B7 (2019 - 2022) - Immune modulatory function of M. tuberculosis infected neutrophils

Development of necrotic granulomas is a hallmark of lung pathogenesis in tuberculosis and a prerequisite for aerosol transmission of the TB agent, Mycobacterium (M.) tuberculosis, to the next human host. As the prime bacterial infection worldwide, with 10.4 million new cases and 1.7 mill deaths in 2017 (WHO Tuberculosis Report 2018), immune modulation by host directed therapies (HDT) are novel approaches to limit inflammatory tissue destruction in TB and transmission in adjunct to desperately needed new antibiotics. Neutrophils (PMN), have been suggested to exacerbate TB pathogenesis and may be interesting HDT targets (Vilaplana et al., 2013; Dallenga et al., 2017). PMN represent the predominant cell population infected with Mtb in active TB lungs and signatures thereof are associated with active TB patients (Eum et al., 2009; Berry et al., 2010). However, M. tuberculosisinduces reactive oxygen intermediates (ROI) in PMN, which requires myeloperoxidase (MPO) and drives these cells quickly into necrotic cell death and thereby facilitates escape of M. tuberculosisfrom PMN effectors (Corleis et al., 2012). Moreover, subsequent uptake of M. tuberculosisinfected necrotic PMN by macrophages promotes intracellular mycobacterial growth and downstream necrotic cell death also of these phagocytes (Dallenga et al., 2017). These data indicate that PMN have limited protective function in tuberculosis, but rather contribute to disease exacerbation, however, their role in downstream immune regulation is not studied yet. Here we will analyze the role of M tuberculosisinfected neutrophil cell death in acquired immune responses in particular, T cell priming and activation.


1. Analyze effects of necrotic PMN lipids on lung T cell recruitment and functions

2. Characterize lung immunological microenvironment in infected C3H vs. C57BL.6 mice

3. Determine whether limiting PMN recruitment in C3H mice will enhance T cell responses and reduce M. tuberculosis loads.