miR-21 Expression Determines the Early Vaccine Immunity Induced by LdCen -/- Immunization

• Published in: Frontiers in immunology Vol. 10; p. 2273
• Main Authors: Gannavaram, Sreenivas, Bhattacharya, Parna, Siddiqui, Abid, Ismail, Nevien, Madhavan, Subha, Nakhasi, Hira L
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 24-09-2019
• Subjects: biomarker; IL-12; Immunology; leishmaniasis; live attenuated Leishmania vaccines; microRNA; miR-21; parasitic vaccines; microRNA; miR-21; IL-12; biomarker; leishmaniasis; live attenuated Leishmania vaccines
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.02273

No vaccine exists against visceral leishmaniasis. Toward developing vaccines against VL, we have reported previously on the immunogenicity of live attenuated
parasites in animal models. Immunization with
parasites has been shown to induce durable protective immunity in pre-clinical animal models. Although the innate immune responses favoring a Th1 type immunity are produced following
immunization, the molecular determinants of such responses remain unknown. To identify early biomarkers of immunogenicity associated with live attenuated parasitic vaccines, we infected macrophages derived from healthy human blood donors with
or
parasites
and compared the early gene expression profiles. In addition to altered expression of immune related genes, we identified several microRNAs that regulate important cytokine genes, significantly altered in
infection compared to
infection. Importantly, we found that
infection suppresses the expression of microRNA-21 (miR-21) in human macrophages, which negatively regulates IL12, compared to
infection. In murine DC experiments,
infection showed a reduced miR-21 expression with a concomitant induction of IL12. Silencing of miR-21 using specific inhibitors resulted in an augmented induction of IL12 in
infected BMDCs, illustrating the role of miR-21 in
mediated suppression of IL12. Further, exosomes isolated from
infected DCs contained significantly reduced levels of miR-21 compared to
infection, that promoted proliferation of CD4
T cells
. Similar miR-21 mediated IL12 regulation was also observed in
human macrophage infection experiments indicating that miR-21 plays a role in early IL12 mediated immunity. Our studies demonstrate that
infection suppresses miR-21 expression, enables IL12 mediated induction of adaptive immunity including proliferation of antigen experienced CD4
T cells and development of a Th1 immunity, and suggest that miR-21 could be an important biomarker for
vaccine immunity in human clinical trials.
Role of miR-21 in vaccine induced immunity.