Immunocompetent and Immunodeficient Mouse Models for Enterovirus 71 Pathogenesis and Therapy
Abstract
:1. Introduction
2. In Vitro Propagation Systems
3. In Vivo Animal Models
3.1. Mouse Models Dependent on Mouse-Adapted EV71 Strains
3.2. Immunodeficient Mouse Models
3.3. Transgenic Mouse Models
3.4. A Hybrid Mouse Model
4. Pathogenesis Mechanism
4.1. Viral Determinants of Virulence
4.2. Host Factors
5. Therapy
6. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Cell Line | Species | Tissue Origin | EV71 Genotype | CPE # | References |
---|---|---|---|---|---|
RD | Human | Rhabdomyosarcoma | A, B, C, D | + | [23,24,25,26,27,28,29,30] |
SK-N-SH | Neuroblastoma | C2, D | + | [24,27] | |
SH-SY5Y | Neuroblastoma | C4 | + | [31,32] | |
NSC-34 | motor neuron cell line | B2, B4 & C2 | − | [33] | |
SF268 | glioblastoma | * | + | [34] | |
Neuro-2A | Mouse | Neuroblastoma | D | + | [24,35] |
HT29 | Human | intestinal epithelial cell | B4, C | + | [25,26,28] |
Caco-2 | colorectal carcinoma | B, C2 | + | [27,29] | |
C2BBel | mature intestinal epithelial cell (derived from Caco-2) | C | + | [28] | |
HeLa | Human | cervical carcinoma | EV71:BS (Accession NO KF514878), C4 | + | [35,36] |
HEK293T | Human | embryonic kidney | EV71:BS (Accession NO KF514878), C4 | + | [35,37] |
THP-1 | Human | monocytic cell line | C2, C4 | [19,37] | |
human PBMC | C2 | [19] | |||
Vero | Monkey | African green monkey kidney | A, EV71:BS (Accession NO KF514878) | + | [30,35] |
COS-7 | African green monkey kidney (SV40 transformed) | EV71:BS (Accession NO KF514878) | + | [35] | |
NIH/3T3 | Mouse | mouse embryonic fibroblast | mouse-adapted strain (EV:TLLm) | + | [35] |
Mouse Strain | Host Age @ | Route | Genotype | Titer/Mouse | Phenotype | Virus-Replicating Tissue | Reference |
---|---|---|---|---|---|---|---|
Balb/C | 1-day-old | i.p. | B4 | 1 × 104 PFU | limb paralysis & death | intestine | [38] |
2-day-old | i.p./i.c. | C4 | 103 TCID50 | * | brain, liver and intestine | [39] | |
5-day-old | i.p. | C4 (mouse adapted strain) | 104 TCID50 | limb paralysis & death | spleen, heart, liver, muscle and brain | [40] | |
7-day-old | i.m. i.p. i.c. | B3 (CHO cell adapted strain; CHO-26M) (mouse adapted strain; MP-26M) | 103 TCID50 | death | muscle (CHO-26M) blood, spleen, heart, liver, muscle and brain (MP-26M) | [41] | |
9-day-old | i.p. | C4 | 104.5 TCID50 | limb paralysis | skeletal muscle, spinal cord, brainstem, lung, and jejunum | [24] | |
ICR | 1-day-old | oral | C (mouse adapted strain) | 106–107 PFU | paralysis & skin lesion | skin, intestine and spinal cord | [42] |
1-day-old | i.p. | C4 (Fuyang-0805a) | 2 × 105 TCID50 | none | muscles, intestines, lungs, and brain | [43] | |
7-day-old | oral | C (mouse adapted strain M2) | 5 × 106 PFU | death | * | [44] | |
7-day-old | i.p. | C2 (mouse adapted strain MP4) | 2.5 × 106 PFU | death | brain, spinal cord, lung and muscle | [21] | |
3-day-old | i.p. | C2 (clinical isolate) | 4 × 106 PFU | death | * | [45] | |
7-day-old | oral | C2 (mouse adapted strain MP4) | 5 × 105 PFU | death | * | [45] | |
12–14-day-old | i.p. | C (mouse adapted strain M2) | 5 × 104–105 PFU | paralysis & death | * | [46] | |
