Table 1.
Genetic deletions that led to the discovery of novel drug or vaccine candidates in VL causing organisms.
| Organism | Target gene | Animal model | Immune response | Persistence | Inference |
Reference | |
|---|---|---|---|---|---|---|---|
| Drug | LAV | ||||||
| L. mexicana | Arginase | NA | NA | NA | + | UC | (41–43) |
| L. major | |||||||
| L. donovani | Ornithine decarboxylase | BALB/c mice | Reduced virulence in vitro and in vivo | NA | + | + | (44–46) |
| L. donovani | Spermidine synthase | BALB/c mice | Decreased organ parasite burden | 4 weeks | + | UC | (47) |
| L. donovani | S-adenosylmethionine decarboxylase | NA | NA | NA | + | UC | (48) |
| L. donovani | Trypanothione reductase | NA | Reduced virulence in vitro | NA | + | UC | (49–52) |
| L. donovani | Trypanothione synthetase | NA | NA | NA | + | UC | (42, 53) |
| L. donovani | Hypoxanthine–guanine phosphoribosyl transferase | NA | No effect on virulence in vitro and in vivo | NA | X | X | (54) |
| L. donovani | Adenine phosphoribosyl transferase | NA | No effect on virulence in vitro and in vivo | NA | X | X | (54, 55) |
| L. donovani | Xanthine phosphoribosyl transferase | NA | No effect on virulence in vitro and in vivo | NA | + | UC | (54, 56) |
| L. donovani | Inosine monophosphate dehydrogenase | BALB/c mice | No effect on virulence in vivo | NA | X | X | (57) |
| L. donovani | Adenine aminohydrolase | BALB/c mice | No significant effect on parasitemia in vitro or in organ parasite burden | NA | + | UC | (58) |
| L. donovani | Hypoxanthine–guanine phosphoribosyl transferase/xanthine phosphoribosyl transferase | NA | Highly reduced virulence in vitro | NA | – | + | (59) |
| L. donovani | Adenine aminohydrolase/hypoxanthine–guanine phosphoribosyl transferase/xanthine phosphoribosyl transferase | BALB/c mice | Avirulent in vitro and in vivo | 4 weeks | – | + | (58) |
| L. donovani | Adenylosuccinate synthetase | BALB/c mice | Reduced virulence in vitro but not in vivo | NA | X | X | (60) |
| L. donovani | Adenylosuccinate lyase | BALB/c mice | Reduced virulence in vitro and in vivo | NA | + | UC | (60) |
| L. donovani | Uridine monophosphate synthase | NA | NA | NA | + | UC | (61) |
| L. donovani | Uracil phosphoribosyl transferase | BALB/c mice | No effect on virulence in vitro or in vivo | NA | + | UC | (62, 63) |
| L. donovani | Carbamoyl phosphate synthetase | BALB/c mice | Reduced virulence in vitro and decreased parasite burden | NA | + | UC | (62) |
| L. donovani | Uracil phosphoribosyl transferase/carbamoyl phosphate synthetase | BALB/c mice | Reduced virulence in vivo | 4 weeks | – | + | (62) |
| L. donovani | Biopterin transporter 1 | BALB/c mice | Reduced virulence in vivo. Protective against challenge infection. Increased IFN-γ production upon splenocyte stimulation | 3 months | UC | + | (64) |
| L. donovani | Centrin | BALB/c mice, SCID mice, golden Syrian hamsters | Long term protection against challenge infection-early clearance. Protective Th1-type immune response. Increase of single and multiple cytokine (IFN-γ, IL-2, and TNFα) producing cells, IFN-γ/IL-10 ratio, IgG2a immunoglobulins and NO production. Reduced organ parasite burden. Cross-protective against L. braziliensis challenge | 10 weeks | UC | + | (65, 66) |
| L. donovani | P27, a cytochrome c oxidase component | BALB/c mice | Reduced virulence in vivo. NO generation, Ag-specific multifunctional CD4 and CD8 T-cells, enhanced secretion of pro-inflammatory cytokines IFN-γ, TNF-α, IL-12, and anti-inflammatory cytokines IL-10, IL-4, and IL-13 | 20 weeks | UC | + | (67) |
| L. donovani | Ubiquitin fold modifier-1 | NA | Reduced virulence in human macrophages | NA | + | + | (68) |
| L. donovani | Golgi GDP mannose transporter | BALB/c mice | Reduced virulence in vitro and in vivo | Long term | + | + | (69) |
| L. donovani | Amastigote specific expression protein-2 | BALB/c mice | Decreased virulence in vitro and in vivo | NA | + | X | (70) |
| L. donovani | Cathepsin b cysteine protease | NA | Decreased virulence in U937 macrophage cells | NA | + | UC | (71) |
| L. donovani | Oligopeptidase b serine protease | BALB/c mice | Decreased virulence in the murine footpad infection model. Massive upregulation in gene-transcription | NA | + | UC | (72) |
| L. donovani | Subtilisin protease | BALB/c mice, golden Syrian hamsters | Reduced virulence in vivo | NA | + | UC | (73) |
| L. donovani | Myosin | NA | NA | NA | + | UC | (74) |
| L. donovani | 70 kDa subunit of outer dynein arm docking complex | NA | Increased virulence in vitro | NA | X | X | (75) |
| L. donovani | Actin | NA | Reduced survival in vitro mice peritoneal macrophage cells | NA | + | UC | (76) |
| L. donovani | ADP-ribosylation factor like protein-3A | NA | NA | NA | + | UC | (77) |
| L. infantum | Heat shock protein 70 type II | L. major model of infection in BALB/c mice, SCID mice, golden Syrian hamster | Increased NO production and protection by type 1 immune response in BALB/c mice | NA | UC | + | (78) |
| L. donovani | Small glutamine rich tetra trichopeptide | NA | NA | NA | + | UC | (79) |
| L. donovani | Casein kinase 1 isoform 4 | NA | Increased virulence in vitro mice peritoneal macrophage cells | NA | + | UC | (80) |
| L. donovani | Glyoxalase I | NA | NA | NA | + | UC | (81) |
| L. donovani | cyp5122A1, a cytochrome P450 | Golden Syrian hamsters | Decreased virulence in vitro and in vivo | NA | + | UC | (82) |
| Color codes | Role | Symbols/short forms | Interpretation | ||||
| Purple | Polyamine metabolism | NA | Not available | ||||
| Blue | Purine metabolism | + | Positive indication | ||||
| Gray | Pyrimidine metabolism | – | Not evaluated | ||||
| Green | Amastigote stage | UC | Uncertain | ||||
| Yellow | Protease | X | Negative indication | ||||
| Peach | Cytoskeletal involvement | ||||||
| Pink | Chaperones | ||||||
| White | Others | ||||||