Modeling the immune response to Salmonella during typhoid

Dhingra, D and Marathe, SA and Sharma, N and Marathe, A and Chakravortty, D (2021) Modeling the immune response to Salmonella during typhoid. In: International Immunology, 33 (5). pp. 281-298.

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Abstract

Several facets of the host immune response to Salmonella infection have been studied independently at great depths to understand the progress and pathogenesis of Salmonella infection. The circumstances under which a Salmonella-infected individual succumbs to an active disease, evolves as a persister or clears the infection are not understood in detail. We have adopted a system-level approach to develop a continuous-time mechanistic model. We considered key interactions of the immune system state variables with Salmonella in the mesenteric lymph node to determine the final disease outcome deterministically and exclusively temporally. The model accurately predicts the disease outcomes and immune response trajectories operational during typhoid. The results of the simulation confirm the role of anti-inflammatory (M2) macrophages as a site for persistence and relapsing infection. Global sensitivity analysis highlights the importance of both bacterial and host attributes in influencing the disease outcome. It also illustrates the importance of robust phagocytic and anti-microbial potential of M1 macrophages and dendritic cells (DCs) in controlling the disease. Finally, we propose therapeutic strategies for both antibiotic-sensitive and antibiotic-resistant strains (such as IFN-γ therapy, DC transfer and phagocytic potential stimulation). We also suggest prevention strategies such as improving the humoral response and macrophage carrying capacity, which could complement current vaccination schemes for enhanced efficiency.

Item Type:	Journal Article
Publication:	International Immunology
Publisher:	Oxford University Press
Additional Information:	The copyright for this article belongs to Oxford University Press.
Keywords:	antibiotic agent; cytokine; gamma interferon, antibiotic resistance; antibiotic sensitivity; antimicrobial activity; Article; bacterial clearance; bacterial strain; cell interaction; cell transfer; clinical outcome; controlled study; dendritic cell; diagnostic accuracy; drug efficacy; gene knockout; human; humoral immunity; immune response; immune system; immunocompetent cell; immunoregulation; M1 macrophage; M2 macrophage; macrophage; macrophage function; mathematical model; mesentery lymph node; molecular dynamics; nonhuman; phagocyte; phagocytosis; prediction; protein expression; recurrent disease; Salmonella; simulation; typhoid fever; animal; immunology; knockout mouse; lymph node; microbiology; mouse; Salmonella; salmonellosis; typhoid fever, Animals; Humans; Immunity, Humoral; Lymph Nodes; Macrophages; Mice; Mice, Knockout; Salmonella; Salmonella Infections; Typhoid Fever
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	28 Nov 2023 07:30
Last Modified:	28 Nov 2023 07:30
URI:	https://eprints.iisc.ac.in/id/eprint/82978

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