to compensate for this loss. One potential compensatory mechanism could involve the upregulation or modification of other pattern recognition receptors (PRRs) that can recognize viral components and initiate immune responses. For example, Toll-like receptors (TLRs) or cytosolic DNA sensors such as cGAS-STING pathway could be upregulated or modified to enhance antiviral immunity in the absence of RIG-I.
Furthermore, vertebrates may have evolved novel signaling pathways or immune regulatory mechanisms to compensate for the loss of RIG-I. This could involve the activation of alternative downstream signaling cascades or the modulation of existing immune pathways to enhance antiviral responses. The evolution of these compensatory mechanisms would contribute to the overall resilience and effectiveness of the immune system in combating viral infections in the absence of RIG-I.

Given the central role of m6A modifications in host-virus coevolution, are there any therapeutic strategies that could target these epigenetic mechanisms to enhance antiviral immunity?

The central role of m6A modifications in host-virus coevolution highlights the potential for targeting these epigenetic mechanisms as a therapeutic strategy to enhance antiviral immunity. One possible therapeutic approach could involve modulating the activity of m6A writers, erasers, or readers to manipulate the host immune response to viral infections. For example, targeting m6A writers such as METTL3 and METTL14 could potentially enhance the stability of antiviral immune factors like MDA5, leading to a more robust immune response against viral pathogens.
Additionally, inhibiting m6A readers such as YTHDF proteins could prevent the degradation of m6A-modified antiviral transcripts, thereby increasing the expression of key immune factors involved in antiviral defense. By targeting specific components of the m6A machinery, it may be possible to fine-tune the host immune response to better combat viral infections and enhance overall antiviral immunity. Further research into the precise mechanisms of m6A regulation in the context of viral infections could uncover novel therapeutic targets for enhancing host immunity against a wide range of viral pathogens.