Ricardo Pérez Sánchez

Spotted fever group rickettsiae in ticks feeding on humans in northwestern Spain: is Rickettsia conorii vanishing?

Abstract:  During a 7‐year study, we identified and analyzed by PCR 4,049 ticks removed from 3,685 asymptomatic patients in Castilla y León (northwestern Spain). A total of 320 ticks (belonging to 10 species) were PCR‐positive for rickettsiae. Comparison of amplicon sequences in databases enabled us to identify eigth different spotted fever group (SFG) rickettsiae: Rickettsia slovaca, Rickettsia sp. IRS3/IRS4, R. massiliae/Bar29, R. aeschlimannii, Rickettsia sp. RpA4/DnS14, R. helvetica, Rickettsia sp. DmS1, and R. conorii. Although Mediterranean spotted fever (MSF) is an endemic disease in Castilla y León, R. conorii was found in only one Rhipicephalus sanguineus tick, whereas other pathogenic SFG rickettsiae were much more prevalent in the same area. Our data suggest that in Castilla y León, many MSF or MSF‐like cases attributed to R. conorii could have been actually caused by other SFG rickettsiae present in ticks biting people in this region of Spain.

Differential proteomic profiling unveils new molecular mechanisms associated with mitochondrial complex III deficiency

UNLABELLED We have analyzed the cellular pathways and metabolic adaptations that take place in primary skin fibroblasts from patients with mutations in BCS1L, a major genetic cause of mitochondrial complex III enzyme deficiency. Mutant fibroblasts exhibited low oxygen consumption rates and intracellular ATP levels, indicating that the main altered molecular event probably is a limited respiration-coupled ATP production through the OXPHOS system. Two-dimensional DIGE and MALDI-TOF/TOF mass spectrometry analyses unambiguously identified 39 proteins whose expression was significantly altered in complex III-deficient fibroblasts. Extensive statistical and cluster analyses revealed a protein profile characteristic for the BCS1L mutant fibroblasts that included alterations in energy metabolism, cell signaling and gene expression regulation, cytoskeleton formation and maintenance, and intracellular stress responses. The physiological validation of the predicted functional adaptations of human cultured fibroblasts to complex III deficiency confirmed the up-regulation of glycolytic enzyme activities and the accumulation of branched-chain among other amino acids, suggesting the activation of anaerobic glycolysis and cellular catabolic states, in particular protein catabolism, together with autophagy as adaptive responses to mitochondrial respiratory chain dysfunction and ATP deficiency. Our data point to an overall metabolic and genetic reprogramming that could contribute to explain the clinical manifestations of complex III deficiency in patients. BIOLOGICAL SIGNIFICANCE Despite considerable knowledge about their genetic origins, the pathophysiological mechanisms that contribute to the clinical manifestations of mitochondrial disorders remain poorly understood. We have investigated the molecular pathways and metabolic adaptations that take place in primary skin fibroblasts from patients with mutations in the BCS1L gene, a primary cause of mitochondrial complex III enzyme deficiency. Two-dimensional DIGE together with MALDI-TOF/TOF mass spectrometry and physiological validation analyses revealed a significant metabolic and genetic reprogramming as an adaptive response to mitochondrial respiratory chain dysfunction. Our data provide information about specific protein targets that regulate the transmitochondrial functional responses to complex III deficiency, thereby opening new doors for future research.