How Can You Give Pertussis To Plants And Animals

Proc Biol Sci. 2010 Jul seven; 277(1690): 2017–2025.

Acellular pertussis vaccination facilitates Bordetella parapertussis infection in a rodent model of bordetellosis

Received 2010 Jan 4; Accepted 2010 February 11.

Abstract

Despite over fifty years of population-wide vaccination, whooping coughing incidence is on the rise. Although Bordetella pertussis is considered the chief causative agent of whooping cough in humans, Bordetella parapertussis infections are not uncommon. The widely used acellular whooping coughing vaccines (aP) are comprised solely of B. pertussis antigens that concur little or no efficacy confronting B. parapertussis. Here, we enquire how aP vaccination affects competitive interactions between Bordetella species within co-infected rodent hosts and thus the aP-driven strength and direction of in-host selection. Nosotros show that aP vaccination helped clear B. pertussis simply resulted in an approximately 40-fold increase in B. parapertussis lung colony-forming units (CFUs). Such vaccine-mediated facilitation of B. parapertussis did not arise as a result of competitive release; B. parapertussis CFUs were higher in aP-relative to sham-vaccinated hosts regardless of whether infections were single or mixed. Further, we show that aP vaccination impedes host immunity confronting B. parapertussis—measured as reduced lung inflammatory and neutrophil responses. Thus, we conclude that aP vaccination interferes with the optimal clearance of B. parapertussisouthward and enhances the performance of this pathogen. Our data raise the possibility that widespread aP vaccination tin create hosts more than susceptible to B. parapertussis infection.

Keywords: pathogen evolution, Bordetella parapertussis, disease, acellular vaccination, epidemiology, co-infection

i. Introduction

Despite decades of worldwide pertussis vaccination, whooping cough is re-emerging in highly vaccinated countries (CDC 2002; Celentano et al. 2005). A rise in non-vaccine alleles ancillary with widespread vaccination has been documented for Bordetella pertussis (Elomaa et al. 2005; Van Amersfoorth et al. 2005; Van Gent et al. 2009) leading some authors to propose that vaccine-driven epitope-evolution in B. pertussis is one cistron—amongst several others (Berbers et al. 2009)—that may contribute to whooping coughing re-emergence in humans (Mooi et al. 2001). However, it is non clear how Bordetella parapertussis—the other major aetiological amanuensis of human whooping cough—might reply to the selective pressure exerted past big-scale pertussis vaccination. Here, nosotros postulate that the widespread and long-term use of acellular subunit pertussis vaccines creates hosts that are more than favourable for B. parapertussis.

All commercial whooping cough vaccines currently incorporate either killed whole cells or purified antigens of B. pertussis—herein referred to as whole cell (wP) and acellular vaccines (aP), respectively. Currently, aP vaccines are largely favoured over their wP predecessors owing to their reduced reactogenicity (Anderson et al. 1988). Although aP vaccines are very constructive at reducing the incidence of B. pertussis infection (Mattoo & Cherry 2005), they hold trivial or no efficacy confronting B. parapertussis (Stehr et al. 1998; Willems et al. 1998; Liese et al. 2003; David et al. 2004). In fact, B. parapertussis prevalence is predicted to increase slightly in response to vaccines that are less protective against B. parapertussis than natural B. pertussis infection (Restif et al. 2008). Thus, analogous to the serotype specificity observed for conjugate vaccines against other infectious diseases and the serotype replacement associated with their use (Obaro et al. 1996; Lipsitch 1997), nosotros hypothesize that the prolonged and widespread utilize of B. pertussis-specific aP vaccines has the potential to increase carriage of species not included in the vaccine, namely B. parapertussis.

The rationale to design and utilise vaccines that target only B. pertussis stems from the assumption that B. parapertussis infections are not widely prevalent. Indeed, the vast majority of whooping cough studies do non attempt to identify B. parapertussis because differential diagnosis does non affect clinical direction and this probably leads to under-reporting. Even so, when differential diagnosis has been carried out, B. parapertussis was institute to comprise between 2 and 36 per cent of cases (Watanabe & Nagai 2004) and, in one written report, to constitute the major aetiological agent (Borska & Simkovicova 1972). Both mixed and sequential infections of B. pertussis and B. parapertussis have been reported in epidemiological studies (Mertsola 1985; Iwata et al. 1991; He et al. 1998; Mastrantonio et al. 1998; Stehr et al. 1998; Bergfors et al. 1999), showing that B. pertussis and B. parapertussis co-circulate in the aforementioned populations and sometimes the same hosts.

