PMID- 35192633 OWN - NLM STAT- MEDLINE DCOM- 20220411 LR - 20220411 IS - 1935-2735 (Electronic) IS - 1935-2727 (Print) IS - 1935-2727 (Linking) VI - 16 IP - 2 DP - 2022 Feb TI - Neutrophil-dendritic cell interaction plays an important role in live attenuated Leishmania vaccine induced immunity. PG - e0010224 LID - 10.1371/journal.pntd.0010224 [doi] LID - e0010224 AB - BACKGROUND: Neutrophils are involved in the initial host responses to pathogens. Neutrophils can activate T cell responses either independently or through indirect involvement of Dendritic cells (DCs). Recently we have demonstrated direct neutrophil-T cell interactions that initiate adaptive immune responses following immunization with live attenuated Leishmania donovani centrin deleted parasite vaccine (LdCen-/-). However, neutrophil-DC interactions in T cell priming in vaccine immunity in general are not known. In this study we evaluated the interaction between neutrophils and DCs during LdCen-/- infection and compared with wild type parasite (LdWT) both in vitro and in vivo. METHODOLOGY/FINDINGS: LdCen-/- parasite induced increased expression of CCL3 in neutrophils caused higher recruitment of DCs capable of inducing a strong proinflammatory response and elevated co-stimulatory molecule expression compared to LdWT infection. To further illustrate neutrophil-DCs interactions in vivo, we infected LYS-eGFP mice with red fluorescent LdWT/LdCen-/- parasites and sort selected DCs that engulfed the neutrophil containing parasites or DCs that acquired the parasites directly in the ear draining lymph nodes (dLN) 5d post infection. The DCs predominantly acquired the parasites by phagocytosing infected neutrophils. Specifically, DCs containing LdCen-/- parasitized neutrophils exhibited a proinflammatory phenotype, increased expression of costimulatory molecules and initiated higher CD4+T cell priming ex-vivo. Notably, potent DC activation occurred when LdCen-/- parasites were acquired indirectly via engulfment of parasitized neutrophils compared to direct engulfment of LdCen-/- parasites by DCs. Neutrophil depletion in LdCen-/- infected mice significantly abrogated expression of CCL3 resulting in decreased DC recruitment in ear dLN. This event led to poor CD4+Th1 cell priming ex vivo that correlated with attenuated Tbet expression in ear dLN derived CD4+ T cells in vivo. CONCLUSIONS: Collectively, LdCen-/- containing neutrophils phagocytized by DC markedly influence the phenotype and antigen presenting capacity of DCs early on and thus play an immune-regulatory role in shaping vaccine induced host protective response. FAU - Bhattacharya, Parna AU - Bhattacharya P AD - Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, United States of America. FAU - Ismail, Nevien AU - Ismail N AUID- ORCID: 0000-0003-0294-8834 AD - Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, United States of America. FAU - Saxena, Ankit AU - Saxena A AD - Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America. FAU - Gannavaram, Sreenivas AU - Gannavaram S AD - Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, United States of America. FAU - Dey, Ranadhir AU - Dey R AD - Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, United States of America. FAU - Oljuskin, Timur AU - Oljuskin T AUID- ORCID: 0000-0001-5494-2237 AD - Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, United States of America. FAU - Akue, Adovi AU - Akue A AD - Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, United States of America. FAU - Takeda, Kazuyo AU - Takeda K AD - Division of Blood Components and Devices, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, United States of America. FAU - Yu, James AU - Yu J AUID- ORCID: 0000-0003-4109-8852 AD - Division of Blood Components and Devices, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, United States of America. FAU - Karmakar, Subir AU - Karmakar S AD - Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, United States of America. FAU - Dagur, Pradeep K AU - Dagur PK AD - Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America. FAU - McCoy, John Philip Jr AU - McCoy JP Jr AD - Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America. FAU - Nakhasi, Hira L AU - Nakhasi HL AUID- ORCID: 0000-0003-4941-1620 AD - Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, United States of America. LA - eng PT - Journal Article PT - Research Support, U.S. Gov't, Non-P.H.S. PT - Research Support, U.S. Gov't, P.H.S. DEP - 20220222 PL - United States TA - PLoS Negl Trop Dis JT - PLoS neglected tropical diseases JID - 101291488 RN - 0 (Leishmaniasis Vaccines) RN - 0 (Vaccines, Attenuated) SB - IM MH - Animals MH - Cell Communication MH - Dendritic Cells MH - *Leishmania donovani/physiology MH - *Leishmaniasis Vaccines MH - *Leishmaniasis, Visceral/parasitology MH - Mice MH - Neutrophils MH - Vaccines, Attenuated PMC - PMC8896671 COIS- The authors have declared that no competing interests exist. EDAT- 2022/02/23 06:00 MHDA- 2022/04/12 06:00 PMCR- 2022/02/22 CRDT- 2022/02/22 17:12 PHST- 2021/05/12 00:00 [received] PHST- 2022/02/02 00:00 [accepted] PHST- 2022/03/04 00:00 [revised] PHST- 2022/02/23 06:00 [pubmed] PHST- 2022/04/12 06:00 [medline] PHST- 2022/02/22 17:12 [entrez] PHST- 2022/02/22 00:00 [pmc-release] AID - PNTD-D-21-00690 [pii] AID - 10.1371/journal.pntd.0010224 [doi] PST - epublish SO - PLoS Negl Trop Dis. 2022 Feb 22;16(2):e0010224. doi: 10.1371/journal.pntd.0010224. eCollection 2022 Feb.