Despite widespread vaccination, whooping cough caused by Bordetella pertussis (Bp) has made a fierce comeback across the world. Mechanisms of selective trafficking of lymphocytes to respiratory tissues are likely to be critical in the immune response to airborne pathogens. This proposal suggests to, study the trafficking capability of immune cells to the respiratory tissues during infection with Bordetella strains and the imprinting mechanism that allows that. To evaluate that we suggest to compare mouse infection with pertussis toxin (PTX) - producing Bp and Bordetella parapertussis (Bpp), a pathogen that lacks PTX, to study the trafficking receptors (TR) required for homing to the airways as well as the imprinting of TR programs by dendritic cells (DC). Our preliminary results and Hematoxylin and Eosin (H&E) stained lung sections reflect impaired leukocyte recruitment at 5 days Bp post infection (p.i.) (but not with Bpp), which is restored at 25 days p.i. Integrin receptors ?4?1, ?4?7 on blood effector/memory T lymphocytes (CD4+, CD44++, and CD45RBlow) are highly up-regulated in mice infected with Bpp 5 days p.i. Their comparative levels in Bp infection are significantly reduced at this time but up-regulated at 25 days p.i., indicating delayed TR imprinting. Yet, no such differences are observed in the lung-memory T cells. Lung DCs from both Bp and Bpp infected mice express high levels of maturation markers 5 days p.i. While those drop to uninfected levels in Bpp mice at 25 days p.i., they strongly persist in the Bp model, even when bacteria are no longer recovered from the lungs. Despite that, 4 day co-culture of isolated lung DC with allogeneic isolated T cells (1:5) suggest a compromised imprinting of ?4?1, ?4?7 by Bp-lung DC but not by the respective Bpp or Bp-PTX mutant lung DC. We suggest that ?4 integrins (in combination with ?7 and ?1) may play an important role in memory T-cell migration during infection with Bp and that this outcome may be addressed in the design of new vaccines. The findings of this study will likely elucidate the effec of this toxin on lung-associated trafficking molecules. Those may lead to reevaluation of the current acellular vaccine and implicate the design of future ones while considering lymphocyte homing in the immune response.
Immunomodulation of Lymphocytes Trafficking Receptors by Bordetella pertussis Bordetella pertussis, the causative agent of whooping cough disease is forcefully reemerging wide-world leading to morbidity and mortality, mainly among infants that had not yet acquired immunity. This is a highly contagious respiratory disease, which is manifested by extreme lymphocytosis, rising immediately after infection. Despite the immune response initiated, the clearance of the pathogen and the resolution of the symptoms are rather similar to those of a chronic disease, with duration of up to several months. The guiding hypothesis of this proposal is that the pertussis toxin, influences dendritic cells'(DC) imprintin of T cell trafficking receptors, thereby inhibiting the ability of immune cells to access the local respiratory mucosa and clear the infection. We will verify here, the role of ?4 integrins receptors (in combination with b7 and b1) in memory CD4+-cells migration to lungs of mice infected with Bordetella species. We anticipate that B. pertussis, perhaps through PTX, may alter levels of ?4 integrins, to delay CD4+-cell mediated immune response that will promptly resolve the infection. We believe that this study has the potential to provide information that may lead to improved approaches to optimizing vaccines as well as a better understanding of trafficking mechanisms during chronic or prolonged respiratory bacterial infection. )
|Wu, V; Smith, A A; You, H et al. (2016) Plasmacytoid dendritic cell-derived IFN? modulates Th17 differentiation during early Bordetella pertussis infection in mice. Mucosal Immunol 9:777-86|
|Nguyen, Tuan M; Ravindra, Dipti; Kwong, Brian et al. (2012) Differential expression of alpha 4 integrins on effector memory T helper cells during Bordetella infections. Delayed responses in Bordetella pertussis. PLoS One 7:e52903|