Some aP vaccine efficacy studies report a significantly college proportion of B. parapertussis relative to B. pertussis in aP-vaccinated compared with unvaccinated individuals (Bergfors et al. 1999; Liese et al. 2003). These information are consequent with the hypothesis that B. parapertussis gains a selective advantage under aP vaccination. We tin envisage at least iii possible mechanisms by which aP vaccination could generate this selective advantage, all of which are based on the ascertainment that aP vaccination confers less protection against B. parapertussis than the immunity induced past natural B. pertussis infection or wP vaccination.

Offset, aP vaccination could drive competitive release inside private hosts (Grech et al. 2008; Read & Mackinnon 2008). The manual success of a given pathogen genotype depends on its intrinsic fitness and competitive power (Read & Taylor 2001). Theory has predicted that B. pertussis must accept a competitive reward over B. parapertussis in unvaccinated co-infected hosts (Restif et al. 2008). Still, aP vaccination can requite B. parapertussis two potential fitness advantages; first, information technology can meliorate survive aP vaccination than B. pertussis (Stehr et al. 1998; Willems et al. 1998; Liese et al. 2003; David et al. 2004) and second, by removing B. pertussis competitors, information technology could open upward ecological space for B. parapertussis, which can greatly enhance the rate of spread of non-vaccine B. parapertussis (competitive release hypothesis; Lipsitch 1997; Hastings & D'Alessandro 2000). A second possibility is that by focusing allowed responses on B. pertussis, aP vaccination interferes with an optimal immune response against B. parapertussis, resulting in slower clearance or enhanced establishment of B. parapertussis (enemy release hypothesis (ERH)). ERH is a term used widely in plant ecology when a found species experiences a decrease in regulation past 'natural enemies' and rapidly increases in distribution and affluence (Mitchell & Ability 2003). Such natural enemies might constitute herbivores in the case of plant ecology and, in pathogen biology, host immunity. Results from ane aP vaccine efficacy study examining B. parapertussis in mice are consequent with an aP-driven enhancement of B. parapertussis infection (David et al. 2004), but is unclear whether a lack of immune regulation was driving this enhancement. A third possibility—but one non easily testable empirically for ethical reasons—is that aP vaccination could increase the number of humans susceptible to B. parapertussis by reducing levels of cross-immunity that would have otherwise been generated by natural B. pertussis infections or wP vaccination. Under this scenario, vaccination is in effect creating new ecological opportunities for B. parapertussis (the vacant niche filling hypothesis).

Here, we used a rodent model of B. pertussis and B. parapertussis infection to investigate the competitive ERH. By vaccinating laboratory mice with a commercial aP vaccine (which selectively targets B. pertussis and not B. parapertussis) and challenging them with single- or mixed-species infections (table S1, electronic supplementary cloth), the level of protection and immune stimulation was estimated over time in terms of changes in lung colony-forming units (CFUs), cytokine milieu, neutrophil recruitment and pathogen-specific antibody responses. If B. parapertussis is competitively suppressed by B. pertussis infection, B. parapertussis lung CFU volition exist lower in mixed relative to single infections (tested with the term 'infection type', a 2-level cistron describing the number of Bordetella species present in an infection; single or mixed). Following from this, competitive release of B. parapertussis would nowadays as a significant interaction between infection type and 'vaccination'—a two-level factor describing the vaccination authorities administered, sham or aP, and the infection type. If enemy release is occurring, we await B. parapertussis CFUs to be college in aP-vaccinated relative to sham-vaccinated hosts (tested with the term vaccination), regardless of whether infections were alone or in a mixture (which would present as a pregnant main consequence of vaccination and a not-pregnant interaction betwixt vaccination and infection type). Evidence that aP vaccination interferes with an optimal host immune response confronting B. parapertussis would further support the ERH. Our results support the enemy release model: aP vaccination interferes with the optimal clearance of B. parapertussidue south and enhances the performance of this pathogen.

