Comparison of Lethal and Nonlethal Mouse Models of Orientia tsutsugamushi Infection Reveals T-Cell Population-Associated Cytokine Signatures Correlated with Lethality and Protection

Authors

Alison Luce-Fedrow, Naval Medical Research Center; Shippensburg University; Henry M. Jackson Foundation for the Advancement of Military Medicine
Suchismita Chattopadhyay, Naval Medical Research Center; Henry M. Jackson Foundation for the Advancement of Military Medicine
Teik-Chye Chan, Naval Medical Research Center; Henry M. Jackson Foundation for the Advancement of Military Medicine
Gregory Pearson, Shippensburg University; Henry M. Jackson Foundation for the Advancement of Military Medicine
John B. Patton, Thomas Jefferson UniversityFollow
Allen L. Richards, Naval Medical Research Center; Uniformed Services University of the Health Sciences

Document Type

Article

Publication Date

7-2-2021

Comments

This article is the authors’ final published version in Tropical Medicine and Infectious Disease, Volume 6, Issue 3, July 2021, Article number 121.

The published version is available at https://doi.org/10.3390/tropicalmed6030121. Copyright © Luce-Fedrow et al.

Abstract

The antigenic diversity of Orientia tsutsugamushi as well as the interstrain difference(s) associated with virulence in mice impose the necessity to dissect the host immune response. In this study we compared the host response in lethal and non-lethal murine models of O. tsutsugamushi infection using the two strains, Karp (New Guinea) and Woods (Australia). The models included the lethal model: Karp intraperitoneal (IP) challenge; and the nonlethal models: Karp intradermal (ID), Woods IP, and Woods ID challenges. We monitored bacterial trafficking to the liver, lung, spleen, kidney, heart, and blood, and seroconversion during the 21-day challenge. Bacterial trafficking to all organs was observed in both the lethal and nonlethal models of infection, with significant increases in average bacterial loads observed in the livers and hearts of the lethal model. Multicolor flow cytometry was utilized to analyze the CD4+ and CD8+ T cell populations and their intracellular production of the cytokines IFNγ, TNF, and IL2 (single, double, and triple combinations) associated with both the lethal and nonlethal murine models of infection. The lethal model was defined by a cytokine signature of double- (IFNγ-IL2) and triple-producing (IL2-TNF-IFNγ) CD4+ T-cell populations; no multifunctional signature was identified in the CD8+ T-cell populations associated with the lethal model. In the nonlethal model, the cytokine signature was predominated by CD4+ and CD8+ T-cell populations associated with single (IL2) and/or double (IL2-TNF) populations of producers. The cytokine signatures associated with our lethal model will become depletion targets in future experiments; those signatures associated with our nonlethal model are hypothesized to be related to the protective nature of the nonlethal challenges.

Recommended Citation

Luce-Fedrow, Alison; Chattopadhyay, Suchismita; Chan, Teik-Chye; Pearson, Gregory; Patton, John B.; and Richards, Allen L., "Comparison of Lethal and Nonlethal Mouse Models of Orientia tsutsugamushi Infection Reveals T-Cell Population-Associated Cytokine Signatures Correlated with Lethality and Protection" (2021). Department of Microbiology and Immunology Faculty Papers. Paper 130.
https://jdc.jefferson.edu/mifp/130

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

34287349

Language

English