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Antibody-mediated enhancement of community-acquired methicillin-resistant Staphylococcus aureus infection.

ABSTRACT: Community-acquired infections caused by methicillin-resistant Staphylococcus aureus (MRSA) expressing the Panton-Valentine leukocidin (PVL) are rampant, but the contribution of PVL to bacterial virulence remains controversial. While PVL is usually viewed as a cytotoxin, at sublytic amounts it activates protective innate immune responses. A leukotoxic effect might predominate in high inoculum studies, whereas protective proinflammatory properties might predominate in settings with lower bacterial inocula that more closely mimic what initially occurs in humans. However, these protective effects might possibly be neutralized by antibodies to PVL, which are found in normal human sera and at increased levels following PVL(+) S. aureus infections. In a low-inoculum murine skin abscess model including a foreign body at the infection site, strains deleted for the pvl genes replicated more efficiently within abscesses than isogenic PVL(+) strains. Coinfection of mice at separate sites with isogenic PVL(+) and PVL(-) MRSA abrogated the differences in bacterial burdens, indicating a systemic effect on host innate immunity from production of PVL. Mice given antibody to PVL and then infected with seven different PVL(+) strains also had significantly higher bacterial counts in abscesses compared with mice given nonimmune serum. Antibody to PVL had no effect on MRSA strains that did not produce PVL. In vitro, antibody to PVL incapacitated PVL-mediated activation of PMNs, indicating that virulence of PVL(+) MRSA is enhanced by the interference of PVL-activated innate immune responses. Given the high rates of primary and recurring MRSA infections in humans, it appears that antibodies to PVL might contribute to host susceptibility to infection.

SUBMITTER: Yoong P

PROVIDER: S-EPMC2836673 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Antibody-mediated enhancement of community-acquired methicillin-resistant Staphylococcus aureus infection.

Yoong Pauline P Pier Gerald B GB

Proceedings of the National Academy of Sciences of the United States of America 20100119 5

Community-acquired infections caused by methicillin-resistant Staphylococcus aureus (MRSA) expressing the Panton-Valentine leukocidin (PVL) are rampant, but the contribution of PVL to bacterial virulence remains controversial. While PVL is usually viewed as a cytotoxin, at sublytic amounts it activates protective innate immune responses. A leukotoxic effect might predominate in high inoculum studies, whereas protective proinflammatory properties might predominate in settings with lower bacterial ...[more]

PMID: 20133867

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Project description:UNLABELLED:Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized in Europe and worldwide in the late 1990s. Within a decade, several genetically and geographically distinct CA-MRSA lineages carrying the small SCCmec type IV and V genetic elements and the Panton-Valentine leukocidin (PVL) emerged around the world. In Europe, the predominant CA-MRSA strain belongs to clonal complex 80 (CC80) and is resistant to kanamycin/amikacin and fusidic acid. CC80 was first reported in 1993 but was relatively rare until the late 1990s. It has since been identified throughout North Africa, the Middle East, and Europe, with recent sporadic reports in sub-Saharan Africa. While strongly associated with skin and soft tissue infections, it is rarely found among asymptomatic carriers. Methicillin-sensitive S. aureus (MSSA) CC80 strains are extremely rare except in sub-Saharan Africa. In the current study, we applied whole-genome sequencing to a global collection of both MSSA and MRSA CC80 isolates. Phylogenetic analyses strongly suggest that the European epidemic CA-MRSA lineage is derived from a PVL-positive MSSA ancestor from sub-Saharan Africa. Moreover, the tree topology suggests a single acquisition of both the SCCmec element and a plasmid encoding the fusidic acid resistance determinant. Four canonical SNPs distinguish the derived CA-MRSA lineage and include a nonsynonymous mutation in accessory gene regulator C (agrC). These changes were associated with a star-like expansion into Europe, the Middle East, and North Africa in the early 1990s, including multiple cases of cross-continent imports likely driven by human migrations. IMPORTANCE:With increasing levels of CA-MRSA reported from most parts of the Western world, there is a great interest in understanding the origin and factors associated with the emergence of these epidemic lineages. To trace the origin, evolution, and dissemination pattern of the European CA-MRSA clone (CC80), we sequenced a global collection of strains of the S. aureus CC80 lineage. Our study determined that a single descendant of a PVL-positive methicillin-sensitive ancestor circulating in sub-Saharan Africa rose to become the dominant CA-MRSA clone in Europe, the Middle East, and North Africa. In the transition from a methicillin-susceptible lineage to a successful CA-MRSA clone, it simultaneously became resistant to fusidic acid, a widely used antibiotic for skin and soft tissue infections, thus demonstrating the importance of antibiotic selection in the success of this clone. This finding furthermore highlights the significance of horizontal gene acquisitions and underscores the combined importance of these factors for the success of CA-MRSA.

