2025-07-14 タフツ大学
Tuberculosis (TB) bacteria appear in red inside a lung granuloma from a mouse infected with Mycbacterium tuberculosis, the bacterium that causes TB. Photo: Amanda Martinot
<関連情報>
- https://now.tufts.edu/2025/07/14/tb-bacteria-play-possum-evade-vaccines
- https://www.nature.com/articles/s41541-025-01150-9
- https://www.cell.com/iscience/fulltext/S2589-0042(23)01040-4
TnSeqにより結核菌がワクチン誘導免疫下で生存するための遺伝的要件が明らかになる TnSeq identifies genetic requirements of Mycobacterium tuberculosis for survival under vaccine-induced immunity
Kimra S. James,Neharika Jain,Kelly Witzl,Nico Cicchetti,Sarah M. Fortune,Thomas R. Ioerger,Amanda J. Martinot & Allison F. Carey
npj Vaccines Published:22 May 2025
DOI:https://doi.org/10.1038/s41541-025-01150-9
Abstract
Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), remains a persistent global health challenge due to the lack of an effective vaccine. The only licensed TB vaccine, Bacille Calmette-Guerin (BCG), is a live attenuated strain of Mycobacterium bovis that protects young children from severe disease but fails to provide protection through adulthood. It is unclear why BCG provides incomplete protection despite inducing a robust Th1 immune response. We set out to interrogate mycobacterial determinants of vaccine escape using a functional genomics approach, TnSeq, to define bacterial genes required for survival in mice vaccinated with BCG, the live attenuated Mtb vaccine strain, ΔLprG, and in mice with Mtb immunity conferred by prior infection. We find that critical virulence genes associated with acute infection and exponential growth are less essential in hosts with adaptive immunity, including genes encoding the Esx-1 and Mce1 systems. Genetic requirements for Mtb growth in vaccinated and previously Mtb-infected hosts mirror the genetic requirements reported for bacteria under in vitro conditions that reflect aspects of the adaptive immune response. Across distinct immunization conditions, differences in genetic requirements between live attenuated vaccines and vaccination routes are observed, suggesting that different immunization strategies impose distinct bacterial stressors. Collectively, these data support the idea that Mtb requires genes that enable stress adaptation and growth arrest upon encountering the restrictive host environment induced by the adaptive immune response. We demonstrate that TnSeq can be used to understand the bacterial genetic requirements for survival in vaccinated hosts across pre-clinical live attenuated vaccines and therefore may be applied to other vaccine modalities. Understanding how Mtb survives vaccine-induced immunity has the potential to inform the development of new vaccines or adjuvant therapies.
低用量マウスチャレンジモデルにおける弱毒化結核菌ワクチンの予防効果 Attenuated Mycobacterium tuberculosis vaccine protection in a low-dose murine challenge model
Samuel J. Vidal ∙ Daniel Sellers ∙ Jingyou Yu ∙ … ∙ Kevin B. Urdah ∙ Amanda J. Martinot ∙ Dan H. Barouch
iScience Published:May 28, 2023
DOI:https://doi.org/10.1016/j.isci.2023.106963
Highlights
- ΔLprG reduces detectable infection in mice after single 1 MID50 challenge
- ΔLprG prevents infection dissemination after single 1 MID50 challenge
- Repeated 1 MID50 challenge facilitates correlates of ΔLprG vaccine protection
Summary
Bacillus Calmette–Guérin (BCG) remains the only approved tuberculosis (TB) vaccine despite limited efficacy. Preclinical studies of next-generation TB vaccines typically use a murine aerosol model with a supraphysiologic challenge dose. Here, we show that the protective efficacy of a live attenuated Mycobacterium tuberculosis (Mtb) vaccine ΔLprG markedly exceeds that of BCG in a low-dose murine aerosol challenge model. BCG reduced bacterial loads but did not prevent establishment or dissemination of infection in this model. In contrast, ΔLprG prevented detectable infection in 61% of mice and resulted in anatomic containment of 100% breakthrough infections to a single lung. Protection was partially abrogated in a repeated low-dose challenge model, which showed serum IL-17A, IL-6, CXCL2, CCL2, IFN-γ, and CXCL1 as correlates of protection. These data demonstrate that ΔLprG provides increased protection compared to BCG, including reduced detectable infection and anatomic containment, in a low-dose murine challenge model.
