Immune response against rickettsiae: lessons from murine infection models

Osterloh, Anke

doi:10.1007/s00430-017-0514-1

Cited by 31 publications

(47 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, few studies evaluated the SAT effect through the Amblyomma - Rickettsia association (67–69) and none of them specifically addressed the R. rickettsii interaction with A. sculptum . Experimental models for rickettsial infections that closely reproduce human disease are largely lacking, particularly for R. rickettsii (70, 71), even though a murine model using the C3H/HeN has been successfully used in the last few years to trial potential vaccine candidates to R. rickettsii (52–57, 72). Our attempts to use the C3H/HePas strain failed in generating a model of susceptibility to our R. rickettsii isolate (data not show), although this murine strain is known to be closely related to the C3H/HeN.…”

Section: Discussionmentioning

confidence: 99%

Amblyomma sculptum Salivary PGE2 Modulates the Dendritic Cell-Rickettsia rickettsii Interactions in vitro and in vivo

et al. 2019

View full text Add to dashboard Cite

Amblyomma sculptum is an important vector of Rickettsia rickettsii, causative agent of Rocky Mountain spotted fever and the most lethal tick-borne pathogen affecting humans. To feed on the vertebrate host's blood, A. sculptum secretes a salivary mixture, which may interact with skin resident dendritic cells (DCs) and modulate their function. The present work was aimed at depicting the A. sculptum saliva-host DC network and the biochemical nature of the immunomodulatory component(s) involved in this interface. A. sculptum saliva inhibits the production of inflammatory cytokines by murine DCs stimulated with LPS. The fractionation of the low molecular weight salivary content by reversed-phase chromatography revealed active fractions eluting from 49 to 55% of the acetonitrile gradient. Previous studies suggested that this pattern of elution matches with that observed for prostaglandin E2 (PGE2) and the molecular identity of this lipid mediator was unambiguously confirmed by a new high-resolution mass spectrometry methodology. A productive infection of murine DCs by R. rickettsii was demonstrated for the first time leading to proinflammatory cytokine production that was inhibited by both A. sculptum saliva and PGE2, a result also achieved with human DCs. The adoptive transfer of murine DCs incubated with R. rickettsii followed by treatment with A. sculptum saliva or PGE2 did not change the cytokine profile associated to cellular recall responses while IgG2a-specific antibodies were decreased in the serum of these mice. Together, these findings emphasize the role of PGE2 as a universal immunomodulator of tick saliva. In addition, it contributes to new approaches to explore R. rickettsii-DC interactions both in vitro and in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

Amblyomma sculptum Salivary PGE2 Modulates the Dendritic Cell-Rickettsia rickettsii Interactions in vitro and in vivo

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In this study, we extended our previously characterized mouse model that has been useful for investigating the immune response to spotted fever group rickettsial infections. 62,63 The label-free proteomics studies enabled identification of pathways involved in sublethal versus lethal infections. Of interest, the complement cascade and the macrophage protein Marco were uniquely expressed in sublethal disease ( Figure 4H).…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomics of the Endothelial Secretome Identifies RC0497 as Diagnostic of Acute Rickettsial Spotted Fever Infections

