PMID- 35236861
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220418
IS  - 2059-0105 (Electronic)
IS  - 2059-0105 (Linking)
VI  - 7
IP  - 1
DP  - 2022 Mar 2
TI  - Centrin-deficient Leishmania mexicana confers protection against New World 
      cutaneous leishmaniasis.
PG  - 32
LID - 10.1038/s41541-022-00449-1 [doi]
LID - 32
AB  - Leishmaniasis is a neglected protozoan disease affecting over 12 million people 
      globally with no approved vaccines for human use. New World cutaneous 
      leishmaniasis (CL) caused by L. mexicana is characterized by the development of 
      chronic non-healing skin lesions. Using the CRISPR/Cas9 technique, we have 
      generated live attenuated centrin knockout L. mexicana (LmexCen(-/-)) parasites. 
      Centrin is a cytoskeletal protein important for cellular division in eukaryotes 
      and, in Leishmania, is required only for intracellular amastigote replication. We 
      have investigated the safety and immunogenicity characteristics of LmexCen(-/-) 
      parasites by evaluating their survival and the cytokine production in 
      bone-marrow-derived macrophages (BMDMs) and dendritic cells (BMDCs) in vitro. Our 
      data shows that LmexCen(-/-) amastigotes present a growth defect, which results 
      in significantly lower parasitic burdens and increased protective cytokine 
      production in infected BMDMs and BMDCs, compared to the wild type (WT) parasites. 
      We have also determined the safety and efficacy of LmexCen(-/-) in vivo using 
      experimental murine models of L. mexicana. We demonstrate that LmexCen(-/-) 
      parasites are safe and do not cause lesions in susceptible mouse models. 
      Immunization with LmexCen(-/-) is also efficacious against challenge with WT L. 
      mexicana parasites in genetically different BALB/c and C57BL/6 mouse models. 
      Vaccinated mice did not develop cutaneous lesions, displayed protective immunity, 
      and showed significantly lower parasitic burdens at the infection site and 
      draining lymph nodes compared to the control group. Overall, we demonstrate that 
      LmexCen(-/-) parasites are safe and efficacious against New World cutaneous 
      leishmaniasis in pre-clinical models.
CI  - (c) 2022. The Author(s).
FAU - Volpedo, Greta
AU  - Volpedo G
AUID- ORCID: 0000-0002-1112-7715
AD  - Department of Microbiology, The Ohio State University, Columbus, OH, 43210, USA.
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA.
FAU - Pacheco-Fernandez, Thalia
AU  - Pacheco-Fernandez T
AUID- ORCID: 0000-0003-2741-0942
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA.
FAU - Holcomb, Erin A
AU  - Holcomb EA
AUID- ORCID: 0000-0003-1368-9858
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA.
FAU - Zhang, Wen-Wei
AU  - Zhang WW
AD  - Department of Microbiology and Immunology, McGill University, Montreal, QC, 
      Canada.
FAU - Lypaczewski, Patrick
AU  - Lypaczewski P
AUID- ORCID: 0000-0002-5550-712X
AD  - Department of Microbiology and Immunology, McGill University, Montreal, QC, 
      Canada.
FAU - Cox, Blake
AU  - Cox B
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA.
FAU - Fultz, Rebecca
AU  - Fultz R
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA.
FAU - Mishan, Chelsea
AU  - Mishan C
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA.
FAU - Verma, Chaitenya
AU  - Verma C
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA.
FAU - Huston, Ryan H
AU  - Huston RH
AUID- ORCID: 0000-0003-1884-1695
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA.
FAU - Wharton, Abigail R
AU  - Wharton AR
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA.
FAU - Dey, Ranadhir
AU  - Dey R
AD  - Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver 
      Spring, MD, USA.
FAU - Karmakar, Subir
AU  - Karmakar S
AD  - Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver 
      Spring, MD, USA.
FAU - Oghumu, Steve
AU  - Oghumu S
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA.
FAU - Hamano, Shinjiro
AU  - Hamano S
AUID- ORCID: 0000-0003-3881-8337
AD  - Department of Parasitology, Institute of Tropical Medicine (NEKKEN), The Joint 
      Usage/Research Center on Tropical Disease, Nagasaki University, Nagasaki 
      University Graduate School of Biomedical Sciences Doctoral Leadership Program, 
      Nagasaki, Japan.
FAU - Gannavaram, Sreenivas
AU  - Gannavaram S
AUID- ORCID: 0000-0002-6557-8220
AD  - Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver 
      Spring, MD, USA.
FAU - Nakhasi, Hira L
AU  - Nakhasi HL
AD  - Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver 
      Spring, MD, USA. hira.nakhasi@fda.hhs.gov.
FAU - Matlashewski, Greg
AU  - Matlashewski G
AD  - Department of Microbiology and Immunology, McGill University, Montreal, QC, 
      Canada. greg.matlashewski@mcgill.ca.
FAU - Satoskar, Abhay R
AU  - Satoskar AR
AUID- ORCID: 0000-0001-5989-1520
AD  - Department of Microbiology, The Ohio State University, Columbus, OH, 43210, USA. 
      Abhay.Satoskar@osumc.edu.
AD  - Department of Pathology, Wexner Medical Center, The Ohio State University, 
      Columbus, OH, 43210, USA. Abhay.Satoskar@osumc.edu.
LA  - eng
GR  - R21 AI138555/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20220302
PL  - England
TA  - NPJ Vaccines
JT  - NPJ vaccines
JID - 101699863
PMC - PMC8891280
COIS- The FDA is currently a co-owner of two US patents that claim attenuated 
      Leishmania species with the centrin gene deletion (US7,887,812 and US 8,877,213). 
      This article reflects the views of the authors and should not be construed to 
      represent FDA's views or policies. The remaining authors declare no competing 
      interests.
EDAT- 2022/03/04 06:00
MHDA- 2022/03/04 06:01
PMCR- 2022/03/02
CRDT- 2022/03/03 05:33
PHST- 2021/08/13 00:00 [received]
PHST- 2022/01/27 00:00 [accepted]
PHST- 2022/03/03 05:33 [entrez]
PHST- 2022/03/04 06:00 [pubmed]
PHST- 2022/03/04 06:01 [medline]
PHST- 2022/03/02 00:00 [pmc-release]
AID - 10.1038/s41541-022-00449-1 [pii]
AID - 449 [pii]
AID - 10.1038/s41541-022-00449-1 [doi]
PST - epublish
SO  - NPJ Vaccines. 2022 Mar 2;7(1):32. doi: 10.1038/s41541-022-00449-1.