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Advancing risk assessment: mechanistic dose-response modelling of Listeria monocytogenes infection in human populations.

ABSTRACT: The utility of characterizing the effects of strain variation and individual/subgroup susceptibility on dose-response outcomes has motivated the search for new approaches beyond the popular use of the exponential dose-response model for listeriosis. While descriptive models can account for such variation, they have limited power to extrapolate beyond the details of particular outbreaks. By contrast, this study exhibits dose-response relationships from a mechanistic basis, quantifying key biological factors involved in pathogen-host dynamics. An efficient computational algorithm and geometric interpretation of the infection pathway are developed to connect dose-response relationships with the underlying bistable dynamics of the model. Relying on in vitro experiments as well as outbreak data, we estimate plausible parameters for the human context. Despite the presence of uncertainty in such parameters, sensitivity analysis reveals that the host response is most influenced by the pathogen-immune system interaction. In particular, we show how variation in this interaction across a subgroup of the population dictates the shape of dose-response curves. Finally, in terms of future experimentation, our model results provide guidelines and highlight vital aspects of the interplay between immune cells and particular strains of Listeria monocytogenes that should be examined.

SUBMITTER: Rahman A

PROVIDER: S-EPMC6124125 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Advancing risk assessment: mechanistic dose-response modelling of <i>Listeria monocytogenes</i> infection in human populations.

Rahman Ashrafur A Rahman Ashrafur A Munther Daniel D Fazil Aamir A Smith Ben B Wu Jianhong J

Royal Society open science 20180801 8

The utility of characterizing the effects of strain variation and individual/subgroup susceptibility on dose-response outcomes has motivated the search for new approaches beyond the popular use of the exponential dose-response model for listeriosis. While descriptive models can account for such variation, they have limited power to extrapolate beyond the details of particular outbreaks. By contrast, this study exhibits dose-response relationships from a mechanistic basis, quantifying key biologi ...[more]

PMID: 30225020

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Project description:Listeria monocytogenes is a gram-positive facultative intracellular pathogen, causing serious illness in immunocompromised individuals and pregnant women. Upon detection by macrophages, which are key players of the innate immune response against infection, L. monocytogenes induces specific host cell responses which need to be tightly controlled at transcriptional and post-transcriptional levels. Here, we ask whether and how host miRNAs, which represent an important mechanism of post-transcriptional regulation in a wide array of biological processes, are altered by a model pathogen upon live infection of murine bone marrow derived macrophages. We first report that L. monocytogenes subverts the host genome-wide miRNA profile of macrophages in vitro. Specifically, we show that miR-155, miR-146a, miR-125a-3p/5p and miR-149 were amongst the most significantly regulated miRNAs in infected macrophages. Strikingly, these miRNAs were highly upregulated upon infection with the Listeriolysin-deficient L. monocytogenes mutant ?hly, that cannot escape from the phagosome thus representing a vacuolar-contained infection. The vacuolar miRNA response was significantly reduced in macrophages deficient for MyD88. In addition, miR-146a and miR-125a-3p/5p were regulated at transcriptional levels upon infection, and miR-125a-3p/5p were found to be TLR2 responsive. Furthermore, miR-155 transactivation in infection was regulated by NF-?B p65, while miR-146a and miR-125a-3p/5p expression was unaffected in p65-deficient primary macrophages upon L. monocytogenes infection. Our results demonstrate that L. monocytogenes promotes significant changes in the miRNA expression profile in macrophages, and reveal a vacuolar-dependent miRNA signature, listeriolysin-independent and MyD88-dependent. These miRNAs are predicted to target immune genes and are therefore most likely involved in regulation of the macrophage innate immune response against infection at post-transcriptional levels.

Project description:AbstractA comprehensive understanding of foodborne pathogen diversity in preharvest environments is necessary to effectively track pathogens on farms and identify sources of produce contamination. As such, this study aimed to characterize Listeria diversity in wildlife feces and agricultural water collected from a New York state produce farm over a growing season. Water samples were collected from a pond (n = 80) and a stream (n = 52). Fecal samples (n = 77) were opportunistically collected from areas <5 m from the water sources; all samples were collected from a <0.5-km2 area. Overall, 86 (41%) and 50 (24%) of 209 samples were positive for Listeria monocytogenes and Listeria spp. (excluding L. monocytogenes), respectively. For each positive sample, one L. monocytogenes or Listeria spp. isolate was speciated by sequencing the sigB gene, thereby allowing for additional characterization based on the sigB allelic type. The 86 L. monocytogenes and 50 Listeria spp. isolates represented 8 and 23 different allelic types, respectively. A subset of L. monocytogenes isolates (n = 44) from pond water and pond-adjacent feces (representing an ∼5,000-m2 area) were further characterized by pulsed-field gel electrophoresis (PFGE); these 44 isolates represented 22 PFGE types, which is indicative of considerable diversity at a small spatial scale. Ten PFGE types were isolated more than once, suggesting persistence or reintroduction of PFGE types in this area. Given the small spatial scale, the prevalence of L. monocytogenes and Listeria spp., as well as the considerable diversity among isolates, suggests traceback investigations may be challenging. For example, traceback of finished product or processing facility contamination with specific subtypes to preharvest sources may require collection of large sample sets and characterization of a considerable number of isolates. Our data also support the adage "absence of evidence does not equal evidence of absence" as applies to L. monocytogenes traceback efforts at the preharvest level.Highlights

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Advancing risk assessment: mechanistic dose-response modelling of Listeria monocytogenes infection in human populations.

Publications

Advancing risk assessment: mechanistic dose-response modelling of <i>Listeria monocytogenes</i> infection in human populations.

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