Listeriosis downregulates hepatic cytochrome P450 enzymes in sublethal murine infection

Kummer, Anne; Nishanth, Gopala; Koschel, Josephin; Klawonn, Frank; Schlüter, Dirk; Jänsch, Lothar

doi:10.1002/prca.201600030

Cited by 6 publications

(6 citation statements)

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“…SCX fractionation was done as described by Kummer et al [ 44 ]. To reduce the number of fractions to eight, peptide-containing fractions were combined.…”

Section: Methodsmentioning

confidence: 99%

Towards the characterization of the hidden world of small proteins in Staphylococcus aureus, a proteogenomics approach

et al. 2021

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Small proteins play essential roles in bacterial physiology and virulence, however, automated algorithms for genome annotation are often not yet able to accurately predict the corresponding genes. The accuracy and reliability of genome annotations, particularly for small open reading frames (sORFs), can be significantly improved by integrating protein evidence from experimental approaches. Here we present a highly optimized and flexible bioinformatics workflow for bacterial proteogenomics covering all steps from (i) generation of protein databases, (ii) database searches and (iii) peptide-to-genome mapping to (iv) visualization of results. We used the workflow to identify high quality peptide spectrum matches (PSMs) for small proteins (≤ 100 aa, SP100) in Staphylococcus aureus Newman. Protein extracts from S. aureus were subjected to different experimental workflows for protein digestion and prefractionation and measured with highly sensitive mass spectrometers. In total, 175 with up to 100 aa (SP100) were identified. Out of these 24 (ranging from 9 to 99 aa) were novel and not contained in the used genome annotation.144 SP100 are highly conserved and were found in at least 50% of the publicly available S. aureus genomes, while 127 are additionally conserved in other staphylococci. Almost half of the identified SP100 were basic, suggesting a role in binding to more acidic molecules such as nucleic acids or phospholipids.

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“…SCX fractionation was done as described by Kummer et al [ 44 ]. To reduce the number of fractions to eight, peptide-containing fractions were combined.…”

Section: Methodsmentioning

confidence: 99%

Towards the characterization of the hidden world of small proteins in Staphylococcus aureus, a proteogenomics approach

et al. 2021

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“…However, it is known that acute infection with Listeria in mice stimulates the production by immune cells of these pro-inflammatory cytokines, which in turn stimulate APP expression in hepatocytes ( Kopf et al., 1994 ). Notably, one study showed that after intravenous inoculation of mice with a sublethal dose of Listeria , a homogeneous infection of mouse livers was observed on day 1, followed by a peak in bacterial loads on day 3 and a highly significant reduction on day 9 p.i., representing the expected process of bacterial clearance ( Kummer et al., 2016 ). At the same time, IL-6 and IL-1β mRNA levels increased in the infected livers on day 1 and remained elevated on day 3, followed by a sharp decrease on day 9 p.i.…”

Section: Discussionmentioning

confidence: 99%

“…These proteins, whose production increases rapidly and substantially in response to inflammatory stimuli are known as acute phase proteins (APPs) ( Gabay and Kushner, 1999 ; Zhou et al., 2016 ). Production of pro-inflammatory cytokines by KC, monocytes and neutrophils, in response to Listeria infection, stimulates APP production by hepatocytes ( Kopf et al., 1994 ; Kummer et al., 2016 ). This first wave of non-specific defenses is essential to host survival, with inflammation also contributing to the development of acquired resistance by stimulating the priming and proliferation of cytotoxic T cells, which mediate the protective primary and memory responses against Listeria ( Pamer, 2004 ; Qiu et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

An Immunomodulatory Transcriptional Signature Associated With Persistent Listeria Infection in Hepatocytes

Descoeudres¹,

Jouneau²,

Henry³

et al. 2021

Front. Cell. Infect. Microbiol.