14-day-old | i.p. | B3 (mouse adapted strain) | 100 CCID50 | paralysis | brain and muscle | [47] | |
14-day- & 28-day-old | i.p. i.m. oral s.c. | B3 (mouse adapted strain) | 105 CCID50 | paralysis | mainly in CNS | [48] | |
C57BL/6 | 9-day-old | oral | C (mouse adapted strain M2) | 3 × 107 PFU | * | * | [44] |
C57BL/6J | 14-day-old | i.p. | C (mouse adapted strain M2) | 3 × 105 PFU | hunched posture, paralysis & death | brain | [49] |
PSGL-1 Tg | 10-day-old | i.p. | C4 (clinical isolate) | 108 TCID50 | no disease onset | brain, spinal cord and skeletal muscle | [50] |
C4 (mouse adapted strain MP10) | 5 × 106 TCID50 | hindlimb paralysis | * | ||||
hSCARB2 Tg | 3-week-old | i.v. | C (Isehara strain) | 102–6 TCID50 | ataxia, paralysis & death | CNS | [51] |
i.c. | A, B and C | 102–6 TCID50 | |||||
i.p. | C (Isehara strain) | 103–6 TCID50 | |||||
oral | C (Isehara strain) | 106–7 TCID50 | |||||
pEF-1α-hSCARB2 | 1-day-old | s.c. | B | 1 × 107 PFU | HFMD-like syndrome & paralysis | CNS, intestine, muscle and skin | [52] |
7-day-old | s.c. | C | 3 × 104 PFU | ||||
AG129 | younger than 2-week-old | i.p. | B4 | 5 × 105–107 PFU | limb paralysis & death | CNS | [53] |
oral | 106–107 PFU | ||||||
AG129 | 10-week-old | i.p. | B2 (mouse adapted strain) | 1.3 × 105 TCID50/mL | limb paralysis & death | ND | [54] |
A129 | |||||||
G129 | 7-day-old | i.p. | B5 (clinical isolates) | 108 PFU | limb paralysis & death | ND | [4] |
stat-1 KO | 7-day-old | i.p. | B5 (clinical isolates) | 108 PFU | limb paralysis & death | CNS | [4] |
pSCARB2x stat-1 KO | younger than 2-week-old | i.p. | C2 (clinical isolates) | 106–108 PFU | [5] | ||
NOD/SCID | 3-day-old | oral | B5 (clinical isolates) | 108 PFU | hair loss, skin lesion, limb paralysis & death | muscle and spleen | [4] |
7-day-old | i.p. | 107–108 PFU | |||||
3–4 week-old | i.v./i.c. | B1 (mouse adapted strain) | 106.5 CCID50 | skeletal muscle and heart | [55] | ||
IP10 KO | 14-day-old | i.p. | C (mouse adapted strain M2) | 3 × 105 PFU | The death rate was higher than C57BL/6J | ND | [49] |
Mouse Strains | Promoter | Virus Strain (Genotype) | Host Age | Virus Dose | Inoculation Route | % Earlier symptom ** (Tg vs. non-Tg) | % Limb Paralysis (Tg vs. non-Tg) | % Death (Tg vs. non-Tg) | References |
---|---|---|---|---|---|---|---|---|---|
pEF-1α- hSCARB2 | ubiquitous EF-1 Promoter | E59 (B4) | 1-day-old | 3 × 104 PFU | s.c. | 100 vs. 57.1 | 18.8 vs. 14.2 | 0 vs. 0 | [52] |
N-2838 (B5) | 100 vs.75 | 44.4 vs. 12.5 | 0 vs. 0 | ||||||
5476 (C2) | 7-day-old | 107 PFU | s.c. | Nd @ | 100 vs. 57.1 | 100 vs. 0 | |||
N3340 (C4) | Nd @ | 100 vs. 100 | 100 vs. 0 | ||||||
pSC2- hSCARB2 | native promoter | Isehara (C2) | 3-wk-old | 106 TCID50 | i.c. | N/A # | 100 vs. 0 * | [51] | |
i.v. | N/A # | 89 vs. 0 * | |||||||
i.p. | N/A # | 39 vs. 0 * | |||||||
oral | N/A # | 5 vs. 0 * |
Therapeutic Approaches | Drug Candidates | Drug Delivery Methods | Human or Animal Model | Host Age at Virus Inoculation | Virus Inoculation | EV71 Clinical Isolates * or Adapted Strains # | Virus Genotype | Ref. |
---|---|---|---|---|---|---|---|---|