2. Material and methods

(a) Leaner strains and growth weather

Bordetella pertussis 1740 is a derivative of Tohama I (Kasuga et al. 1954), rendered kanamycin resistant by the chromosomal insertion of pSS4266 (Goebel et al. 2008) and was a kind gift from Dr Scott Stibitz (USDA). Bordetella parapertussis 12822 was isolated from German clinical trials (Heininger et al. 2002) and 12822G is a gentamicin-resistant derivative of the parent strain (Wolfe et al. 2005). Bordetellae were maintained on Bordet-Gengou (BG) agar (Difco) containing 10 per cent defibrinated sheep blood (Hema Resources) at 37°C for approximately 72 h. Supplementing BG plates with kanamycin or gentamicin (50 and xx µg ml⁻¹, respectively; Sigma Aldrich) immune differentiation between leaner in mixed infections. For experimental inocula, liquid civilization bacteria were grown overnight at 37°C and shaken to mid-log phase (optical density at 600 nm of approx. 0.3) in Stainer-Scholte broth.

(b) Hosts, vaccination and inoculation

Four- to six-week-old female C57BL/6 mice (Jackson Laboratories) were maintained in specific pathogen-gratis rooms at Pennsylvania State University and were handled in accordance with Institutional Animal Care and Employ Committee guidelines. In two experiments, a total of 200 mice were divided into eight treatment groups. One-half of all mice received ii 50 µl subcutaneous injections (on days 0 and 14) of the commercial Adacel vaccine (referred to every bit aP; Sanofi Pasteur) at 1-5th the homo dose, whereas the other one-half were sham vaccinated sterile phosphate buffered saline (PBS) and both treatments were administered with Imject Alum adjuvant (Thermo Scientific). Using this vaccination protocol, vaccine efficacy in human being clinical trials was shown to correlate with bacterial clearance in a murine model of B. pertussis (Mills et al. 1998; Guiso et al. 1999). Adacel vaccines are provided as combined tetanus–diphtheria–pertussis formulation adsorbed to alum and contain the following v B. pertussis antigens: 5 µg ml⁻¹ of detoxified pertussis toxin, 10 µg ml⁻¹ filamentous haemagglutinin, six µg of pertactin and 10 µg of fimbriae types 2 and 3.

In both vaccinated and sham-vaccinated groups, 27 mice were each infected with B. pertussis alone, B. parapertussis alone or a mixture of both, and 21 were sham infected with sterile PBS (table S1, electronic supplementary material). Mice were challenged intranasally with 5 × 10^{half dozen} CFU iii weeks later on the second vaccination (day 35), as described (Harvill et al. 1999). For mixed infections, the 50 µl inocula contained five × 10⁶ CFU of each of B. pertussis and B. parapertussis. The same dose of each bacterium in mixed and unmarried infections was used as nosotros wanted to compare the dynamics of each bacterium on its own versus in mixed infections. On each day of sacrifice (table S1, electronic supplementary material; experiment 1: days 0, 3, 7, 14 and 35 post-infection (p.i.) and experiment two: days 0, 3 and 7 p.i.), three to four mice per group were sacrificed in experiments 1 and 2, respectively. In both experiments, lungs were aseptically removed and homogenized in 1 ml of sterile PBS. Series dilutions of organ homogenate were plated on BG agar plates containing the relevant antibiotics and cells were incubated for 3–five days at 37°C to quantify the number of feasible bacteria. In experiment i, claret was collected on each day of sacrifice for the assessment of Bordetella-specific serum antibodies.

(c) Lung cytokines, neutrophil numbers and antibody enzyme linked immunosorbent assays (ELISAs)

In experiment 1, levels of the lung cytokines interleukin (IL)-4, IL-5, interferon gamma (IFN-γ) and granulocyte macrophage-colony stimulating cistron (GM-CSF) were quantified using a flow cytometric cytokine assay, according to the manufacturer'south instructions (Bio-Plex Mouse Cytokine T_H1/T_Hii Panel Cytokine Assay and a Bio-Plex cytokine reagent kit, Bio-Rad).

In experiment 2, lung leukocyte numbers were quantified by performing lung perfusions on days 0, 3 and 7 p.i. Briefly, lungs were perfused with sterile PBS on day of sacrifice to remove ruby-red blood cells before homogenizing through sterile cell strainers (BD Biosciences). Homogenates were laid on a Histopaque gradient 1119 (Sigma Aldrich), centrifuged at 1500 m for thirty min and the leukocyte layer collected and counted on a haemocytometer at ×40 magnification. Aliquots of cells were stained with fluorescein labelled antibodies (FITC)-labelled anti-Ly-6G to detect neutrophils (eastBioscience). The per centum of FITC-positive cells was multiplied by the total number of leukocytes to calculate neutrophil numbers.

