Killed but metabolically active Leishmania infantum as a novel whole-cell vaccine for visceral leishmaniasis.
There are currently no effective vaccines for visceral leishmaniasis, the second most deadly parasitic infection in the world. Here, we describe a novel whole-cell vaccine approach using Leishmania infantum chagasi promastigotes treated with the psoralen compound amotosalen (S-59) and low doses of UV A radiation. This treatment generates permanent, covalent DNA cross-links within parasites and results in Leishmania organisms termed killed but metabolically active (KBMA). In this report, we characterize the in vitro growth characteristics of both KBMA L. major and KBMA L. infantum chagasi. Concentrations of S-59 that generate optimally attenuated parasites were identified. Like live L. infantum chagasi, KBMA L. infantum chagasi parasites were able to initially enter liver cells in vivo after intravenous infection. However, whereas live L. infantum chagasi infection leads to hepatosplenomegaly in mice after 6 months, KBMA L. infantum chagasi parasites were undetectable in the organs of mice at this time point. In vitro, KBMA L. infantum chagasi retained the ability to enter macrophages and induce nitric oxide production. These characteristics of KBMA L. infantum chagasi correlated with the ability to prophylactically protect mice via subcutaneous vaccination at levels similar to vaccination with live, virulent organisms. Splenocytes from mice vaccinated with either live L. infantum chagasi or KBMA L. infantum chagasi displayed similar cytokine patterns in vitro. These results suggest that KBMA technology is a potentially safe and effective novel vaccine strategy against the intracellular protozoan L. infantum chagasi. This approach may represent a new method for whole-cell vaccination against other complex intracellular pathogens.
Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center, Torrance, California, USA.
Kevin W
KW
Bruhn
Ron
R
Birnbaum
Jacquelyn
J
Haskell
Veena
V
Vanchinathan
Stephanie
S
Greger
Rupa
R
Narayan
Pei-Lin
PL
Chang
Thu Anh
TA
Tran
Suzanne M
SM
Hickerson
Stephen M
SM
Beverley
Mary E
ME
Wilson
Noah
N
Craft
D000825:Animal Structures / Q000469:parasitology; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D005260:Female; D011564:Furocoumarins / Q000494:pharmacology; D018314:Leishmania infantum / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity / Q000528:radiation effects; D054332:Leishmaniasis Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000517:prevention & control*; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D014466:Ultraviolet Rays; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology
D000891:Anti-Infective Agents, Local; D011564:Furocoumarins; D054332:Leishmaniasis Vaccines; D015164:Vaccines, Inactivated; C118577:amotosalen