Pseudomonas aeruginosa infection in the cystic fibrosis airways: early detection and functionality of the specific humoral immune response

Author(s)

Renan Marrichi Mauch

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2018-08-24

Examining board members

Carlos Emilio Levy; Luiz Vicente Ribeiro Ferreira da Silva Filho; Adriana Gut Lopes Riccetto; Maria Heloisa de Souza Lima Blotta; Paul Marquis Quinton

• Advisor: Carlos Emilio Levy; Niels Høiby

Abstract

Cystic fibrosis (CF) is a genetic condition resulting in absence or misfunction of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, the main regulator of chloride and bicarbonate transport in the epithelial cells. The resulting ionic unbalance will impair the function of several organs, mainly due to increased viscosity of the mucus lining the epithelia. Pulmonary disease is the preponderant manifestation, where mucus buildup in the airways leads to impairment in the mucociliary clearance followed by bacterial colonization/infection and intense inflammatory response. Pseudomonas aeruginosa infection is the main morbidity and mortality cause in CF, due to the mechanisms this bacterium uses to adapt to stress conditions in the CF lungs, including biofilm formation, causing persistent infection despite the intense specific humoral immune response. Thus, early detection of P. aeruginosa infection is essential, as well as the better understanding of possible flaws in the specific humoral immune response. Here, we assessed the diagnostic usefulness of an ELISA test for measuring the concentration of specific P. aeruginosa secretory IgA (sIgA) in saliva for detection of chronic lung infection. SIgA in saliva is a potential marker of upper airway colonization, which can precede lung infection. Also, we analyzed the maturation of serum IgG avidity against a pooled P. aeruginosa antigen (St-Ag) and against P. aeruginosa alginate, the major biofilm component. We found positive sIgA concentrations (>47.2 U/mL) in 87% of the patients with P. aeruginosa chronic lung infection, whose median sIgA concentration (181.5 U/mL) was significantly higher when compared to intermittently colonized and non-infected patients. The test also showed a negative predictive value of 92% to rule out chronic infection, and, in a three-year longitudinal study, a positive median sIgA result in the first year of follow-up implied up to 12.5-fold increased risk of exposure to P. aeruginosa in the lower airways in the two subsequent years. Thereby, we have standardized a potential test for early detection and for identification of patients at risk of developing P. aeruginosa lung infection. Despite significant increase in the IgG avidity to the St-Ag upon onset of chronic lung infection, IgG avidity to alginate did not significantly enhanced as chronic infection progressed, even with the repeated exposure to the antigen. This is a possible explanation for the persistent lung biofilm infection with P. aeruginosa. However, such issue must be better explored, as well as the background comprising B cell production, stimulation and differentiation and the quality of the humoral immune response in CF, in general (AU)

• FAPESP's process: 14/00007-8 - Investigation of Pseudomonas aeruginosa respiratory infection in patients with cystic fibrosis in a reference center in Brazil: evaluation of the utility of four different diagnostic methods
• Grantee: Renan Marrichi Mauch
• Support Opportunities: Scholarships in Brazil - Doctorate