Bacteria were grown overnight (optical density of 0.7 at 600 nm), diluted in carbonate buffer and 200 µl added to each well of a 96-well plate. Serum from experiment 1 was added to the get-go row of coated 96-well plates at a 1 : fifty dilution and serially diluted across the plates to a final dilution of i : 102 400. Incubation, wash and development steps were carried out as detailed (Wolfe et al. 2005). Total immunoglobulin (Ig) titre was quantified using biotin-conjugated anti-mouse Ig (Southern Biotechnology Assembly) and peroxidase-conjugated streptavidin (BD Pharmingen). Results were reported as endpoint titres.

(d) Statistical analyses

All analyses were performed in R five. two.7.0 (http://www.R-project.org) using generalized linear models (GLM; Crawley 2007; R 2008). Analyses focused on 200 mice, with experimental groups as detailed to a higher place and in table S1, electronic supplementary material. Nosotros assumed lognormal errors in CFU, cytokine and antibody titres and carried out the analysis on the log₁₀ transformed information, using to the lowest degree squares with normal errors and the identity link. Information from duplicate bioassay and triplicate antibiotic enzyme linked immunosorbent assay (ELISA) plate wells were averaged and the respective titres induced by naive animals were subtracted from experimental animals earlier being log₁₀(n + 1) transformed to satisfy homogeneity-of-variance and normality-of-mistake assumptions of models used.

CFU, lung cytokine and antibody data were analysed from days iii to 35 p.i. inclusive in gild to capture the full post-peak dynamics of infection. Master effects were vaccination (aP versus sham vaccinated), infection type (unmarried versus mixed infection) and day p.i. (fitted every bit a categorical variable). The principal effects of infection, vaccination and the infection by vaccination interaction terms explicitly test the chief hypothesis of this study. To control for the dynamic kinetics of Bordetella infection, the main result of day—too as all two-way interactions between day and vaccination or infection type—was included in all analyses. In no cases were whatever of the 3-way interactions significant and so they are not reported. Qualitative differences owing to infection blazon and vaccination were stiff and consistent across experimental blocks and quantitative differences were controlled for past including experimental block as a factor in all analyses. Maximal models were showtime fit to the data and minimal models reached by removing non-significant terms (p > 0.05), beginning with the highest level interaction. Reported parameter estimates were taken from the relevant minimal models.

three. Results

(a) Vaccine-mediated interactions and mixed infection

As expected, aP vaccination significantly reduced the CFU of B. pertussis (figure 1 a,b; CFU days 3–35 inclusive, vaccination (acellular or sham): F _1,72 = 145.nine, p < 0.0001; vaccination × 24-hour interval: F _3,72 = 6.5, p = 0.001). The boilerplate bacterial abundance produced throughout the infection was approximately 700-fold lower in aP-vaccinated relative to sham-vaccinated hosts. By dissimilarity, aP vaccination significantly increased B. parapertussis CFU (figure one c,d; CFU days 3–35 inclusive, vaccination: F _one,72 = 16.9, p < 0.0001; vaccination × day: F _iii,72 = v.v, p = 0.002). The average bacterial abundance produced throughout infection was approximately forty-fold higher in aP-vaccinated relative to sham-vaccinated hosts.

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Bacterial lung CFUs. (a) Timeline of B. pertussis and (c) B. parapertussis in unmarried and mixed infections of aP- or sham-vaccinated hosts. Average CFU betwixt days 3–35 p.i. (least-squares hateful ± s.e.chiliad.) from (b) GLMs of B. pertussis CFU and (d) B. parapertussis CFU. Shown is the log_ten transformed mean CFU from 200 independent infections produced in two replicate experiments. The x-axis is jittered for clarity and dotted gray lines indicate limit of detection. (a) Filled (sham) and open (aP) squares represent B. pertussis infections alone (sold lines) or in a mixed infection (dashed lines). (c) Filled (sham) and open (aP) triangles correspond B. parapertussis infections solitary (solid lines) or in a mixed infection (dashed lines).

