Evaluation of Adenylate Cyclase Toxoid Antigen in Acellular Pertussis Vaccines by Using a Bordetella pertussis Challenge Model in Mice.

Bordetella pertussis is the primary causative agent of pertussis (whooping cough), which is a respiratory infection that leads to a violent cough and can be fatal in infants. There is a need to develop more effective vaccines because of the resurgence of cases of pertussis in the United States since the switch from the whole-cell pertussis vaccines (wP) to the acellular pertussis vaccines (aP; diphtheria-tetanus-acellular-pertussis vaccine/tetanus-diphtheria-pertussis vaccine). Adenylate cyclase toxin (ACT) is a major virulence factor of B. pertussis that is (i) required for establishment of infection, (ii) an effective immunogen, and (iii) a protective antigen. The C-terminal repeats-in-toxin domain (RTX) of ACT is sufficient to induce production of toxin-neutralizing antibodies. In this study, we characterized the effectiveness of vaccines containing the RTX antigen against experimental murine infection with B. pertussis RTX was not protective as a single-antigen vaccine against B. pertussis challenge, and adding RTX to 1/5 human dose of aP did not enhance protection. Since the doses of aP used in murine studies are not proportionate to mouse/human body masses, we titrated the aP from 1/20 to 1/160 of the human dose. Mice receiving 1/80 human aP dose had bacterial burden comparable to those of naive controls. Adding RTX antigen to the 1/80 aP base resulted in enhanced bacterial clearance. Inclusion of RTX induced production of antibodies recognizing RTX, enhanced production of anti-pertussis toxin, decreased secretion of proinflammatory cytokines, such as interleukin-6, and decreased recruitment of total macrophages in the lung. This study shows that adding RTX antigen to an appropriate dose of aP can enhance protection against B. pertussis challenge in mice.

Clustered cortical organization and the enhanced probability of intra-areal functional integration.

Similarly responsive neurons organize into submillimeter-sized clusters (domains) across many neocortical areas, notably in Areas V1 and V2 of primate visual cortex. While this clustered organization may arise from wiring minimization or from self-organizing development, it could potentially support important neural computation benefits. Here, we suggest that domain organization offers an efficient computational mechanism for intra-areal functional integration in certain cortical areas and hypothesize that domain proximity could support a higher-than-expected spatial correlation of their respective terminals yielding higher probabilities of integration of differing domain preferences. To investigate this hypothesis we devised a spatial model inspired by known parameters of V2 functional organization, where neighboring domains prefer either colored or oriented stimuli. Preference-selective joint probabilities were calculated for model terminal co-occurrence with configurations encompassing diverse domain proximity, shape, and projection. Compared to random distributions, paired neighboring domains (< or =1200 microm apart) yielded significantly enhanced coincidence of terminals converging from each domain. Using this reference data, a second larger-scale model indicated that V2 domain organization may accommodate relatively complete sets of intra-areal color/orientation integrations. Together, these data indicate that domain organization could support significant and efficient intra-areal integration of different preferences and suggest further experiments investigating prevalence and mechanisms of domain-mediated intra-areal integration.