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Listeria monocytogenes causes severe foodborne illness in pregnant women and immunocompromised individuals. After the intestinal phase of infection, the liver plays a central role in the clearance of this pathogen through its important functions in immunity. However, recent evidence suggests that during long-term infection of hepatocytes, a subpopulation of Listeria may escape eradication by entering a persistence phase in intracellular vacuoles. Here, we examine whether this long-term infection alters hepatocyte defense pathways, which may be instrumental for bacterial persistence. We first optimized cell models of persistent infection in human hepatocyte cell lines HepG2 and Huh7 and primary mouse hepatocytes (PMH). In these cells, Listeria efficiently entered the persistence phase after three days of infection, while inducing a potent interferon response, of type I in PMH and type III in HepG2, while Huh7 remained unresponsive. RNA-sequencing analysis identified a common signature of long-term Listeria infection characterized by the overexpression of a set of genes involved in antiviral immunity and the under-expression of many acute phase protein (APP) genes, particularly involved in the complement and coagulation systems. Infection also altered the expression of cholesterol metabolism-associated genes in HepG2 and Huh7 cells. The decrease in APP transcripts was correlated with lower protein abundance in the secretome of infected cells, as shown by proteomics, and also occurred in the presence of APP inducers (IL-6 or IL-1β). Collectively, these results reveal that long-term infection with Listeria profoundly deregulates the innate immune functions of hepatocytes, which could generate an environment favorable to the establishment of persistent infection.

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“…SCX fractionation was done as described by Kummer et al (55). To reduce the number of fractions to eight, peptide-containing fractions were combined.…”

Section: Gel-free Approachmentioning

confidence: 99%

A proteogenomics workflow to uncover the world of small proteins inStaphylococcus aureus

Fuchs

Kucklick

Lehmann

et al. 2020

Preprint

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Small proteins play diverse and essential roles in bacterial physiology and virulence. Despite their importance, automated genome annotation algorithms still cannot accurately annotate all respective small open reading frames (sORFs), as they usually provide insufficient sequence information for domain and homology searches, tend to be species specific and only a few experimentally validated examples are covered in standard proteomics studies. The accuracy and reliability of genome annotations, particularly for sORFs, can be significantly improved by integrating protein evidence from experimental approaches that enrich for small proteins. Here we present a highly optimized and flexible workflow for bacterial proteogenomics, which covers all steps from (i) creation of protein databases, (ii) database searches, (iii) peptide-to-genome mapping to (iv) result interpretation and whose automated execution is supported by two open source tools (SALT & Pepper). We used the workflow to identify high quality peptide spectrum matches (PSMs) for both annotated and unannotated small proteins (≤ 100 aa; SP100) in Staphylococcus aureus Newman. Proteins isolated from cells at the exponential and stationary growth phase were digested with different endopeptidases (trypsin, Lys-C, AspN), the resulting peptides fractionated by gel-based and gel-free methods and measured with highly sensitive mass spectrometers. PSMs or sORF predictions from sORFfinder were stringently filtered allowing us to detect 185 soluble SP100, 69 of which were missing in the used genome annotation. Most interestingly, almost half of the identified SP100 were basic, suggesting a role in binding to more acidic molecules such as nucleic acids or phospholipids. In addition, phage-related functions were proposed for 30 SP100, based on the localization of their coding sequences in the genome.

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Listeriosis downregulates hepatic cytochrome P450 enzymes in sublethal murine infection

Abstract: Sublethal Lm infection deregulates hepatic drug metabolizing pathways. This finding indicates the need to monitor drug administration along Lm infections, especially in all patients needing constant medication.

Cited by 6 publications

References 62 publications

Towards the characterization of the hidden world of small proteins in Staphylococcus aureus, a proteogenomics approach

Towards the characterization of the hidden world of small proteins in Staphylococcus aureus, a proteogenomics approach

An Immunomodulatory Transcriptional Signature Associated With Persistent Listeria Infection in Hepatocytes

A proteogenomics workflow to uncover the world of small proteins inStaphylococcus aureus

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