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Transcriptional events during the recovery from MRSA lung infection: a mouse pneumonia model.

ABSTRACT: Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging threat to human health throughout the world. Rodent MRSA pneumonia models mainly focus on the early innate immune responses to MRSA lung infection. However, the molecular pattern and mechanisms of recovery from MRSA lung infection are largely unknown. In this study, a sublethal mouse MRSA pneumonia model was employed to investigate late events during the recovery from MRSA lung infection. We compared lung bacterial clearance, bronchoalveolar lavage fluid (BALF) characterization, lung histology, lung cell proliferation, lung vascular permeability and lung gene expression profiling between days 1 and 3 post MRSA lung infection. Compared to day 1 post infection, bacterial colony counts, BALF total cell number and BALF protein concentration significantly decreased at day 3 post infection. Lung cDNA microarray analysis identified 47 significantly up-regulated and 35 down-regulated genes (p<0.01, 1.5 fold change [up and down]). The pattern of gene expression suggests that lung recovery is characterized by enhanced cell division, vascularization, wound healing and adjustment of host adaptive immune responses. Proliferation assay by PCNA staining further confirmed that at day 3 lungs have significantly higher cell proliferation than at day 1. Furthermore, at day 3 lungs displayed significantly lower levels of vascular permeability to albumin, compared to day 1. Collectively, this data helps us elucidate the molecular mechanisms of the recovery after MRSA lung infection.

SUBMITTER: Chen J

PROVIDER: S-EPMC3731344 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Transcriptional events during the recovery from MRSA lung infection: a mouse pneumonia model.

Chen Jiwang J Feng Gang G Guo Qiang Q Wardenburg Juliane B JB Lin Simon S Inoshima Ichiro I Deaton Ryan R Yuan Jason X J JX Garcia Joe G N JG Machado Roberto F RF Otto Michael M Wunderink Richard G RG

PloS one 20130801 8

Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging threat to human health throughout the world. Rodent MRSA pneumonia models mainly focus on the early innate immune responses to MRSA lung infection. However, the molecular pattern and mechanisms of recovery from MRSA lung infection are largely unknown. In this study, a sublethal mouse MRSA pneumonia model was employed to investigate late events during the recovery from MRSA lung infection. We compared lung b ...[more]

PMID: 23936388

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Project description:Pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of morbidity and mortality in infants particularly following lower respiratory tract viral infections such as Respiratory Syncytial Virus (RSV). However, the mechanisms by which co-infection of infants by MRSA and RSV cause increased lung pathology are unknown. Because the infant immune system is qualitatively and quantitatively different from adults we developed a model of infant MRSA pneumonia which will allow us to investigate the effects of RSV co-infection on disease severity. We infected neonatal and adult mice with increasing doses of MRSA and demonstrate that neonatal mice have delayed kinetics in clearing the bacteria in comparison to adult mice. There were differences in recruitment of immune cells into the lung following infection. Adult mice exhibited an increase in neutrophil recruitment that coincided with reduced bacterial titers followed by an increase in macrophages. Neonatal mice, however, exhibited an early increase in neutrophils that did not persist despite continued presence of the bacteria. Unlike the adult mice, neonatal mice failed to exhibit an increase in macrophages. Neonates exhibited a decrease in phagocytosis of MRSA suggesting that the decrease in clearance was partially due to deficient phagocytosis of the bacteria. Both neonates and adults responded with an increase in pro-inflammatory cytokines following infection. However, in contrast to the adult mice, neonates did not express constitutive levels of the anti-microbial peptide Reg3γ in the lung. Infection of neonates did not stimulate expression of the co-stimulatory molecule CD86 by dendritic cells and neonates exhibited a diminished T cell response compared to adult mice. Overall, we have developed a neonatal model of MRSA pneumonia that displays a similar delay in bacterial clearance as is observed in the neonatal intensive care unit and will be useful for performing co-infection studies.

Project description:Vaccination reduces morbidity and mortality from pneumonia but its effect on the tissue-level response to infection is still poorly understood. We evaluated pneumonia disease progression, acute phase response and lung gene expression profiles in mice inoculated intranasally with virulent gram-positive Streptococcus pneumoniae serotype (ST) 3, with and without prior immunization with pneumococcal polysaccharide ST 3 (PPS3), or co-immunization with PPS3 and with a low dose of lipopolysaccharide (LPS). Pneumonia severity was assessed in the acute phase, 5, 12, 24 and 48 h post-inoculation (p.i.) and the resolution phase of 7 days p.i. Primary PPS3 specific antibody production was upregulated and IgM binding to pneumococci increased in PPS3-immunized mice. Immunizations with PPS3 or PPS3 + LPS decreased bacterial recovery the lung and blood at 24 and 48 h and increased survival. Microarray analysis of whole lung RNA revealed significant changes in the acute phase protein serum amyloid A (SAA) between noninfected and infected mice, which were attenuated by immunization. SAA transcripts were higher in the liver and lungs of infected controls, and SAA protein was elevated in serum, but decreased in PPS3-immunized mice. Thus, during a virulent pneumonia infection, prior immunization with PPS3 in an IgM-dependent manner as well as co-immunization with PPS3 + LPS attenuated pneumonia severity and promoted resolution of infection, concomitant with significant regulation of cytokine gene expression in the lungs, and acute phase proteins in the lungs, liver and serum. Each lung RNA sample represented an individual mouse, creating biological repeats for each treatment. In-vivo treatments were as follows: non-infected lung (vehicle-immunized) control (n=5), infected lung (vehicle-immunized) control at 48 hr post-inoculation (n=5), PPS3 and LPS co-immunized lung at 48 hr post-inoculation (n=4) and PPS3 and LPS co-immunized lung at 7 days post-inoculation (n=4).

Dataset Information

Transcriptional events during the recovery from MRSA lung infection: a mouse pneumonia model.

Publications

Transcriptional events during the recovery from MRSA lung infection: a mouse pneumonia model.

Similar Datasets

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