We found no evidence to support within-host competitive suppression of either pathogen species by the other. For B. pertussis, the vaccine-driven decrease in bacterial abundance was observed independent of whether infections were lone or in a mixture with B. parapertussis (figure 1 a,b; CFU days 3–35 inclusive, infection type (mixed versus single) and infection type × vaccination, infection type × solar day, all p > 0.05) and was of similar magnitude in both experimental blocks (block × vaccination: p > 0.05). Likewise, the increment in B. parapertussis CFU was unaffected by the presence of B. pertussis (figure 1 c,d; CFU days 3–35 inclusive, infection blazon, infection type × vaccination, infection type × day and block × vaccination, all p > 0.05). Thus, nosotros constitute no support for the competitive release hypothesis: there was no contest and hence no expansion of B. parapertussis when B. pertussis was selectively suppressed by aP vaccination.

Consistent with this absence of contest, mixed infections had an approximately twofold higher average CFU relative to single infections (CFU days iii–35 inclusive, infection type: B. pertussis, F _1,75 = 67.9, p < 0.0001; B. parapertussis, F _ane,75 = 39.4, p < 0.0001, respectively), implying that there is no constrained 'niche space' over which the two species were competing. Thus, aP vaccination enhanced B. parapertussis CFUs in the lung, reversing the say-so from B. pertussis to B. parapertussis independent of the multiplicity of infection, consequent with the ERH.

(b) Lung cytokines and neutrophil recruitment

The lung immune response was skewed from a T_Hi towards a predominantly T_H2 response by aP vaccination. Specifically, aP-vaccinated mice produced significantly lower IFN-γ and higher lung IL-5 and IL-4 levels—a cytokine profile characteristic of T_H2 cells—relative to sham-vaccinated mice (figure 2 a–c; (cytokine) between days iii and 35, inclusive: IFN-γ vaccination, F _1,64=23.75, p < 0.0001 and vaccination × day, F _3,64=eight.ix, p < 0.0001; IL-five vaccination, F _1,67 = xiv.5, p < 0.0001 and vaccination × day, p > 0.05; IL-4 vaccination, F _one,70 = vi.0, p = 0.02 and vaccination × 24-hour interval, p > 0.05) and this was true for both Bordetella species (infection type, infection type × vaccination and infection type × day terms, all p > 0.05). In addition, lung GM-CSF levels were significantly reduced from day iii p.i. onwards in aP-vaccinated hosts, regardless of the Bordetella species or multiplicity of infection (figure ii d; (cytokine) betwixt days 3 and 35 inclusive: vaccination, F _1,64 = 20.39, p < 0.0001; vaccination × twenty-four hours, F _three,64=3.0, p = 0.03; infection type, infection type × vaccination and infection blazon × day terms, all p > 0.05).

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Lung cytokine profiles. Plots show (a) timeline of IFN-γ, (b) IL-v, (c) IL-4 and (d) GM-CSF levels induced in lung homogenate during single- and mixed-B. pertussis and B. parapertussis infections in aP- or sham-vaccinated hosts. The values from xc independent infections are presented as hateful lung cytokine titres ± s.east.m. The x-axis is jittered for clarity and dotted grey lines indicate lower limit of detection of assay used. Filled (sham) and open (aP) triangles represent B. parapertussis; filled (sham) and open (aP) squares represent B. pertussis; and filled (sham) and open up (aP) circle represent mixed infections.

Although the number of neutrophils recruited to the lungs early in infection was significantly lower in aP- relative to sham-vaccinated hosts, the extent of this aP-driven reduction in neutrophils depended on Bordetella species; aP-vaccinated hosts infected with B. parapertussis (either as a single or mixed infection) had significantly lower neutrophil numbers compared with B. pertussis-infected individuals (figure iii; lung neutrophil numbers on days iii–vii: vaccination, F _1,58 = 4.ii, p = 0.04; vaccination × day, p > 0.05; infection type, F _2,58 = 0.46, p = 0.six; infection type × day, F _2,58 = 3.one, p = 0.02; infection type × vaccination, F _2,58 = three.eight, p = 0.03).

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Lung neutrophil recruitment. Plots bear witness neutrophil numbers in the lung on days 3 and 7 p.i. cleaved down by infection. Each plotted point represents the mean of 12 mice ± s.east.m. Filled (sham) and open (aP) triangles represent B. parapertussis; filled (sham) and open up (aP) squares represent B. pertussis; and filled (sham) and open (aP) circle correspond mixed infections.