Zhao

Fang

Zhang

et al. 2020

The American Journal of Pathology

View full text Add to dashboard Cite

Mediterranean spotted fever is a reemerging acute tick-borne infection produced by the a-proteobacterium, Rickettsia conorii. Rickettsia conorii infects vascular endothelial cells producing disseminated plasma leakage, manifesting as nonspecific fever, headache, and maculopapular rash. Because there are no available tests of early infection, Mediterranean spotted fever is often undiagnosed and untreated, resulting in significant mortality. To address this critical need, we have applied a quantitative proteomics pipeline for analyzing the secretome of primary human umbilical vein endothelial cells. Of the 104 proteins whose abundance changed significantly in the R. conoriieinfected human umbilical vein endothelial cells' secretome, 46 proteins were up-regulated: 45 were host secreted proteins (including cytokines), and 1 was a rickettsial protein, the putative N-acetylmuramoyl-L-alanine amidase RC0497. Proteins with sequence highly homologous to RC0497 were found to be shared by many species of the spotted fever group rickettsiae, but not typhus group rickettsiae. Quantitative targeted proteomics studies of plasma from a mouse model of sublethal and lethal R. conorii identified RC0497 in the blood, and its circulating levels were proportionally associated with infection outcome. Finally, the presence of RC0497 in the serum samples from a cohort of humans presenting with acute rickettsioses was confirmed. The detection of RC0497 has the potential to be a sensitive and specific marker for acute rickettsial spotted rickettsioses. (Am J Pathol 2020, 190: 306e322; https://doi.

show abstract

“…The R. conorii mouse model of infection has routinely been used for in vivo investigations because R. conorii infection in susceptible C3H/HeN mice closely mimics the disseminated endothelial infection, which is the major feature of pathogenesis and displays the overall pathology of Rocky Mountain Spotted Fever (RMSF) and Mediterranean Spotted Fever (MSF) in humans. Also, a direct and authenticated R. rickettsii mouse model is not yet available, mainly due to resistance of a number of mouse strains to pathogenic R. rickettsii [46,47].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-Regulated Rickettsial Invasion into Host Endothelium via Fibroblast Growth Factor 2 and Its Receptor FGFR1

Sahni

Narra

Patel

et al. 2018

Cells

View full text Add to dashboard Cite

Microvascular endothelial cells (ECs) represent the primary target cells during human rickettsioses and respond to infection via the activation of immediate–early signaling cascades and the resultant induction of gene expression. As small noncoding RNAs dispersed throughout the genome, microRNAs (miRNAs) regulate gene expression post-transcriptionally to govern a wide range of biological processes. Based on our recent findings demonstrating the involvement of fibroblast growth factor receptor 1 (FGFR1) in facilitating rickettsial invasion into host cells and published reports suggesting miR-424 and miR-503 as regulators of FGF2/FGFR1, we measured the expression of miR-424 and miR-503 during R. conorii infection of human dermal microvascular endothelial cells (HMECs). Our results revealed a significant decrease in miR-424 and miR-503 expression in apparent correlation with increased expression of FGF2 and FGFR1. Considering the established phenomenon of endothelial heterogeneity and pulmonary and cerebral edema as the prominent pathogenic features of rickettsial infections, and significant pathogen burden in the lungs and brain in established mouse models of disease, we next quantified miR-424 and miR-503 expression in pulmonary and cerebral microvascular ECs. Again, R. conorii infection dramatically downregulated both miRNAs in these tissue-specific ECs as early as 30 min post-infection in correlation with higher FGF2/FGFR1 expression. Changes in the expression of both miRNAs and FGF2/FGFR1 were next confirmed in a mouse model of R. conorii infection. Furthermore, miR-424 overexpression via transfection of a mimic into host ECs reduced the expression of FGF2/FGFR1 and gave a corresponding decrease in R. conorii invasion, while an inhibitor of miR-424 had the expected opposite effect. Together, these findings implicate the rickettsial manipulation of host gene expression via regulatory miRNAs to ensure efficient cellular entry as the critical requirement to establish intracellular infection.

show abstract

Immune response against rickettsiae: lessons from murine infection models

Cited by 31 publications

References 120 publications

Amblyomma sculptum Salivary PGE2 Modulates the Dendritic Cell-Rickettsia rickettsii Interactions in vitro and in vivo

Amblyomma sculptum Salivary PGE2 Modulates the Dendritic Cell-Rickettsia rickettsii Interactions in vitro and in vivo

Quantitative Proteomics of the Endothelial Secretome Identifies RC0497 as Diagnostic of Acute Rickettsial Spotted Fever Infections

MicroRNA-Regulated Rickettsial Invasion into Host Endothelium via Fibroblast Growth Factor 2 and Its Receptor FGFR1

Contact Info

Product

Resources

About