Project description:Approximatively 75% of the genome of S. aureus (“core” genome) are highly conserved between strains, whereas the remaining 25% (“accessory” genome) are composed of variable regions that are mostly composed of mobile genetic elements (MGE), containing virulence and resistance genes. We have developed a composite DNA-microarray (StaphVar Array) which selectively targets 403 genes located on the accessory or core variable genome. Target genes encode antimicrobial resistance factors (35 %), virulence factors (28 %) and adhesins (31%). This microarray was validated with reference strains and used to characterize the genomic DNA of 13 community-acquired methicillin resistant S. aureus (CA-MRSA) strains representative of all the Multilocus Sequence Types (STs) described to date in Belgium. Analysis of gene content of 8 reference strains by the StaphVar Array matched 96 to 99% of the theoretical results. Analysis of CA-MRSA strains showed that 54.4 % of the genes tested were strain-dependent. Strains presented specific exotoxin, enterotoxin, cytolysin and adhesin gene profile by multi-locus sequence typing (MLST) lineage. One exception to these “lineage-specific” gene profile was the variable presence of the Arginin Catabolic Mobile Element (ACME, characteristic of the USA300 clone) within ST8 strains. In conclusion, this novel StaphVar array enables characterization of more than 400 variable resistance and virulence determinants in S. aureus strains. CA-MRSA strains from Belgium displayed extensive diversity in virulence and resistance profile. The presence of the USA 300 clone in our country was confirmed. Although mainly located on MGE, association of virulence genes were highly conserved within strains of the same MLST lineage. CGH microarray was performed on 13 epidemiologically distinct clinical isolates of methicillin resistant S. aureus. S. aureus labeled genomic DNA were hybridized to StaphVar arrays containing 1326 60mer oligonucleotide probes (Eurogentec, Belgium).

Project description:BackgroundBacterial pneumonia is a well described complication of influenza. In recent years, community-onset methicillin-resistant Staphylococcus aureus (cMRSA) infection has emerged as a contributor to morbidity and mortality in patients with influenza. Since the emergence and rapid dissemination of pandemic A(H1N1)2009 influenzavirus in April 2009, initial descriptions of the clinical features of patients hospitalized with pneumonia have contained few details of patients with bacterial co-infection.Methodology/principal findingsPatients with community-acquired pneumonia (CAP) caused by co-infection with pandemic A(H1N1)2009 influenzavirus and cMRSA were prospectively identified at two tertiary hospitals in one Australian city during July to September 2009, the period of intense influenza activity in our region. Detailed characterization of the cMRSA isolates was performed. 252 patients with pandemic A(H1N1)2009 influenzavirus infection were admitted at the two sites during the period of study. Three cases of CAP due to pandemic A(H1N1)2009/cMRSA co-infection were identified. The clinical features of these patients were typical of those with S. aureus co-infection or sequential infection following influenza. The 3 patients received appropriate empiric therapy for influenza, but inappropriate empiric therapy for cMRSA infection; all 3 survived. In addition, 2 fatal cases of CAP caused by pandemic A(H1N1)2009/cMRSA co-infection were identified on post-mortem examination. The cMRSA infections were caused by three different cMRSA clones, only one of which contained genes for Panton-Valentine Leukocidin (PVL).Conclusions/significanceClinicians managing patients with pandemic A(H1N1)2009 influenzavirus infection should be alert to the possibility of co-infection or sequential infection with virulent, antimicrobial-resistant bacterial pathogens such as cMRSA. PVL toxin is not necessary for the development of cMRSA pneumonia in the setting of pandemic A( H1N1) 2009 influenzavirus co-infection.

Dataset Information

Antibody-mediated enhancement of community-acquired methicillin-resistant Staphylococcus aureus infection.

Publications

Antibody-mediated enhancement of community-acquired methicillin-resistant Staphylococcus aureus infection.

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