Dissemination of Orientia tsutsugamushi and Inflammatory Responses in a Murine Model of Scrub Typhus

Autor: Bernhard Fleischer, Julia Kolbaum, Matthias Hauptmann, Christian Keller, Markus Glatzel, Melanie Neumann, Mohammad Gharaibeh
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Bacterial Diseases
Pathology
medicine.medical_specialty
lcsh:Arctic medicine. Tropical medicine
Orientia tsutsugamushi
lcsh:RC955-962
Inflammation
Mouse Models
Scrub typhus
Research and Analysis Methods
Polymerase Chain Reaction
Typhus
Pathogenesis
Interferon-gamma
Mice
Model Organisms
Meningoencephalitis
medicine
Medicine and Health Sciences
Macrophage
Animals
Humans
Lung
Cells
Cultured
Mice
Inbred BALB C
biology
business.industry
lcsh:Public aspects of medicine
Public Health
Environmental and Occupational Health
Biology and Life Sciences
lcsh:RA1-1270
Animal Models
Macrophage Activation
medicine.disease
biology.organism_classification
bacterial infections and mycoses
Orientia
Disease Models
Animal
medicine.anatomical_structure
Infectious Diseases
Scrub Typhus
Immunology
medicine.symptom
business
Research Article
Zdroj: PLoS Neglected Tropical Diseases
PLoS Neglected Tropical Diseases, Vol 8, Iss 8, p e3064 (2014)
ISSN: 1935-2735
1935-2727
Popis: Central aspects in the pathogenesis of scrub typhus, an infection caused by Orientia (O.) tsutsugamushi, have remained obscure. Its organ and cellular tropism are poorly understood. The purpose of this study was to analyze the kinetics of bacterial dissemination and associated inflammatory responses in infected tissues in an experimental scrub typhus mouse model, following infection with the human pathogenic strain Karp. We provide a thorough analysis of O. tsutsugamushi infection in inbred Balb/c mice using footpad inoculation, which is close to the natural way of infection. By a novel, highly sensitive qPCR targeting the multi copy traD genes, we quantitatively monitored the spread of O. tsutsugamushi Karp from the skin inoculation site via the regional lymph node to the internal target organs. The highest bacterial loads were measured in the lung. Using confocal imaging, we also detected O. tsutsugamushi at the single cell level in the lung and found a predominant macrophage rather than endothelial localization. Immunohistochemical analysis of infiltrates in lung and brain revealed differently composed lesions with specific localizations: iNOS-expressing macrophages were frequent in infiltrative parenchymal noduli, but uncommon in perivascular lesions within these organs. Quantitative analysis of the macrophage response by immunohistochemistry in liver, heart, lung and brain demonstrated an early onset of macrophage activation in the liver. Serum levels of interferon (IFN)-γ were increased during the acute infection, and we showed that IFN-γ contributed to iNOS-dependent bacterial growth control. Our data show that upon inoculation to the skin, O. tsutsugamushi spreads systemically to a large number of organs and gives rise to organ-specific inflammation patterns. The findings suggest an essential role for the lung in the pathogenesis of scrub typhus. The model will allow detailed studies on host-pathogen interaction and provide further insight into the pathogenesis of O. tsutsugamushi infection.
Author Summary Many details of the pathogenesis of scrub typhus, an infection caused by the intracellular bacterium Orientia tsutsugamushi that is endemic in Southeast Asia, have remained unclear until today. In this study, we present an experimental self-healing mouse model of scrub typhus based on footpad skin inoculation of the human pathogenic Karp strain of O. tsutsugamushi that shares many features with human infection. We established a novel quantitative PCR with increased sensitivity for the measurement of bacterial organ loads of infected mice. It was thereby shown that O. tsutsugamushi initially accumulated in the regional lymph node and subsequently spread to many organs with the highest bacterial loads found in the lung. The predominant host cells in the lung were macrophages located in the parenchymal interstitium, rather than endothelial cells. Our data also show unexpected organ-specific differences in the dynamics of macrophage activation. This mouse model will help to advance our understanding of scrub typhus pathogenesis.
Databáze: OpenAIRE
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