Association of Vitamin D Receptor Polymorphism with Susceptibility to Symptomatic Pertussis.

Pertussis, caused by infection with the gram negative B. pertussis bacterium, is a serious respiratory illness that can last for months. While B. pertussis infection rates are estimated between 1-10% in the general population, notifications of symptomatic pertussis only comprise 0.01-0.1% indicating that most individuals clear B. pertussis infections without developing (severe) clinical symptoms. In this study we investigated whether genetic risk factors are involved in the development of symptomatic pertussis upon B. pertussis infection. Single-nucleotide polymorphisms (SNPs) in candidate genes, MBL2, IL17A, TNFα, VDR, and IL10 were genotyped in a unique Dutch cohort of symptomatic clinically confirmed (ex-)pertussis patients and in a Dutch population cohort. Of the seven investigated SNPs in five genes, a polymorphism in the Vitamin D receptor (VDR) gene (rs10735810) was associated with pertussis. The VDR major allele and its homozygous genotype were more present in the symptomatic pertussis patient cohort compared to the control population cohort. Interestingly, the VDR major allele correlated also with the duration of reported pertussis symptoms. Vitamin D3 (VD3) and VDR are important regulators of immune activation. Altogether, these findings suggest that polymorphisms in the VDR gene may affect immune activation and the clinical outcome of B. pertussis infection.

Ex vivo peptide-MHC II tetramer analysis reveals distinct end-differentiation patterns of human pertussis-specific CD4(+) T cells following clinical infection.

Pertussis is occurring in highly vaccinated populations, suggesting insufficient protective memory CD4(+) T cells to Bordetella (B.) pertussis. P.69 Pertactin (P.69 Prn) is an important virulence factor of B. pertussis, and P.69 Prn7-24 is an immunodominant CD4(+) T cell epitope in mice and broadly recognized in humans. P.69 Prn7-24 peptide-MHC II tetramers (DRB4*0101/IVKT) were designed to ex vivo interrogate the presence and differentiation state of P.69 Prn7-24 specific CD4(+) T cells in six symptomatic pertussis cases. Cases with relatively more CD45RA(-)CCR7(+) central memory CD4(+)DRB4*0101/IVKT(+) T cells secreted Th1 cytokines, while cases with more CD45RA(-)CCR7(-) effector memory CD4(+)DRB4*0101/IVKT(+) T cells secreted both Th1 and Th2 cytokines upon peptide stimulation. CD45RA(+)CCR7(-) terminal differentiation pattern was associated with low or non-functionality based on cytokine secretion. This study provides proof of principle for further peptide-MHC II tetramer guided approaches in the elucidation of limited immunological memory to B. pertussis and the resurgence of pertussis.