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Centrin-deficient Leishmania mexicana confers protection against New World cutaneous leishmaniasis.
Volpedo, Greta; Pacheco-Fernandez, Thalia; Holcomb, Erin A; Zhang, Wen-Wei; Lypaczewski, Patrick; Cox, Blake; Fultz, Rebecca; Mishan, Chelsea; Verma, Chaitenya; Huston, Ryan H; Wharton, Abigail R; Dey, Ranadhir; Karmakar, Subir; Oghumu, Steve; Hamano, Shinjiro; Gannavaram, Sreenivas; Nakhasi, Hira L; Matlashewski, Greg; Satoskar, Abhay R.
Afiliación
  • Volpedo G; Department of Microbiology, The Ohio State University, Columbus, OH, 43210, USA.
  • Pacheco-Fernandez T; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Holcomb EA; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Zhang WW; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Lypaczewski P; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
  • Cox B; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
  • Fultz R; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Mishan C; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Verma C; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Huston RH; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Wharton AR; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Dey R; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Karmakar S; Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA.
  • Oghumu S; Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA.
  • Hamano S; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Gannavaram S; 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.
  • Nakhasi HL; Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA.
  • Matlashewski G; Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA. hira.nakhasi@fda.hhs.gov.
  • Satoskar AR; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada. greg.matlashewski@mcgill.ca.
NPJ Vaccines ; 7(1): 32, 2022 Mar 02.
Article en En | MEDLINE | ID: mdl-35236861
ABSTRACT
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.
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Texto completo: 1 Bases de datos: MEDLINE Tipo de estudio: Prognostic_studies País/Región como asunto: Mexico Idioma: En Revista: NPJ Vaccines Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Tipo de estudio: Prognostic_studies País/Región como asunto: Mexico Idioma: En Revista: NPJ Vaccines Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos