Gene deleted live attenuated Leishmania vaccine candidates against visceral leishmaniasis elicit pro-inflammatory cytokines response in human PBMCs.
Currently no effective vaccine is available for human visceral leishmaniasis(VL) caused by Leishmania donovani. Previously, we showed that centrin1 and p27gene deleted live attenuated Leishmania parasites (LdCen1(-/-) and Ldp27(-/-)) are safe, immunogenic and protective in animal models. Here, to assess the correlates of protection, we evaluated immune responses induced by LdCen1(-/-) and Ldp27(-/-) in human blood samples obtained from healthy, healed VL (HVL), post kala-azar dermal leishmaniasis(PKDL) and VL subjects. Both parasites infected human macrophages, as effectively as the wild type parasites. Further, LdCen1(-/-) and Ldp27(-/-) strongly stimulated production of pro-inflammatory cytokines including, IL-12, IFN-γ, TNF-α, IL-2, IL-6 and IL-17 in the PBMCs obtained from individuals with a prior exposure to Leishmania (HVL and PKDL). There was no significant stimulation of anti-inflammatory cytokines (IL-4 and IL-10). Induction of Th1 biased immune responses was supported by a remarkable increase in IFN-γ secreting CD4(+) and CD8(+) T cells and IL-17 secreting CD4(+) cells in PBMCs from HVL cases with no increase in IL-10 secreting T cells. Hence, LdCen1(-/-) and Ldp27(-/-) are promising as live vaccine candidates against VL since they elicit strong protective immune response in human PBMCs from HVL, similar to the wild type parasite infection, mimicking a naturally acquired protection following cure.
National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi, India.
Kumar
K
Avishek
National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi, India.
Himanshu
H
Kaushal
Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Bethesda, MD, USA.
Sreenivas
S
Gannavaram
Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Bethesda, MD, USA.
Ranadhir
R
Dey
JH-Institute of Molecular Medicine, Jamia Hamdard, New Delhi, India.
Angamuthu
A
Selvapandiyan
Department of Dermatology, VMMC and Safdarjung Hospital, India.
V
V
Ramesh
Department of Medicine, VMMC &Safdarjung Hospital, New Delhi, India.
Narender Singh
NS
Negi
Department of Biological Sciences, Birla Institute of Technology and Science Pilani, Rajasthan, India.
Uma S
US
Dubey
Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Bethesda, MD, USA.
Hira L
HL
Nakhasi
National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi, India.
Poonam
P
Salotra
D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D055785:Gene Knockdown Techniques; D017125:Genes, Protozoan; D006801:Humans; D007893:Leishmania donovani / Q000235:genetics / Q000276:immunology; D054332:Leishmaniasis Vaccines / Q000235:genetics / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000469:parasitology; D008297:Male; D015846:Monokines / Q000276:immunology; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology
D018797:Cell Cycle Proteins; D054332:Leishmaniasis Vaccines; D015846:Monokines; D014613:Vaccines, Attenuated