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 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 RTX was not protective as a single-antigen vaccine against 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 challenge in mice.
Hematopoietic stem and progenitor cell (HSPC) compartments are altered to direct immune responses to infection. Their roles during immunization are not well-described. To elucidate mechanisms for waning immunity following immunization with acellular vaccines (ACVs) against Bordetella pertussis (Bp), we tested the hypothesis that immunization with Bp ACVs and whole cell vaccines (WCVs) differ in directing the HSPC characteristics and immune cell development patterns that ultimately contribute to the types and quantities of cells produced to fight infection. Our data demonstrate that compared to control and ACV-immunized CD-1 mice, immunization with an efficacious WCV drives expansion of hematopoietic multipotent progenitor cells (MPPs), increases circulating white blood cells (WBCs), and alters the size and composition of lymphoid organs. In addition to MPPs, common lymphoid progenitor (CLP) proportions increase in the bone marrow of WCV-immunized mice, while B220+ cell proportions decrease. Upon subsequent infection, increases in maturing B cell populations are striking in WCV-immunized mice. RNAseq analyses of HSPCs revealed that WCV and ACV-immunized mice vastly differ in developing VDJ gene segment diversity. Moreover, gene set enrichment analyses demonstrate WCV-immunized mice exhibit unique gene signatures that suggest roles for interferon (IFN) induced gene expression. Also observed in naïve infection, these IFN stimulated gene (ISG) signatures point toward roles in cell survival, cell cycle, autophagy, and antigen processing and presentation. Taken together, these findings underscore the impact of vaccine antigen and adjuvant content on skewing and/or priming HSPC populations for immune response.
18Bordetella pertussis (B. pertussis) is the causative agent of pertussis (whooping cough). 19 Since the 1990s, pertussis has re-emerged in the United States despite an estimated 20 95% vaccine coverage. Our goal was to characterize neutrophil responses and gene 21 expression profiles of murine lungs in the context of vaccination and B. pertussis 22 challenge. We utilized a bioluminescent neutrophil mouse model (NECre luc) to track 23 neutrophil recruitment. NECre luc mice were immunized with whole cell vaccine (WCV), 24 acellular vaccine (ACV), or a truncated adenylate cyclase toxoid (RTX) vaccine. 25 Neutrophil recruitment was measured in live mice across time and corroborated by flow 26 cytometry and other data. WCV immunized mice showed signs of neutrophilia in response 27 to B. pertussis challenge. Mice immunized with either ACV or WCV cleared the challenge 28 infection; however immunization with RTX alone was not protective. RNA sequencing 29 revealed distinctive gene expression profiles for each immunization group. We observed 30 an increase in expression of genes associated with responses to infection, and changes 31 in expression of distinct genes in each vaccine group, providing a complex view of the 32 immune response to B. pertussis infection in mice. This study suggests that combination 33 of immunological analysis with transcriptomic profiling can facilitate discovery of pre-34 clinical correlates of protection for vaccine development.35 36 37 38 39 41Pertussis is a human disease primarily caused by a respiratory infection of the Gram-42 negative pathogen Bordetella pertussis (B. pertussis). The hallmark of pertussis is a distinctive 43 whooping cough. What is surprising about pertussis is that the cause of the cough has never been 44 elucidated, which highlights the fact that there are many under-researched aspects of this 45 disease. Aerosolized B. pertussis bacterium are inhaled and adhere to airway respiratory 46 epithelial cells through bacterial adhesins such as filamentous hemagglutinin (FHA), fimbriae and 47 pertactin 1 . After colonization B. pertussis express multiple toxins including pertussis toxin (PT) 48 and adenylate cyclase toxin (ACT). B. pertussis releases PT, which dysregulates the immune 49 response through ADP-ribosylation of the G-protein α-subunit of cytokine receptors present on a 50 range of leukocytes 2-5 . The secretion of PT has long range effects, ACT is thought to act locally 51 on host cells by converting ATP into supraphysiological levels of cAMP, further dysregulating the 52 host immune response 6 . 53In the 1940s, an effective whole cell vaccine (WCV) was developed and as a result, basic research 54 efforts on B. pertussis decreased. The WCVs were highly reactogenic and caused prolonged and 55 unusual crying after administration, hyporesponsivness, and febrile convulsions 7-9 . These issues 56 led to the development of acellular vaccines (ACV), known today as DTaP/Tdap (hereafter 57 referred to as ACV). The ACVs utilize an alum adjuvant and induce a Th2 response ...
Pertussis is a re-emerging infectious disease world-wide. It is hypothesized that current acellular vaccines (ACVs) wane in efficacy each year after immunization. We hypothesized that whole cell vaccines (WCVs) induce hematopoietic stem and progenitor cell (HSPC) expansion and differentiation processes necessary for life-long protection. While HSPC innate immune signaling and expansion play a critical role in directing immune response to infection, their role in vaccine efficacy is unclear. To test our hypothesis, we assessed bone marrow (BM) HSPC frequency, peripheral blood composition, and immune cell proportions in the spleen and thymus upon vaccination. We find that the BM Lineage-Sca1+cKit+ (LSK) cell population undergoes progressive expansion in WCV mice when compared to ACV and PBS-injected control mice. Additionally, peripheral white blood cells and spleen size increase in WCV mice, suggesting that BM cells mobilize to the blood and spleen, where extramedullary hematopoiesis can occur. Upon infection, myeloid cells have been demonstrated to leave the spleen, enter infected tissues, and produce cytokines that favor the generation of Th1 cells. Occurring more rapidly in WCV mice, LSK cell frequency increases and spleen size decreases upon B. pertussis challenge in both WCV and PBS-injected mice when compared to ACV mice. WCV mice exhibit increased peripheral blood monocytes, neutrophils, and lymphocytes when compared to other groups. Taken together, our data suggest that HSPC expansion, differentiation, and mobilization upon WCV immunization may prime the host to better respond to pathogen, and that ACVs formulated with adjuvants that stimulate HSPC expansion, such as TLR4 agonists, may enhance vaccine efficacy.
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