Table 1.
Function of interferon-stimulated genes against alphaviruses
| ISG | Viruses | In vitro studies | In vivo studies | References |
|---|---|---|---|---|
| PKR | SFV SINV CHIKV |
Human PKR siRNA KD in foreskin fibroblasts: ■ No change in cellular translation or type I IFN levels (CHIKV) |
PKR−/− mouse SFV: ■ No death ■ Delayed viral clearance in brain SINV: ■ 100% survival |
92–95, 98 |
|
Mouse PKR−/− MEFs or PKR siRNA KD in NIH-3T3 cells: ■ ↑ Infection/viral titer (SFV, CHIKV, SINV) ■ ↓ Type I IFNs (SFV, CHIKV) ■ ↓ Cellular translation (CHIKV) ■ Prolonged infection (SINV) PKR−/− BMDCs: ■ ↑ Viral titer (SINV) ■ ↑ Replication or translation (SINV) Dominant-negative PKR mutant in NIH-3T3 cells: ■ Partial ↓ cellular translation (SINV) ■ No change in viral titers (SINV) | ||||
| GADD34 | CHIKV |
Mouse Gadd34−/− MEFs: ■ ↑ Viral titer (CHIKV) ■ ↓ IFN-β (CHIKV) |
Gadd34−/− neonate mouse CHIKV: ■ ↑ Lethality ■ ↑ Viral load ■ ↓ Type I IFNs |
95 |
| OAS | SFV SINV CHIKV |
Human Oas3−/− or Rnasel−/− A549 cells: ■ No total RNA degradation (SINV) ■ ↑ Viral titers (SINV) Ectopic expression of OAS3 in HeLa cells: ■ ↓ Viral titers (CHIKV, SINV, SFV) ■ ↓ Viral RNA accumulation (CHIKV) Mouse Rnasel−/− BMDCs: ■ No change in viral titer (SINV) ■ ↓ Replication or translation (SINV) |
Rnasel−/− mouse SINV: ■ 100% survival |
91, 97 |
| ISG20 | SINV CHIKV VEEV |
Mouse Ectopic expression in MEFs: ■ ↓ Replication (SINV) ■ ↓ Viral titers (CHIKV, VEEV) ■ ↓ Translation (CHIKV) |
Mouse SINV encoding ISG20 (neonate): ■ ↑ Survival Isg20−/− mouse CHIKV (neonate): ■ No change in survival VEEV: ■ Virulent strain—no change in survival ■ Attenuated strain—↑ lethality and disease |
100, 101 |
| Bst2/Tetherin | SFV CHIKV VEEV |
Human Ectopic expression in 293T and HeLa cells: ■ ↓ Viral titer (SFV, CHIKV) ■ ↓ Virus release (SFV, CHIKV) Rodent Bst2−/− MEFs and macrophages: ■ ↑ Viral titers in the presence of type I IFNs (CHIKV) NIH-3T3 or BHK-21 cells infected with VEEV expressing Bst2: ■ ↓ Virus release (VEEV) |
Bst2−/− mouse CHIKV: ■ ↑ Viral burden ■ ↓ Type I IFNs, IFN-γ, and CD40 expression |
102–105 |
| RSAD2/Viperin | SINV CHIKV |
Mouse Ectopic expression in MEFs: ■ ↓ replication (SINV) Rsad2−/− tail fibroblasts: ■ ↑ Viral antigen and load (CHIKV) ■ ↑ Type I IFN expression (CHIKV) |
Mouse SINV encoding Viperin (neonate): ■ ↑ Survival Rsad2−/− mouse CHIKV (young): ■ ↑ Foot titer early ■ ↑ Viremia ■ ↑ Cytokines, chemokines, and inflammation ■ ↑ F4/80+ cells and monocyte recruitment ■ CD4+ T cell–mediated disease with ↑ IFN-γ |
101, 106, 107 |
| IFITM | CHIKV VEEV SFV ONNV MAYV |
