genomewide characterization of host-pathogen interactions by ...
genomewide characterization of host-pathogen interactions by ... genomewide characterization of host-pathogen interactions by ...
Maren Depke Introduction linking. In the presence of methicillin, MRSA induce the expression of PBP2a from their mecA gene, and survive antibiotic treatment because PBP2a resumes peptide cross-linking instead of the inhibited standard PBPs. Other resistance mechanisms including a methicillin-specific lactamase (methicillinase) and PBP2 mutations with reduced methicillin binding are discussed (Chambers 1997, Stapleton/Taylor 2002). First, hospitals were the primary setting of transmission of and infection with such strains, certainly also favored by the gathering of people who might be regarded as pre-disposed victims for infection because of pre-existing illnesses or poor health state which additionally have frequent injections and insertions of medical devices (Lindsay/Holden 2004). But nowadays, MRSA has left the hospital as its transmission site and so-called “communityassociated” MRSA arise. Existence of this new group has been published beginning from 1990 for different countries. Interestingly, hospital-acquired / healthcare-associated (HA) and communityassociated (CA) MRSA consist of distinct strains, although of course CA-MRSA can cause nosocomial infections when transmitted by a carrier into hospital. CA-MRSA strains have characteristics which distinguish them from HA-MRSA. They often colonize non-classical niches in the human body and not the nares, and the distribution of the Staphylococcal Cassette Chromosome mec (SCCmec) types is different between HA- and CA- MRSA. Additionally, in CA-MRSA a higher frequency of Panton-Valentine leukocidin (PVL)-positive strains is found, although the PVL virulence factor is not a universal marker for CA-MRSA. Although the prevalence of CA-MRSA in Europe seems to be low, the number is already increasing and additionally might be underestimated because of difficulties in monitoring (symptom-free non-nasal carriage). Such unrecognized and hidden reservoir of MRSA is challenging with respect to attempts in controlling staphylococcal infectious disease (Otter/French 2010). A B C Fig. I.5: Proportion of MRSA isolates in EARSS-participating counties in 1999 (A), 2001 (B), and 2008 (C). Graphics from European Antimicrobial Resistance Surveillance System (EARSS), a european wide network of national surveillance systems, providing reference data on antimicrobial resistance for public health purposes (http://www.rivm.nl/earss/). 30
Maren Depke Introduction STUDIES OF HOST-PATHOGEN INTERACTIONS Different approaches can be applied to define even more and specific interactions between the host and the pathogen. Besides classical physiological and microbiological methods, the modern molecular technologies can considerably help to improve the understanding of the processes acting during encounter of host and pathogen provided that genome sequence information is available. On the first level, RNA expression profiling will generate an overview on the potential changes of physiology and metabolism. This approach has the advantage of monitoring the whole repertoire of the organism using a single analysis method and only one small sample, because nucleic acid material can be easily amplified by laboratory methods. Whether such changes of the RNA messenger really will be substantiated by changes on protein level must be analyzed by global or specific proteomic approaches. Here, different methods address the diverse cellular fractions and can provide a comprehensive impression of the different cellular states referring to protein abundance, but also to protein modification and subcellular protein localization, which is not accessible with the transcriptomic analysis. A limitation is in some cases the amount of sample material and the bigger effort needed to perform proteome studies in comparison to transcriptome studies. Results of both studies complement one another. Hence, a combination of several different approaches in co-operation studies is strongly recommended. Model Systems for Studies of Host Reactions Potentially Influencing the Outcome of Infections Liver gene expression pattern in a mouse psychological stress model Psychological and physiological stressors can disturb neuroendocrine, immunological, behavioral, and metabolic functions (Harris et al. 1998, Leibowitz/Wortley 2004, Mizock 1995) and adaptive physiological processes aim to reconstitute a dynamic equilibrium (McEwen 2004, Viswanathan/Dhabhar 2005). In a murine model of severe, chronic psychological stress due to 4.5 days of intermittent combined acoustic and restraint stress BALB/c mice developed severe systemic immunosuppression, neuroendocrinological disturbances and depression-like behavior. Besides heightened anti-inflammatory cytokine bias, lymphocytopenia, T cell anergy, impaired phagocytic and oxidative burst responses, increased susceptibility to experimental infection with E. coli, spontaneous bacterial infiltrations of gut commensals into the lung, reduced clearance of experimental infections in the long term, attenuation of a hyperinflammatory septic shock, and finally, behavioral and neuroendocrine alterations and a prominent stress-induced loss of body mass without significant changes of food and water intake during the observation period became detectable (Kiank et al. 2006, 2007a, 2007b, 2008). 31
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Maren Depke<br />
Introduction<br />
linking. In the presence <strong>of</strong> methicillin, MRSA induce the expression <strong>of</strong> PBP2a from their mecA<br />
gene, and survive antibiotic treatment because PBP2a resumes peptide cross-linking instead <strong>of</strong><br />
the inhibited standard PBPs. Other resistance mechanisms including a methicillin-specific<br />
lactamase (methicillinase) and PBP2 mutations with reduced methicillin binding are discussed<br />
(Chambers 1997, Stapleton/Taylor 2002).<br />
First, hospitals were the primary setting <strong>of</strong> transmission <strong>of</strong> and infection with such strains,<br />
certainly also favored <strong>by</strong> the gathering <strong>of</strong> people who might be regarded as pre-disposed victims<br />
for infection because <strong>of</strong> pre-existing illnesses or poor health state which additionally have<br />
frequent injections and insertions <strong>of</strong> medical devices (Lindsay/Holden 2004).<br />
But nowadays, MRSA has left the hospital as its transmission site and so-called “communityassociated”<br />
MRSA arise. Existence <strong>of</strong> this new group has been published beginning from 1990 for<br />
different countries. Interestingly, hospital-acquired / healthcare-associated (HA) and communityassociated<br />
(CA) MRSA consist <strong>of</strong> distinct strains, although <strong>of</strong> course CA-MRSA can cause<br />
nosocomial infections when transmitted <strong>by</strong> a carrier into hospital.<br />
CA-MRSA strains have characteristics which distinguish them from HA-MRSA. They <strong>of</strong>ten<br />
colonize non-classical niches in the human body and not the nares, and the distribution <strong>of</strong> the<br />
Staphylococcal Cassette Chromosome mec (SCCmec) types is different between HA- and CA-<br />
MRSA. Additionally, in CA-MRSA a higher frequency <strong>of</strong> Panton-Valentine leukocidin (PVL)-positive<br />
strains is found, although the PVL virulence factor is not a universal marker for CA-MRSA.<br />
Although the prevalence <strong>of</strong> CA-MRSA in Europe seems to be low, the number is already<br />
increasing and additionally might be underestimated because <strong>of</strong> difficulties in monitoring<br />
(symptom-free non-nasal carriage). Such unrecognized and hidden reservoir <strong>of</strong> MRSA is<br />
challenging with respect to attempts in controlling staphylococcal infectious disease<br />
(Otter/French 2010).<br />
A B C<br />
Fig. I.5: Proportion <strong>of</strong> MRSA isolates in EARSS-participating counties in 1999 (A), 2001 (B), and 2008 (C).<br />
Graphics from European Antimicrobial Resistance Surveillance System (EARSS), a european wide network <strong>of</strong> national surveillance<br />
systems, providing reference data on antimicrobial resistance for public health purposes (http://www.rivm.nl/earss/).<br />
30