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Comparison of the immune response during acute and chronic Staphylococcus aureus infection.

ABSTRACT: Staphylococcus aureus bacteria are able to grow in a planktonic state that is associated with acute infections and in biofilms that are associated with chronic infections. Acute infections, such as skin infections, are often self-limiting. However, chronic infections, such as implant infections, can be difficult to clear and may require surgical intervention. The host immune response may contribute to the different outcomes often associated with these two disease types. We used proteomic arrays and two murine models for an initial, descriptive characterization of the contribution of the host immune response to outcomes of acute versus chronic S. aureus disease. We compared the immune responses between a model of self-limiting skin and soft tissue infection caused by the planktonic form of S. aureus versus a model of surgical mesh implant infection, which we show to be caused by a bacterial biofilm. The significantly altered host cytokines and chemokines were largely different in the two models, with responses diminished by 21 days post-implantation in surgical mesh infection. Because bacterial levels remained constant during the 21 days that the surgical mesh infection was followed, those cytokines that are significantly increased during chronic infection are not likely effective in eradicating biofilm. Comparison of the levels of cytokines and chemokines in acute versus chronic S. aureus infection can provide a starting point for evaluation of the role of specific immune factors that are present in one disease manifestation but not the other.

SUBMITTER: Brady RA

PROVIDER: S-EPMC5875981 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Osteomyelitis is a difficult-to-eradicate bone infection typically caused by Staphylococcus aureus. In this study, we investigated the in vivo transcriptional adaptation of S. aureus during bone infection. To this end, we determined the transcriptome of S. aureus during the acute (day 7) and chronic (day 28) phases of experimental murine osteomyelitis using RNA sequencing (RNA-Seq). We identified a total of 180 genes significantly more highly expressed by S. aureus during acute or chronic in vivo infection than under in vitro growth conditions. These genes encoded proteins involved in gluconeogenesis, proteolysis of host proteins, iron acquisition, evasion of host immune defenses, and stress responses. At the regulatory level, sarA and -R and saeR and -S as well as the small RNA RsaC were predominantly expressed by S. aureus during in vivo infection. Only nine genes, including the genes encoding the arginine deiminase (ADI) pathway and those involved in the stringent response, were significantly more highly expressed by S. aureus during the chronic than the acute stage of infection. Analysis by quantitative reverse transcription-PCR (qRT-PCR) of a subset of these in vivo-expressed genes in clinical specimens yielded the same results as those observed in the murine system. Collectively, our results show that during acute osteomyelitis, S. aureus induced the transcription of genes that mediate metabolic adaptation, immune evasion, and replication. During the chronic phase, however, S. aureus switched its transcriptional response from a proliferative to a persistence mode, probably driven by the severe deficiency in nutrient supplies. Interfering with the survival strategies of S. aureus during chronic infection could lead to more effective treatments. The key to the survival success of pathogens during an infection is their capacity to rapidly adjust to the host environment and to evade the host defenses. Understanding how a pathogen redirects and fine-tunes its gene expression in response to the challenges of infection is central to the development of more efficient anti-infective therapies. Osteomyelitis is a debilitating infection of the bone predominantly caused by S. aureus. In this study, we evaluated the transcriptional response of S. aureus during bone infection. Our results indicate that S. aureus reprograms its genetic repertoire during the acute phase of infection to adapt to nutrient availability and to replicate within the host. During the chronic phase, S. aureus upregulates a survival genetic program activated in response to nutrient starvation. Thus, we have uncovered key survival pathways of S. aureus during acute and chronic osteomyelitis that can be used as therapeutic targets.

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Comparison of the immune response during acute and chronic Staphylococcus aureus infection.

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