Matrix metalloproteinase expression, producon and polymorphisms in Q fever

Anne F.M. Jansen1,2, Teske Schoffelen1,2, Julien Textoris3, Jean Louis Mege3, Chantal P. Bleeker-Rovers1,2, Esther van de Vosse4, Hendrik Jan Roest5, Marcel van Deuren1,2 1. Department of Internal Medicine, Division of Experimental Medicine, Radboud university medical center, Nijmegen, The Netherlands 2. Radboud Expert Centre for Q fever, Radboud university medical center, Nijmegen, the Netherlands, 3. URMITE, CNRS UMR 7278, IRD 198, INSERM 1095 Aix-Marseille University, Marseille, France 4. Department of Infecous Diseases, Leiden University Medical Center, Leiden, The Netherlands 5. Department of Bacteriology and TSEs, Central Veterinary Instute, part of Wageningen UR, Lelystad, the Netherlands

Background C. burnei induces MMP-1 and MMP-9 producon in PBMCs

Chronic Q fever is a life threatening condion caused by the Gram-negave bacterium Coxiella burnei, manifesng as an infecon of aneurysms, aorc prosthesis or heart valves. Matrix metalloproteinases (MMPs) are proteolyc enzymes that cleave extracellular matrix and are implicated in the pathology of aneurysms and endocardis. Currently, the contribuon of MMPs to the pathogenesis of chronic Q fever is unknown.

Methods We invesgated the C. burnei specific gene expression of MMPs in PBMCs and protein producon by ELISA in chronic Q fever paents (n=6, n=10, respecvely), cardiovascular paents with a history of Q fever (n=10) and healthy controls (n=4, n=10, respecvely), in some

experiments, the controls had vascular disease (n=10). Circulang MMP levels were assessed with Luminex technology and these groups were also genotyped for 20 SNPs in MMP and Tissue Inhibitor of MMP (TIMP) genes. MMP-7 serum levels are higher in chronic Q fever paents

Circulang MMP-2, MMP-7 and MMP-10 was C. burnei specifically upregulates MMP gene expression and induces MMP producon measured in serum using Luminex technology in Funconal enrichment analysis revealed C. burnei specific upregulaon compared to LPS controls with vascular

smulaon in healthy controls of 4 MMP genes: MMP1, MMP7, MMP10 and MMP19. This disease (n=10),

encouraged us to look further into the role of MMPs in Q fever. cardiovascular paents

with a history of Q fever Genec variaon in MMP genes is associated with chronic Q fever (n=10) and chronic Q

fever paents (n=27).

We genotyped 139 chronic Q fever paents and 220 cardiovascular paents with a history of Q fever for 20

SNPs in MMP or TIMP genes. e

Polymorphism Genotype distribuon P-valuea Conclusions Wild type Heterozygous Homozygous C. burnei: No (%) No (%) No (%) v upregulates MMP1, MMP7, MMP10 and MMP19 gene expression in PBMCs MMP2 CC CT TT rs243865 Controls 128 (58%) 84 (38%) 7 (3%) C>T v induces MMP producon in PBMCs Paents 80 (58%) 48 (35%) 11 (8%) 0.05* MMP7 AA AG GG In chronic Q fever: rs11568818 Controls 72 (33%) 97 (44%) 49 (22%)

A>G v Polymorphisms in MMP2, MMP7 and MMP9 are more common in chronic Q fever Paents 32 (23%) 63 (46%) 43 (31%) 0.05**

paents compared to cardiovascular paents with a history of Q fever MMP9 AA AG GG rs17576, Controls 106 (48%) 86 (39%) 27 (12%) A>G Paents 50 (36%) 71 (51%) 18 (13%) 0.02** v Serum levels of MMP-7 are higher in chronic Q fever paents compared to control a Logistic regression, * recessive model analysis, ** dominant model analysis groups Anne Jansen, MD Geert Grooteplein Zuid 8, 6525 GA Nijmegen, The Netherlands. ( +31-24-3619086 * [email protected]