Neutrophil Dynamics Affect Mycobacterium tuberculosis Granuloma Outcomes and Dissemination

Abstract

Neutrophil infiltration into tuberculous granulomas is often associated with higher bacteria loads and severe disease but the basis for this relationship is not well understood. To better elucidate the connection between neutrophils and pathology in primate systems, we paired data from experimental studies with our next generation computational model GranSim to identify neutrophil-related factors, including neutrophil recruitment, lifespan, and intracellular bacteria numbers, that drive granuloma-level outcomes. We predict mechanisms underlying spatial organization of neutrophils within granulomas and identify how neutrophils contribute to granuloma dissemination. We also performed virtual deletion and depletion of neutrophils within granulomas and found that neutrophils play a nuanced role in determining granuloma outcome, promoting uncontrolled bacterial growth in some and working to contain bacterial growth in others. Here, we present three key results: We show that neutrophils can facilitate local dissemination of granulomas and thereby enable the spread of infection. We suggest that neutrophils influence CFU burden during both innate and adaptive immune responses, implying that they may be targets for therapeutic interventions during later stages of infection. Further, through the use of uncertainty and sensitivity analyses, we predict which neutrophil processes drive granuloma severity and structure.

An In Vivo Model of Separate M. tuberculosis Phagocytosis by Neutrophils and Macrophages: Gene Expression Profiles in the Parasite and Disease Development in the Mouse Host

“…Given that the secondary M. tuberculosis seeding of the lung tissue from lymphoid organs in mice occurs at day 16–17 post-challenge [ 59 ], we assume that, as early as week 3 post-challenge, we could observe a complex picture of mycobacteria-host cell interactions reflecting a mixture of primary and secondary responses. Consider this, the recently modeled and analyzed heterogeneity within neutrophil populations during TB infection [ 60 ] deserves specific attention. Bearing in mind that both mycobacterial and phagocyte populations contain cells expressing a wide spectrum of metabolic activity at each and every time point, the phenotypes we are assessing often seem to demonstrate pure stochastic diversity, but, in reality, represent superposition of metabolic activity of individual cells at different stages of infection progression.…”

Optimizing tuberculosis treatment efficacy: comparing the standard regimen with Moxifloxacin-containing regimens

“…To do that, we sampled 250 granuloma parameter sets within biological feasible ranges using the LHS method and simulating three replications with each parameter set to capture both types of uncertainty present [48]. We then classified granulomas that have nonzero bacterial loads (those that did not sterilize) by measuring their colony forming units (CFUs) as either low-CFU or high-CFU granulomas, depending on their CFU trends (Fig Each curve represents a single granuloma simulation with a single parameter set using GranSim, and black dots are data from NHP studies [46,47]. Based on their CFU trajectories, we categorize granulomas into low-CFU (blue curves) and high-CFU (red curves) granulomas.…”

“…We first generated an in silico library of 750 granulomas over 300 days that matches NHP dataset of 600 granulomas [46,47]. To do that, we sampled 250 granuloma parameter sets within biological feasible ranges using the LHS method and simulating three replications with each parameter set to capture both types of uncertainty present [48].…”

Type I IFN signaling mediates NET release to promoteMycobacterium tuberculosisreplication and granuloma caseation

“…The copyright holder for this preprint this version posted November 29, 2022. ; https://doi.org/10.1101/2022.11.29.518376 doi: bioRxiv preprint 3 Neutrophils are the most abundant and predominantly-infected cell type in the sputum 2 , bronchoalveolar lavage (BAL) fluid 3 , and caseum contents from resected lung tissue of active TB patients 2 . Studies of TB in mice [4][5][6][7][8][9][10][11][12][13][14][15][16][17] , nonhuman primates [18][19][20][21] , and humans 9,[22][23][24][25][26][27][28] have identified a correlation between neutrophil abundance and increased disease severity. In contrast to their antibacterial role in numerous other infectious diseases 29 , neutrophils in TB have impaired capacity for killing phagocytosed Mtb [30][31][32] .…”