Biomedical subjects

Arie Havelaar

Publications and source records attributed to Arie Havelaar.

5 recordsLinked to original sources

PubMed2006

Dose response for infectivity of several strains of Campylobacter jejuni in chickens.

Although some major risk studies have been done for Campylobacter jejuni, its dose response is not well characterized. Only a single human study is available, providing dose-response information for only a single isolate. As substantial heterogeneity in infectivity has been acknowledged for other pathogens, it remains unknown how well this single study represents the dose-response relation for this pathogen. As future human challenge studies with Campylobacter are unlikely, we have to find other means of studying its infectivity. Several dose-response studies have been done using chickens as host organisms. These studies may be used to obtain quantitative information on the variation in infectivity among different isolates of this pathogen. A hierarchical Bayesian model is well suited to describe heterogeneity, and we demonstrate how the beta-Poisson model of microbial infection may be adapted to allow for within- and between-isolate variation. Isolates tested in chickens can be categorized into two distinct groups: lab-adapted and fresh isolates, and we show how the hierarchical dose-response model can be used to quantitatively describe their differences. Fresh isolates show higher colonization potential and less within-isolate variation than lab isolates. The results indicate that Campylobacter jejuni is highly infectious in chickens. Different isolates show great variation in infectivity, especially between lab and fresh isolates, indicating that human clinical (volunteer) studies on infectivity must be interpreted cautiously.

Animals↗

PubMed2005

A poultry-processing model for quantitative microbiological risk assessment.

A poultry-processing model for a quantitative microbiological risk assessment (QMRA) of campylobacter is presented, which can also be applied to other QMRAs involving poultry processing. The same basic model is applied in each consecutive stage of industrial processing. It describes the effects of inactivation and removal of the bacteria, and the dynamics of cross-contamination in terms of the transfer of campylobacter from the intestines to the carcass surface and the environment, from the carcasses to the environment, and from the environment to the carcasses. From the model it can be derived that, in general, the effect of inactivation and removal is dominant for those carcasses with high initial bacterial loads, and cross-contamination is dominant for those with low initial levels. In other QMRA poultry-processing models, the input-output relationship between the numbers of bacteria on the carcasses is usually assumed to be linear on a logarithmic scale. By including some basic mechanistics, it is shown that this may not be realistic. As nonlinear behavior may affect the predicted effects of risk mitigations; this finding is relevant for risk management. Good knowledge of the variability of bacterial loads on poultry entering the process is important. The common practice in microbiology to only present geometric mean of bacterial counts is insufficient: arithmetic mean are more suitable, in particular, to describe the effect of cross-contamination. The effects of logistic slaughter (scheduled processing) as a risk mitigation strategy are predicted to be small. Some additional complications in applying microbiological data obtained in processing plants are discussed.

Algorithms↗

PubMed2004

Release kinetics and cell trafficking in relation to bacterial growth explain the time course of blood neutrophils and monocytes during primary Salmonella infection.

Granulocytes and neutrophils are predominantly responding cells during the early phase of infection of rats with Salmonella. We propose mathematical and experimental models of the kinetics of neutrophil and monocyte responses in Salmonella infection via the oral route. Using the models, we estimate that approximately 1 in 500 inoculated Salmonella cells actually infected the rat and multiplied with a doubling time of 5 h in Peyer's patches, reaching a maximum of approximately 10(6) c.f.u./g. In low-dose infection, neutrophil and monocyte responses are delayed, but further resemble the responses in high-dose infection. Important processes influencing neutrophil and monocyte recruitment are: massive migration into the infected tissue, and non-linear release kinetics of neutrophils and monocytes from the bone marrow. In conclusion, we can predict time series of neutrophil and monocyte responses in low-dose and high-dose experimental infection via the oral route.

Animals↗

PubMed2004

Intraspecies variability in the dose-response relationship for Salmonella Enteritidis associated with genetic differences in cellular immune response.

To evaluate the effects of differences in host cellular immunity, we studied the dose-response relationship for infection with Salmonella enterica serovar Enteritidis (SE) in two different rat strains, skewed towards T helper 1 (Th1, Lewis rats) or T helper 2 (Th2, Brown Norway rats) immunoregulation. Rats were exposed orally to different doses of SE after overnight starvation and neutralization of gastric acid. Animals were observed for clinical signs of disease, fecal excretion and SE load in spleen and cecum, histopathology of the cecum, hematology, and cellular and humoral immune responses. Exponential dose-response models were used for binary or continuous outcomes to analyze the experimental data. Cytokine patterns, antibody isotypes, and contact hypersensitivity tests confirmed that Lewis rats are Th1 prone, whereas Brown Norway rats are Th2 prone. The probability of infection per single SE cell was approximately 100 times higher in Brown Norway rats than in Lewis rats. Cellular immune responses were more pronounced in Lewis rats but antibody responses were higher in Brown Norway rats. When infected, colonization levels and inflammation are highest in the intestinal tract of Th2 skewed rats, but systemic infection is more intense in Th1 skewed rats. Successful colonization by only one or two SE clones resulted in a marked increase of neutrophil counts by a factor of two to three in both rat strains.

Administration, Oral↗

PubMed2002

A quantitative model for neutrophil response and delayed-type hypersensitivity reaction in rats orally inoculated with various doses of Salmonella Enteritidis.

Our aim was to investigate the quantitative relationship between inoculation doses and physiological responses to infection by Salmonella enterica serovar Enteritidis. Rats were orally inoculated with 10-10(9) c.f.u. of S. Enteritidis and monitored for 6 days. Neutrophil and delayed-type hypersensitivity (DTH) responses were assessed, and the spleens were analyzed for the pathogen. The experimental data were analyzed by a mathematical model for the host response to salmonella infection, which is based on the assumptions that: (i) the number of pathogens in the inoculum is Poisson distributed, (ii) any cell that is inoculated can multiply and form a clone to infect the animal, (iii) the probability of infection by any cell of the pathogen is independent of the number of cells ingested, and (iv) the magnitude of the immune response increases with dose, but eventually saturates to a maximum level. The probability of infection assessed by the DTH response is 7.5 x 10(-3)/c.f.u. of the inoculum (confidence interval 5.1 x 10(-5), 1.2 x 10(-2)). When five S. Enteritidis independently initiated the infection, the DTH response to the resulting clones of the salmonellae saturated to the maximum level. The probability of infection assessed by the neutrophil response is 3.4 x 10(-4)/c.f.u. (1.0 x 10(-4), 6.8 x 10(-4)). The response saturated when six S. Enteritidis independently initiated the infection. The probability of infection assessed by the analysis of spleens is 1.2 x 10(-3)/c.f.u. (4.1 x 10(-4), 2.6 x 10(-3)). We conclude that at low inocula, infections are initiated by very small numbers of bacteria. The magnitude of the immune responses is similar whether only a few or a larger number of bacteria initiated the infection.

Animals↗