Naomi Daniels Poster 2023

Naomi Daniels

Dr Naomi Daniels

University of Otago, New Zealand

Investigating the evasion of BCG-mediated trained innate immune responses by Beijing-Mtb

Poster Abstract

The bacille Calmette–Guérin (BCG) vaccine only protects against TB in ~50% of cases. Remarkably, there is no BCG-mediated protection against disease caused by Beijing-genotype Mtb strains that predominate in East Asia1. This is alarming as Beijing-Mtb is associated with large TB outbreaks, global spread, and dissemination of multidrug-resistance. Our research seeks to understand why BCG fails to protect against Beijing-Mtb. 

 The innate immune system substantively contributes to protective immunity generated by BCG vaccination, a process known as innate immune training. As Beijing-Mtb is capable of circumventing BCG-induced protection, we tested the hypothesis that Beijing-Mtb strains evade and subvert trained innate immunity.

 Mice were vaccinated intranasally with BCG to establish a strong mucosal immune response. Early innate immune responses revealed a notable increase in the CD11bhi subset of alveolar macrophages (AMs) in the lungs of BCG-vaccinated mice, compared to unvaccinated mice2. Accordingly, we developed an in vitro mycobacterial growth-inhibition assay using a clinical strain of Beijing-Mtb and a matched clinical isolate of non-Beijing-Mtb to determine whether the early phagocytic response is dysfunctional after Beijing Mtb infection, compared to non-Beijing Mtb. Trained innate cell subsets, including CD11bhi and CD11blo AMs, were sorted from murine lungs 4 weeks after BCG-vaccination; these cells were co-cultured with Beijing- or non-BeijingMtb for 2-4 days followed by plating of cell lysates on selective agar. This allowed for investigation of the antimicrobial activity of BCG-trained lung-resident innate immune cells against Beijing and non-Beijing Mtb.  

These data, along with in vivo studies currently underway, will inform the design of secondary endpoints to be measured in an Indonesia-based clinical study of TBexposed case contacts or health care students entering clinical exposures, to improve TB vaccine function against Beijing Mtb. 

  • Verrall AJ, Chaidir L, Ruesen C, Apriani L, Koesoemadinata RC, van Ingen J, Sharples K, van Crevel R, Alisjahbana B, Hill PC; INFECT study group. Lower Bacillus Calmette-Guérin Protection against Mycobacterium tuberculosis Infection after Exposure to Beijing Strains. Am J Respir Crit Care Med. 2020 May 1;201(9):1152-1155. 
  • Ryder BM, Sandford SK, Manners KM, Dalton JP, Wiles S, Kirman JR. Gr1int/high Cells Dominate the Early Phagocyte Response to Mycobacterial Lung Infection in Mice. Front Microbiol. 2019 Mar 8;10:402.

 

Biography

Dr Daniels is a postdoctoral research fellow based at the University of Otago, Dunedin, New Zealand.

Current research primarily involves investigating how Beijing-genotype Mycobacterium tuberculosis evades protective immunity generated by the BCG vaccine. This work specifically focuses on determining the role of the innate immune system in the anti-mycobacterial response and ultimately aims to improve protective outcomes for the development of novel Tuberculosis vaccines.