GROUP 1 Passive immunization | bispecific anti-EV71 & CA16 Ab Bs(scFv) | i.p. injection at 24 h after inoculation | BALB/c | 1-day-old | i.c. | EV71/pSVA-MP4 # | B3 | [104] |
VP1-specific mAb | i.p. injection at 3, 24, and 48 h after inoculation | SCARB2-Tg | 1-day & 7-day-old | s.c. | E59 & 5746-TW98 * | B4 & C2 | [105] | |
human plasma or IVIG | in vitro pre-mix with EV71 at 37 °C for 1 h | ICR | 2-day-old | i.p. | KM593929 * | C4 | [106] | |
human IVIG | 3 i.p. injections at 4 h, 1- and 2-days after inoculation | Kunming mice | 7-day-old | i.p. | AH08/06 * | C4 | [107] | |
EV71-specific Ab | i.p. injection 1 day before and 1 day after (ICR), or 2 and 4 days after inoculation (C57BL/6) | ICR & C57BL/6 | 7-day & 9-day-old | oral | M2 # | C2 | [44] | |
adult immune sera | i.p. injection at 1hr before and 24 h after inoculation | young gerbils | 21-day-old | i.p. or i.m. | strain 58301 * | C4 | [108] | |
human IVIG | i.v. infusion at a dosage of 1 g/kg/day for 2 days | human patients | <2-yr-old | natural infection | N/A | N/A | [17] | |
GROUP 2 Immune modulators | Poly (I:C) | i.p. injection at 12 h before inoculation | ICR | 3-day-old | i.p. or oral | MP4 # | C2 | [45] |
Ad-IFN-a | one intranasal shot within 12 h post-inoculation | BALB/c | 6-day-old | i.p. | strain 41 * | B4 | [71] | |
antagomir -146a | i.p. injection before or after virus inoculation | C57BL/6 | 7-day-old | i.p. | mEV71 # | B2 | [109] | |
GS-9620 | oral uptake at 2, 26, 50 h post-inoculation | ICR | 10-day-old | i.p. | MP10 # | C4 | [95] | |
GROUP 3 Anti-inflammation | anti-IL6 Ab | i.p. co-injection of Ab and virus (day 0) | BALB/c | 1-day-old | i.p. | strain 41 * | B4 | [38] |
complement inhibitor (CR2-crry) | treatment post-inoculation | ICR | 7-day-old | i.c. | BrCr * | A | [97] | |
GROUP 4 Others | Retro-2cycl | i.p. injection following EV71 inoculation | BALB/c | <1-day-old | i.c. | KJ508817 * | C4 | [98] |
Pleconaril | daily i.p. injection for 5 days | ICR | 1-day-old | i.p. | BrCr * | A | [99] | |
andrographolide sulfonate | i.p. injection once daily until 10 days post-inoculation | ICR | 7-day-old | i.p. | BJ09/07 # | C4 | [100] | |
adoptive transfer of macrophage | i.p. injection with adult macrophage at 1 day post-inoculation | ICR | 10-day-old | i.p. | MP10 # | C4 | [101] | |
Milrinone | i.v. injection within 2–6 h after admission at dosage 0.35–0.55 mg/kg/min for 72 h. | human patients | <2-yr-old | natural infection | N/A | N/A | [22] |
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Shih, C.; Liao, C.-C.; Chang, Y.-S.; Wu, S.-Y.; Chang, C.-S.; Liou, A.-T. Immunocompetent and Immunodeficient Mouse Models for Enterovirus 71 Pathogenesis and Therapy. Viruses 2018, 10, 674. https://doi.org/10.3390/v10120674
Shih C, Liao C-C, Chang Y-S, Wu S-Y, Chang C-S, Liou A-T. Immunocompetent and Immunodeficient Mouse Models for Enterovirus 71 Pathogenesis and Therapy. Viruses. 2018; 10(12):674. https://doi.org/10.3390/v10120674
Chicago/Turabian StyleShih, Chiaho, Chun-Che Liao, Ya-Shu Chang, Szu-Yao Wu, Chih-Shin Chang, and An-Ting Liou. 2018. "Immunocompetent and Immunodeficient Mouse Models for Enterovirus 71 Pathogenesis and Therapy" Viruses 10, no. 12: 674. https://doi.org/10.3390/v10120674