IDIVAL's Clinical and Molecular Microbiology group has participated in a study about the evolution of the Pseudomonas aeruginosa mutational resistome in an international Cystic Fibrosis clone.

Pseudomonas aeruginosa chronic respiratory infection (CRI) is the main driver of morbidity and mortality in patients suffering from cystic fibrosis (CF). The CF respiratory tract is a dynamic, heterogeneous, hostile, stressful and very challenging scenario for invading bacteria, but P. aeruginosa populations can overcome all these challenges and chronically persist in the CF lungs. Mechanisms underlying early acquisition of P. aeruginosa infection and the eventual establishment of CRI are complex and, many factors, related to the patient, the environment and the microorganism, are involved.

Emergence of epidemic clones and antibiotic resistance development compromises the management of Pseudomonas aeruginosa cystic fibrosis (CF) chronic respiratory infections. Whole genome sequencing (WGS) was used to decipher the phylogeny, interpatient dissemination, WGS mutator genotypes (mutome) and resistome of a widespread clone (CC274), in isolates from two highly-distant countries, Australia and Spain, covering an 18-year period. The coexistence of two divergent CC274 clonal lineages was revealed, but without evident geographical barrier; phylogenetic reconstructions and mutational resistome demonstrated the interpatient transmission of mutators. The extraordinary capacity of P. aeruginosa to develop resistance was evidenced by the emergence of mutations in >100 genes related to antibiotic resistance during the evolution of CC274, catalyzed by mutator phenotypes. While the presence of classical mutational resistance mechanisms was confirmed and correlated with resistance phenotypes, results also showed a major role of unexpected mutations. Among them, PBP3 mutations, shaping up β-lactam resistance, were noteworthy. A high selective pressure for mexZ mutations was evidenced, but we showed for the first time that high-level aminoglycoside resistance in CF is likely driven by mutations in fusA1/fusA2, coding for elongation factor G. Altogether, our results provide valuable information for understanding the evolution of the mutational resistome of P. aeruginosa CF clones and it is correlation with resistance phenotypes, which might be useful for guiding new diagnostic tools and therapeutic strategies in CRI.

Reference: López-Causapé C, Sommer LM, Cabot G, Rubio R, Ocampo-Sosa AA, Johansen HK, Figuerola J, Cantón R, Kidd TJ, Molin S, Oliver A. Evolution of the Pseudomonas aeruginosa mutational resistome in an international Cystic Fibrosis clone. Sci Rep. 2017 Jul 17;7(1):5555.

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The first genome-wide association study (GWAS) in IgA vasculitis worldwide has been conducted by the research group of IDIVAL “Genetic epidemiology and atherosclerosis in systemic inflammatory diseases”, led by Dr. Miguel Ángel González-Gay, in collaboration with other Hospitals and national and international Institutes. 

Immunoglobulin-A (IgA) vasculitis, also known as Henoch-Schöenlein purpura (HSP), is the most common type of primary small-sized blood vessel leukocytoclastic vasculitis in children, although it may also develop in adults. Although the classic clinical triad of IgA vasculitis consists of palpable purpura (involving the lower extremities), joints and the gastrointestinal tract, renal complications may also develop in affected individuals. In this regard, the outcome of IgA vasculitis patients is related to the presence of glomerulonephritis, which may lead to chronic renal failure. IgA vasculitis has a multifactorial etiology in which both environmental and genetic factors seem to contribute to the predisposition and clinical phenotype of the disease. However, the genetic component of this type of vasculitis remains poorly understood, as only a few candidate gene studies have been performed to date.

This study aimed at conducting the first GWAS of IgA vasculitis using the largest series of IgA vasculitis patients in which numerous National Hospitals participated. To achieve this goal, 308 IgA vasculitis patients (currently the largest cohort of patients with this disease for genetic studies) and 1,018 healthy controls from Spain were genotyped. 

The results suggest the involvement of HLA class II region in the pathophysiology of IgA vasculitis, thus supporting the high relevance of the immune system in the development of this disease and suggesting that IgA vasculitis may be related to other class II vasculitides such as giant cell arteritis and antineutrophil cytoplasmic antibody (ANCA).

López-Mejías R, Carmona FD, Castañeda S, Genre F, Remuzgo-Martínez S, Sevilla-Perez B, Ortego-Centeno N, Llorca J, Ubilla B, Mijares V, Pina T, Miranda-Filloy JA, Navas Parejo A, de Argila D, Aragües M, Rubio E, Luque ML, Blanco-Madrigal JM, Galíndez-Aguirregoikoa E, Jayne D, Blanco R, Martín J, González-Gay MA. A genome-wide association study suggests the HLA Class II region as the major susceptibility locus for IgA vasculitis. Sci Rep. 2017 Jul 11;7(1):5088. doi: 10.1038/s41598-017-03915-2.

Following the success achieved in the first program of Santander Biomedical Lectures, IDIVAL introduces the second program of conferences. World’s prestigious and recognized researchers for their international contributions in the advancement of fields such as Immunology, Nanomedicine, Molecular Biology or Rheumatology are taken part on this program. 

Topic 1:Development and validation of technology enabled, quantitative and sensitive measures of functional decline in people with early stage Alzheimer’s Disease (RADAR-AD).
Topic 2:FAIRification of IMI and EFPIA data.
Topic 3:Development of sensitive and validated clinical endpoints in primary Sjögren’s Syndrome (pSS).
Topic 4:European Health Data Network (EHDN).
Topic 5:Analysing the infectious disease burden and the use of vaccines to improve healthy years in aging populations.
Topic 6:Discovery and characterisation of blood-brain barrier targets and transport mechanisms for brain delivery of therapeutics to treat neurodegenerative & metabolic diseases.
Topic 7:European Screening Centre: unique library for attractive biology (ESCulab).

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