Fibroblast growth factor receptor-1 mediates internalization of pathogenic spotted fever rickettsiae into host endothelium

Abha Sahni, Jignesh Patel, Hema P. Narra, Casey L.C. Schroeder, David Walker, Sanjeev Sahni

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Rickettsial infections continue to cause serious morbidity and mortality in severe human cases around the world. Host cell adhesion and invasion is an essential requisite for intracellular growth, replication, and subsequent dissemination of pathogenic rickettsiae. Heparan sulfate proteoglycans [HSPGs] facilitate the interactions between fibroblast growth factor(s) and their tyrosine kinase receptors resulting in receptor dimerization/activation and have been implicated in bacterial adhesion to target host cells. In the present study, we have investigated the contributions of fibroblast growth factor receptors [FGFRs] in rickettsial entry into the host cells. Inhibition of HSPGs by heparinase and FGFRs by AZD4547 (a selective small-molecule inhibitor) results in significant reduction in rickettsial internalization into cultured human microvascular endothelial cells (ECs), which represent the primary targets of pathogenic rickettsiae during human infections. Administration of AZD4547 during R. conorii infection in a murine model of endothelial-target spotted fever rickettsiosis also diminishes pulmonary rickettsial burden in comparison to mock-treated controls. Silencing of FGFR1 expression using a small interfering RNA also leads to similar inhibition of R. rickettsii invasion into ECs. Consistent with these findings, R. rickettsii infection of ECs also results in phosphorylation of tyrosine 653/654, suggesting activation of FGFR1. Using isobaric tag for relative and absolute quantitation [iTRAQ]-based proteomics approach, we further demonstrate association of β-peptide of rickettsial outer membrane protein OmpA with FGFR1. Mechanistically, FGFR1 binds to caveolin-1 and mediates bacterial entry via caveolin-1 dependent endocytosis. Together, these results identify host cell FGFR1 and rickettsial OmpA as another novel receptor-ligand pair contributing to the internalization of pathogenic rickettsiae into host endothelial cells and the potential application of FGFR-inhibitor drugs as adjunct therapeutics against spotted fever rickettsioses.

Original languageEnglish (US)
Article numbere0183181
JournalPLoS One
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

Receptor, Fibroblast Growth Factor, Type 1
Rickettsia
Endothelial cells
endothelium
Fibroblast Growth Factor Receptors
endothelial cells
fever
Endothelium
Fever
Endothelial Cells
rickettsial diseases
Caveolin 1
Heparan Sulfate Proteoglycans
proteoglycans
Infection
receptors
tyrosine
Chemical activation
Heparin Lyase
infection

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Fibroblast growth factor receptor-1 mediates internalization of pathogenic spotted fever rickettsiae into host endothelium. / Sahni, Abha; Patel, Jignesh; Narra, Hema P.; Schroeder, Casey L.C.; Walker, David; Sahni, Sanjeev.

In: PLoS One, Vol. 12, No. 8, e0183181, 01.08.2017.

Research output: Contribution to journalArticle

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