Human Loss of IFITM3 activity in HeLa cells: ■ ↑ Infection (CHIKV, MAYV) ■ ↑ Virus spread (CHIKV) Ectopic expression of IFITM1 or IFITM2 in HeLa cells: ■ ↓ Infection (CHIKV, MAYV) Mouse Ifitm3−/− MEFs: ■ ↓ Infection (CHIKV, VEEV, SFV, ONNV) ■ ↓ Viral fusion (CHIKV) |
Ifitm3−/− mouse CHIKV (young): ■ ↑ Foot swelling ■ ↑ Tissue titers and macrophage infection ■ ↑ Inflammatory cytokines VEEV: ■ ↑ Mortality ■ ↑ Early CNS titers |
108, 109 |
| PLZF | SFV |
Mouse Zbtb16−/− MEFs: ■ ↓ Infection Zbtb16−/− BMMs: ■ ↓ PLZF-dependent ISGs: Oas1g, Viperin, Ifit2, Cxcl10 Zbtb16−/− NK cells: ■ ↓ Effector function |
Zbtb16−/− mouse ■ ↑ Tissue titers ■ No change in serum IFN levels ↓ PLZF-dependent ISGs: ■ Oas1g, Viperin, Ifit2, Cxcl10 ■ ↓ NK cell effector function ■ ↓ Granzyme B |
110 |
| ZC3HAV1/ZAP | SINV SFV RRV VEEV |
Human ZC3HAV1−/− 293T cells: ■ Cofactor TR1M25 silenced ■ ↑ Viral replication (SINV) siRNA KD in Huh-7 cells: ■ ↑ Viral replication (SINV) Rodent ZAP-transduced fibroblasts: ■ ↓ Viral replication (SINV, SFV, RRV, VEEV) ■ ↓ Viral RNA translation (SINV) BHK-21 cells with ZAP overexpression: ■ + KD of 69 ISGs: ↑↑ viral replication (SINV) Mouse Overexpression in MEFs: ■ ↓ Virus release (SINV) ■ ↓↓ Virus release with IFN treatment (SINV) siRNA KD in MEFs: ■ ↑ Viral replication (SINV) |
Mouse Inoculation with SINV encoding ZAP (neonate): ■ ↑ Survival |
101, 111–114 |
| ISG15 | SINV CHIKV |
Mouse Ectopic expression in MEFs: ■ ↓ Virus release (SINV) siRNA KD in MEFs: ■ ↑ Viral replication (SINV) |
Mouse Inoculation with SINV encoding ISG15 (neonates): ■ No change in survival (SINV) IFN-α/βR−/− mouse inoculated with SINV encoding ISG15: ■ ↑ Survival (SINV) ■ ↓ Viral titers (SINV) ■ ↓ Immunopathology (SINV) ISG15−/− mouse ■ ↑ Lethality (SINV, CHIKV) ■ No change in tissue titers and type I IFN (CHIKV) ■ ↑ TNF-α, IL-1β, IL-6, CCL2, CCL3, CCL5 (CHIKV) |
101, 115–117 |
Abbreviations: BMDC, bone marrow–derived dendritic cell; BMM, bone marrow–derived macrophage; CHIKV chikungunya virus; CNS, central nervous system; GADD34, growth arrest and DNA damage–inducible protein 34; IFN, interferon; ISG, interferon-stimulated gene; ITIFM, interferon-induced transmembrane; KD, knockdown; MAYV, Mayaro virus; MEF, mouse embryonic fibroblast; OAS, 2′,5′-oligoadenylate synthetase; ONNV, o’nyong-nyong virus; PKR, protein kinase R; PLZF, promyelocytic zinc finger; RRV Ross River virus; SFV, Semliki Forest virus; SINV, Sindbis virus; siRNA, small interfering RNA; VEEV Venezuelan equine virus; VLP, virus-like particle; ZAP, zinc finger antiviral protein.