The susceptibility to and the severity of Bordetella pertussis infections in infants and children varies widely, suggesting that genetic differences between individuals influence the course of infection. We have previously identified three novel loci that influence the severity of whooping cough by using recombinant congenic strains of mice: Bordetella pertussis susceptibility loci 1, 2, and 3 (Bps1, -2, and -3). Because these loci could not account for all genetic differences between mice, we extended our search for additional susceptibility loci. We therefore screened 11 inbred strains of mice for susceptibility to a pertussis infection after intranasal infection. Susceptibility was defined by the number of bacteria in the lungs, being indicative of the effect between the clearance and replication of bacteria. The most resistant (A/J) and the most susceptible (C3H/HeJ) strains were selected for further genetic and phenotypic characterization. The link between bacterial clearance and chromosomal location was investigated with 300 F 2 mice, generated by crossing A/J and C3H/HeJ mice. We found a link between the delayed clearance of bacteria from the lung and a large part of chromosome 4 in F 2 mice with a maximum log of the odds score of 33.6 at 65.4 Mb, which is the location of Tlr4. C3H/HeJ mice carry a functional mutation in the intracellular domain of Tlr4. This locus accounted for all detectable genetic differences between these strains. Compared to A/J mice, C3H/HeJ mice showed a delayed clearance of bacteria from the lung, a higher relative lung weight, and increased body weight loss. Splenocytes from infected C3H/HeJ mice produced almost no interleukin-1␤ (IL-1␤) and tumor necrosis factor alpha (TNF-␣) upon ex vivo restimulation with B. pertussis compared to A/J mice and also showed a delayed gamma interferon (IFN-␥) production. TNF-␣ expression in the lungs 3 days after infection was increased fivefold compared to uninfected controls in A/J mice and was not affected in C3H/HeJ mice. In conclusion, Tlr4 is a major host factor explaining the differences in the course of infection between these inbred strains of mice. Functional Tlr4 is essential for an efficient IL-1-␤, TNF-␣, and IFN-␥ response; efficient clearance of bacteria from the lung; and reduced lung pathology.The clinical course of Bordetella pertussis infection varies widely. Knowledge about host genetic and immunological factors that influence susceptibility and severity of infection may lead to the identification of new approaches for prevention or treatment of this disease (13). Knowledge of human genetic factors that influence B. pertussis infection is still very limited. A number of studies have provided clues for the role of host genes in the susceptibility of mice to B. pertussis infection (4,11,19,23). We have recently shown that host genes of mice affect the clearance of bacteria from the lung and that B. pertussis infection is under multigenic control. This study resulted in the identification of three novel loci (Bps1 to -3) that inf...

Nevi and melanomas correlate to childhood and intermittent solar UV exposure, xeroderma pigmentosum patients run increased risk, and p16Ink4a expression is often lost in malignant progression. To ascertain the effect of these risk factors, pigmented hairless Ink4a/ArfÀ, XpaÀ knockout mice were subjected to various combinations of neonatal [7,12-dimethylbenz(a)

Pertussis is an infectious disease of the respiratory tract that is caused by the gram-negative bacterium Bordetella pertussis. Although acellular pertussis (aP) vaccines are safe, they are not fully effective and thus require improvement. In contrast to whole-cell pertussis (wP) vaccines, aP vaccines do not contain lipopolysaccharide (LPS). Monophosphoryl lipid A (MPL) and Neisseria meningitidis LpxL2 LPS have been shown to display immune-stimulating activity while exerting little endotoxin activity. Therefore, we evaluated whether these LPS analogs could increase the efficacy of the aP vaccine. Mice were vaccinated with diphtheriatetanus-aP vaccine with aluminum, MPL, or LpxL2 LPS adjuvant before intranasal challenge with B. pertussis. Compared to vaccination with the aluminum adjuvant, vaccination with either LPS analog resulted in lower colonization and a higher pertussis toxin-specific serum immunoglobulin G level, indicating increased efficacy. Vaccination with either LPS analog resulted in reduced lung eosinophilia, reduced eosinophil numbers in the bronchoalveolar lavage fluid, and the ex vivo production of interleukin-4 (IL-4) by bronchial lymph node cells and IL-5 by spleen cells, suggesting reduced type I hypersensitivity. Vaccination with either LPS analog increased serum IL-6 levels, although these levels remained well below the level induced by wP, suggesting that supplementation with LPS analogs may induce some reactogenicity but reactogenicity considerably less than that induced by the wP vaccine. In conclusion, these results indicate that supplementation with LPS analogs forms a promising strategy that can be used to improve aP vaccines.Pertussis is caused by Bordetella pertussis infection of the respiratory tract and is among the 10 infectious diseases with the highest rates of morbidity and mortality worldwide. After introduction of whole-cell pertussis (wP) vaccines in the 1950s, the incidence of pertussis has decreased significantly. Although they are efficacious, wP vaccines were found to be reactogenic, leading to concerns about their safety in the 1970s. Therefore, acellular pertussis (aP) vaccines that comprise purified B. pertussis proteins have been developed. In many countries, pertussis has recently reemerged, despite the high rates of vaccine coverage (13). Several approaches to reducing disease incidence and severity have been suggested, one of them being the improvement of the existing aP vaccines.In contrast to wP vaccines, aP vaccines are devoid of lipopolysaccharide (LPS). By engaging Toll-like receptor 4 (TLR4), this molecule induces Th1 adaptive immunity (12,15,22,29,39). Consequently, concerns have been raised with respect to the relative efficacies of aP vaccines compared with those of wP vaccines as well as those of simultaneously administered vaccines, such as diphtheria, tetanus, polio, and Haemophilus influenzae type b (Hib) vaccines. In fact, this concern has been substantiated by an increase in the incidence of invasive Hib disease in the United Kingdom that coincided...

Susceptibility to and severity of Bordetella pertussis infection in infants and children vary widely. The spectrum of clinical symptoms ranges from subclinical infection to mild disease, severe whooping cough, and death. The aims of this study were to examine genetic susceptibilities of mice to B. pertussis and to identify genetic loci in the mouse genome that are involved in susceptibility to B. pertussis infection. For this purpose we screened two sets of recombinant congenic strains (RCS) of mice, HcB and CcS, for differences in the numbers of bacteria in the lung 7 days after inoculation. For both CcS and in HcB mice, a wide range in numbers of bacteria in the lung was found, suggesting that the course of infection is under multigenic control. From both RCS sets of mice, we selected one strain to identify possible susceptibility loci in F 2 hybrid mice. The degree of lung colonization 7 days postinoculation in these F 2 mice was evaluated in relation to genetic markers by linkage analysis. We found three novel loci that are involved in the control of B. pertussis infection. One locus, designated B. pertussis susceptibility locus 1 (Bps-1), was identified on chromosome 12. The presence of the C57BL/10 genome on this locus instead of the C3H genome significantly decreased the number of B. pertussis bacteria in the lung. Bps-1 has a dominant-positive effect on the clearance of B. pertussis from the lung. The function of most genes in this region is unknown. Two other loci, Bps-2 and Bps-3, showed genetic interaction and are located on chromosomes 5 and 11. We aim to identify the gene(s) in these regions which modify susceptibility to B. pertussis.