(c) Pathogen-specific antibody response

Acellular vaccination enabled both B. pertussis- and B. parapertussis-infected hosts to mount more than rapid anti-B. pertussis- and anti-B. parapertussis-specific Ig responses, respectively, relative to their sham-vaccinated counterparts (effigy 4 a,b; B. pertussis: vaccination, F _i,37 = 23.three, p < 0.001; vaccination × mean solar day, F _3,37 = 4.9, p = 0.006; figure four c,d; B. parapertussis: vaccination, F _1,37 = 24.ii, p < 0.0001; vaccination × day, F _iii,37 = 3.9, p = 0.02, respectively). The extent to which aP vaccination affected the anamnestic responses depended on whether the infection was single or a mixture (effigy four a–d; B. pertussis: infection type, F _1,37 = 0.viii, p = 0.4; infection blazon × vaccination, F _1,37 = 4.6, p = 0.03; B. parapertussis, infection type, F _1,37 = 0.08, p = 0.eight; infection type × vaccination, F _i,37 = iv.7, p = 0.04).

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Bordetella species-specific serum Ig titres. Timeline showing titres of (a) anti-B. pertussis total Ig and (c) anti-B. parapertussis total Ig during single and mixed B. pertussis and B. parapertussis infections of sham or vaccinated hosts. (a and c) Filled (sham) and open (aP) triangles correspond B. parapertussis, filled (sham) and open (aP) squares correspond B. pertussis, and filled (sham) and open (aP) circles represent mixed infections. Shown is the log_x transformed hateful endpoint titre ± due south.eastward.m. Average Ig titre betwixt days iii–35 p.i. (least-squares mean ± s.e.m.) from (b) GLMs of anti-B. pertussis Ig and (d) anti-B. parapertussis Ig. The means from 120 independent infections are presented. The x-centrality is jittered for clarity and dotted grey lines betoken limit of detection.

four. Give-and-take

Here we show that aP vaccination accelerated the clearance of B. pertussis from the lower respiratory tract (LRT) of mice (figure 1 a,b), but delayed B. parapertussis clearance, resulting in approximately twoscore-fold higher total B. parapertussis lung CFUs (figure i c,d). Importantly, no evidence to support competitive interactions between B. pertussis and B. parapertussis was constitute in either sham- or aP-vaccinated co-infected hosts (effigy 1 a–d). An aP vaccine-driven reduction in inflammatory cytokine responses (figure ii) likewise as neutrophil recruitment to the lung in response to B. parapertussis infection (figure 3)—2 key players in the clearance of this pathogen (Kirimanjeswara et al. 2005; Isle of mann et al. 2005; Wolfe et al. 2009)—correlated with delayed B. parapertussis clearance. In improver, antibiotic responses in vaccinated B. parapertussis-infected hosts, although robust, were likely to have reduced efficacy relative to non-vaccinated hosts owing to species differences in prominent surface molecules preventing immune cross-protection (Wolfe et al. 2007; Zhang et al. 2009a,b). Thus aP vaccination, by priming the host response against B. pertussis clearance, confers an advantage to B. parapertussis past interfering with optimal allowed clearance and resulting in increased lung CFUs, consequent with the ERH outlined in §1 (Mitchell & Power 2003).

Bordetella parapertussis and B. pertussis have been thought to compete directly with ane some other as they exploit the same respiratory tract niche (Bjørnstad & Harvill 2005). However, nosotros found no show of within-host contest between B. parapertussis and B. pertussis in our study: CFUs of each species appeared to be unaffected past the presence of the other (figure 1 a–d). The lack of competition probably arose as total infection densities were not constrained in the lung: infection with two species resulted in total pathogen densities twice that of single-species infections. Indeed, by colonizing detached areas in the LRT, these distinct infections may avoid direct interaction. Another possibility is that by focusing solely on the LRT, nosotros failed to capture within-host competition between B. parapertussis and B. pertussis in the upper respiratory tract (URT). Bordetella infection is initiated past the zipper of organisms to epithelial prison cell cilia of the URT, a respiratory expanse that is thought to act as an important reservoir of Bordetella infection (Mattoo & Cherry 2005). Experiments examining the localization of distinct bacterial populations in both the URT and LRT, too equally transmission of bacteria from the respiratory tract (which can be carried out experimentally in rat or rabbit models of bordetellosis), would increase our understanding of colonization and shedding processes respectively, and how these may vary with vaccination condition or Bordetella species.

