Biological Sciences Division
Published February 25, 2025 | Version v1
Journal article Open

Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate

Creators

  • 1. Texas Biomedical Research Institute
  • 2. University of Chicago
  • 3. Tulane University
  • 4. Houston Methodist Research Institute

Description

The need for novel vaccination strategies to control tuberculosis (TB) is underscored by the limited and variable efficacy of the currently licensed vaccine, Bacille Calmette-Guerin (BCG). SigH is critical for Mycobacterium tuberculosis (Mtb) to mitigate oxidative stress, and in its absence Mtb is unable to scavenge host oxidative/nitrosative bursts. The MtbΔsigH (ΔsigH) isogenic mutant induces signatures of the innate immunity in macrophages and protects rhesus macaques from a lethal Mtb challenge. To understand the immune mechanisms of protection via mucosal vaccination with ΔsigH, we employed the resistant cynomolgus macaque model; and our results show that ΔsigH vaccination significantly protects against lethal Mtb challenge in this species. ΔsigH-vaccinated macaques are devoid of granulomas and instead generate inducible bronchus associated lymphoid structures, and robust antigen-specific CD4+ and CD8+ T cell responses, driven by a hyper-immune, trained immunity-like phenotype in host macrophages with enhanced antigen presentation. Correlates of protection in ΔsigH-vaccinated macaques include gene signatures of T cell activation, IFNG production, including IFN-responsive, activated T cells, concomitant with IFNG production, and suppression of IDO+ Type I IFN-responsive macrophage recruitment. Thus, ΔsigH is a promising lead candidate for further development as an antitubercular vaccine.

Data availability

Source data are provided with this paper. All data supporting the findings of this study are available within this manuscript and its Supplementary Information. Any additional data can be requested from the corresponding authors upon reasonable request. The scRNAseq raw data generated in this study have been deposited to the Gene Expression Omnibus- GEO (NCBI) under accession number GSE283562. The RNAseq dataset have been deposited in the NCBI BioProject database under accession number PRJNA1202673. Source data are provided with this paper.

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Additional details

Identifiers

DOI
10.1038/s41467-025-57090-4
Other
oai:uchicago.tind.io:14652

Funding

National Institutes of Health
AI185028
National Institutes of Health
AI134240
National Institutes of Health
AI138587
National Institutes of Health
AI111914
National Institutes of Health
OD011133
National Institutes of Health
OD010442
National Institutes of Health
OD032443
National Institutes of Health
OD028732
National Institutes of Health
AI161943
National Institutes of Health
AI168439
National Institutes of Health
OD028653

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Microbiology