An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis.

Autor:	Karanika S; Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States.; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Gordy JT; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Neupane P; Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States.; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Karantanos T; Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, MD, United States., Ruelas Castillo J; Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States.; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Quijada D; Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States.; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Comstock K; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Sandhu AK; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Kapoor AR; Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States.; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Hui Y; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Ayeh SK; Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States.; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Tasneen R; Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States.; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Krug S; Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States.; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Danchik C; Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States.; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Wang T; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Schill C; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Markham RB; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Karakousis PC; Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States.; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Sep 16; Vol. 13, pp. 972266. Date of Electronic Publication: 2022 Sep 16 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.972266
Abstrakt:	Lengthy tuberculosis (TB) treatment is required to overcome the ability of a subpopulation of persistent Mycobacterium tuberculosis ( Mtb ) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the Rel Mtb -mediated stringent response. We developed a novel therapeutic DNA vaccine containing a fusion of the rel Mtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3α/CCL20. To augment mucosal immune responses, intranasal delivery was also evaluated. We found that intramuscular delivery of the MIP-3α / rel Mtb (fusion) vaccine or intranasal delivery of the rel Mtb (non-fusion) vaccine potentiate isoniazid activity more than intramuscular delivery of the DNA vaccine expressing rel Mtb alone in a chronic TB mouse model (absolute reduction of Mtb burden: 0.63 log 10 and 0.5 log 10 colony-forming units, respectively; P=0.0002 and P=0.0052), inducing pronounced Mtb -protective immune signatures. The combined approach involving intranasal delivery of the DNA MIP-3α / rel Mtb fusion vaccine demonstrated the greatest mycobactericidal activity together with isoniazid when compared to each approach alone (absolute reduction of Mtb burden: 1.13 log 10 , when compared to the intramuscular vaccine targeting rel Mtb alone; P<0.0001), as well as robust systemic and local Th1 and Th17 responses. This DNA vaccination strategy may be a promising adjunctive approach combined with standard therapy to shorten curative TB treatment, and also serves as proof of concept for treating other chronic bacterial infections. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Karanika, Gordy, Neupane, Karantanos, Ruelas Castillo, Quijada, Comstock, Sandhu, Kapoor, Hui, Ayeh, Tasneen, Krug, Danchik, Wang, Schill, Markham and Karakousis.)
Databáze:	MEDLINE
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