What mechanisms are behind the 'enemy release' of B. parapertussis under aP vaccination and why does wP vaccination or prior exposure to B. pertussis not bulldoze like increases in B. parapertussis CFU (Wolfe et al. 2007; Zhang et al. 2009b)? First, robust T_Hane inflammatory responses and neutrophil recruitment to the LRT are required for optimal anamnestic responses confronting B. parapertussis (Kirimanjeswara et al. 2005; Mann et al. 2005; Wolfe et al. 2005, 2009). Here, nosotros show that aP vaccination skews the host immune response towards a T_H2 response (Barnard et al. 1996; Ryan et al. 1997) and it is probable that this lack of inflammatory assist—reduced lung inflammatory responses and neutrophil recruitment—enables B. parapertussis to evade rapid antibody-mediated clearance in our study (Wolfe et al. 2009). 2d, omission of the critical protective O-antigen from aP vaccine preparations is also likely to reduce aP vaccine efficacy confronting B. parapertussis (Zhang et al. 2009a) and could contribute towards enhanced infection. 3rd, aP vaccination may have the potential to provoke allowed interference in the class of original antigenic sin. Of those B. pertussis antigens independent in the aP vaccine expressed by B. parapertussis, antigenic differences exist between the Bordetella species and then individuals exposed to a B. parapertussis antigen like, but non identical to one encountered previously, may induce an immune response to the latter antigen directed confronting the start (Francis 1953; Webster 1966; Klenerman & Zinkernagel 1998). Thus, subunit vaccines with limited epitopes—such equally the aP vaccine—may have the potential to foreclose appropriate allowed responses confronting challenging B. parapertussis leaner whose epitopes are divergent from those of the vaccine variant and atomic number 82 to sub-optimal clearance and perchance enhanced infection.

Importantly, following the effects of aP vaccination on infection dynamics over time allowed us to resolve previously alien results concerning the effect of aP on B. parapertussis (David et al. 2004; Zhang et al. 2009b). Specifically, we show that the effect of aP vaccination on B. parapertussis infection varied temporally—aP vaccination did not affect B. parapertussis lung CFU on twenty-four hour period 3 p.i. consequent with Zhang et al. (2009b), just enhanced CFU on day 7 p.i. consistent with David et al. (2004) (effigy 1 a–d)—which resolves these previously alien studies and highlights the importance of tracking dynamics throughout infection in guild to capture full furnishings of the handling of interest. It is possible that these findings may exist relevant simply to the specific strains we have examined and further studies should be carried out to make up one's mind if our results hold across B. pertussis and B. parapertussis strains.

As ever, it is important to be cautious about extrapolating from animal models to humans. The dynamics of B. pertussis and B. parapertussis infection in rodent hosts shares many similarities with human being infection, but like all experimental models, differs from the human situation in a number of key ways (Elahi et al. 2007). Nevertheless, the relative efficacies of pertussis vaccines in the rodent model stand for to those obtained in clinical trials (Mills et al. 1998; Guiso et al. 1999), and we note that epidemiological evidence in human whooping cough infections is consistent with an enhancement upshot for B. parapertussis (Bergfors et al. 1999; Liese et al. 2003). Directly proving aP vaccination puts treated people at risk of acquiring B. parapertussis is very difficult, just we hope our report highlights the need for more than thorough B. parapertussis epidemiological data and encourages further piece of work in this neglected area. If our experiments are capturing the phenomenology of what is happening under aP vaccination in humans, information technology may exist important to consider the introduction of vaccines that better protect confronting both bordetellae; for instance, live attenuated B. pertussis nasal vaccines (Mielcarek et al. 2006), wP vaccines containing both B. pertussis and B. parapertussis (Burianova-Vysoka et al. 1970), or supplementation of aP vaccines with B. parapertussis protective antigens (Zhang et al. 2009a). An enhanced understanding of the evolutionary consequences of widespread aP vaccination is needed in order to optimize the side by side generation of vaccination strategies and fully reap the benefits of this powerful medical intervention.

Acknowledgements

All procedures were carried out in accord with Institutional Animal Care and Apply Committee guidelines.

We are grateful to D. Bann for help with ELISAs, for valuable discussions with D. Wolfe, A. Buboltz, X. Zhang, J. Thakar and S. Perkins and two bearding reviewers for comments that greatly improved the manuscript. This research was supported by a Heart for Infectious Disease Dynamics Postdoctoral Fellowship (GHL), NSF grant EF-0520468 every bit function of the joint NSF-NIH Ecology of Infectious Disease program (PJH) and NIH grant GM083113 (ETH) and benefitted from the RAPIDD working group on zoonoses and emerging disease threats.

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