Table 1.
The effect of viral and host m6A on pathogenesis and innate immune responses to infection.
| Virus (Family) |
Genome DNA/RNA |
Effect on Viral Replication/ Pathogenesis |
Effect on Innate/ IFN Response |
Effect on Specific Genes/Signaling Cascades | Ref. |
|---|---|---|---|---|---|
| HCV (Flaviviridae) |
(+)ssRNA | Neg[−] | METTL3/14 siRNA increases IFN-β expression. | M6A interferes with viral packaging and assembly. Negatively affects RIG-I recognition of viral RNA and pathway activation. Differentially expressed m6A-modified host transcripts for innate immune response and ER-stress response pathways. | [53,63,64] |
| Zika (Flaviviridae) |
(+)ssRNA | Neg[−] | n/a | Differentially expressed m6A-modified host transcripts for innate immune response and ER-stress response pathways. | [54,64] |
| Influenza A (Orthomyxoviridae) |
(−)ssRNA | Pos[+] | M6A is a negative regulator of IFN-α, IFN-β, and ISG expression. m6A-modified IFNA and IFNB transcripts degrade faster. | Knockout of METTL3 decreases viral protein production. M6A-deficient IAV is less pathogenic in vivo. | [55,65] |
| SARS-CoV-2 (Coronaviridae) |
(+)ssRNA | Pos[+] | Low METTL3/14 levels result in weak Type I and III IFN response. | METTL3 KD results in increased RIG-I recognition of viral RNA and up-regulates cytokine/chemokine genes. | [56] |
| HMPV (Pneumoviridae) |
(−)ssRNA | Pos[+] | Infection with m6A-deficient virus increases Type I IFN response. | Infection with m6A-deficient virus increase RIG-I expression. RIG-I binds more efficiently to m6A-deficient viral RNA. | [57] |
| HIV-1 (Retroviridae) |
(+)ssRNA | Pos[+] | n/a | METTL3/14 KD decreases Rev-RRE interactions and viral RNA export from the nucleus. Host proviral gene transcripts are uniquely methylated upon infection. | [58] |
| HBV (Hepadnaviridae) |
dsDNA | Neg[−] | METTL3/14 siRNA increases IFNB expression. | M6A negatively affects RIG-I recognition of viral RNA and pathway activation. M6A promotes reverse transcription of viral pgRNA but reduces its half-life and viral protein expression. | [60,63] |
| KSHV (Herpesviridae) |
dsDNA | Neg[−]/Pos[+] | n/a | YTHDF2 restricts lytic replication. Host m6A dynamics: during latent infection affect genes with roles in cell transformation; during lytic infection affect genes related to ERK/MAPK, integrin, and hypoxia signaling pathways. | [61,66] |
| HCMV (Herpesviridae) |
dsDNA | Pos[+] | METTL14 siRNA increases IFNB1 expression. | METTL14 siRNA upregulates host genes for innate immunity and inflammation, proliferation, and metabolic control in response to dsDNA. | [62] |