Essential Role of Neutrophils in the Protective Immune Response Induced by a Live Attenuated Leishmania Vaccine

Abstract

No licensed vaccine exists against visceral leishmaniasis (VL), a disease caused by the Leishmania donovani parasite. We have previously reported both macrophages and dendritic cells play important role in the protection induced by a live attenuated centrin gene-deleted L. donovani (LdCen 2/2 ) parasite vaccine. The role of neutrophils in orchestrating the initial innate response to pathogens is widely recognized. To investigate the early interaction of LdCen 2/2 with neutrophils, we immunized mice intradermally in the ear pinna with LdCen 2/2 . Compared with LdWT infection, LdCen 2/2 parasites induced higher recruitment of neutrophils to the ear dermis and ear draining lymph nodes (dLN) as early as 6-18 h after immunization, which were predominantly proinflammatory in nature. Neutrophils from ear dLN of LdCen 2/2 -immunized mice exhibited heightened expression of costimulatory molecules and attenuated expression of coinhibitory molecules necessary for higher T cell activation. Further phenotypic characterization revealed heterogeneous neutrophil populations containing Na and Nb subtypes in the ear dLN. Of the two, the parasitized Na subset from LdCen 2/2 -immunized mice exhibited much stronger Ag-specific CD4 + T cell proliferation ex vivo. Adoptive transfer of neutrophils bearing LdCen 2/2 parasites induced an increased Th1 response in naive mice. Importantly, neutrophil depletion significantly abrogated Ag-specific CD4 + T cell proliferation in LdCen 2/2 -immunized mice and impaired protection against virulent challenge. Conversely, replenishing of neutrophils significantly restored the LdCen 2/2 -induced host-protective response. These results suggest that neutrophils are indispensable for protective immunity induced by LdCen 2/2 parasite vaccine.

Determinants of Innate Immunity in Visceral Leishmaniasis and Their Implication in Vaccine Development

“…Similar studies elucidating the functional roles of distinct neutrophil subsets revealed diverse roles of neutrophils in VL. Characterization of recruited dermal neutrophils in C57BL/6 mice during VL revealed the presence of heterogeneous Nα and Nβ neutrophil populations; Nα being the predominant population susceptible to infection ( 47 ). Further, studies in human VL identified the presence of a subset of HLA-DR + low density circulating neutrophils that expressed elevated levels of arginase-1 and IL-10.…”

“…The protective role of neutrophils following immunization against tuberculosis is demonstrated when depletion of neutrophils abrogated the induction of Th1-specific responses ( 52 ). Similarly, neutrophil depletion significantly abrogated Ag-specific CD4 + T cell proliferation in live attenuated centrin gene-deleted L. donovani ( LdCen -/- )-immunized mice and impaired protective immunity against virulent L. donovani challenge ( 47 ). In contrast, depletion of neutrophils in animals immunized with killed L. major + CpG vaccine enhanced protection upon sandfly mediated challenge ( 19 ).…”

“…In LdCen -/- immunization studies, distinct functional roles of neutrophil subsets were observed. Specifically, Nα subsets from LdCen −/− infected mice expressed significantly higher levels of costimulatory molecules along with attenuation of coinhibitory molecules, resulting in significantly higher CD4 + T cell activation compared with the Nα population from L. donovani wild type-infected mice ( 47 ). More studies are needed to elucidate the role of neutrophil subsets in other anti-leishmanial vaccination regimens.…”

Role of Tumor-Associated Neutrophils in the Molecular Carcinogenesis of the Lung

“…Similarly, during immunization with the pneumococcal conjugate vaccine, adequate neutrophil function and activation are a prerequisite [ 88 ]. A mouse study showed, for instance, that neutrophils play a crucial role in the response to an experimental live attenuated Leishmania vaccine [ 89 ]. Immunized mice showed higher neutrophil recruitment to the vaccination site and adjacent lymph nodes when compared to controls [ 89 ].…”

“…A mouse study showed, for instance, that neutrophils play a crucial role in the response to an experimental live attenuated Leishmania vaccine [ 89 ]. Immunized mice showed higher neutrophil recruitment to the vaccination site and adjacent lymph nodes when compared to controls [ 89 ]. Another study on bladder cancer, which is frequently treated with the BCG vaccine, showed that neutrophils are essentially linked to the anticarcinogenic effect of the BCG vaccine [ 90 ].…”