Streptococcus pneumoniae Modulates Staphylococcus aureus Biofilm Dispersion and the Transition from Colonization to Invasive Disease

ABSTRACTStreptococcus pneumoniaeandStaphylococcus aureusare ubiquitous upper respiratory opportunistic pathogens. Individually, these Gram-positive microbes are two of the most common causative agents of secondary bacterial pneumonia following influenza A virus infection, and they constitute a significant source of morbidity and mortality. Since the introduction of the pneumococcal conjugate vaccine, rates of cocolonization with both of these bacterial species have increased, despite the traditional view that they are antagonistic and mutually exclusive. The interactions betweenS. pneumoniaeandS. aureusin the context of colonization and the transition to invasive disease have not been characterized. In this report, we show thatS. pneumoniaeandS. aureusform stable dual-species biofilms on epithelial cellsin vitro. When these biofilms are exposed to physiological changes associated with viral infection,S. pneumoniaedisperses from the biofilm, whereasS. aureusdispersal is inhibited. These findings were supported by results of anin vivostudy in which we used a novel mouse cocolonization model. In these experiments, mice cocolonized in the nares with both bacterial species were subsequently infected with influenza A virus. The coinfected mice almost exclusively developed pneumococcal pneumonia. These results indicate that despite our previous report thatS. aureusdisseminates into the lungs of mice stably colonized with these bacteria following influenza A virus infection, cocolonization withS. pneumoniae in vitroandin vivoinhibitsS. aureusdispersal and transition to disease. This study provides novel insight into both the interactions betweenS. pneumoniaeandS. aureusduring carriage and the transition from colonization to secondary bacterial pneumonia.IMPORTANCEIn this study, we demonstrate thatStreptococcus pneumoniaecan modulate the pathogenic potential ofStaphylococcus aureusin a model of secondary bacterial pneumonia. We report that host physiological signals related to viral infection cease to elicit a dispersal response fromS. aureuswhile in a dual-species setting withS. pneumoniae, in direct contrast to results of previous studies with each species individually. This study underscores the importance of studying polymicrobial communities and their implications in disease states.

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Dynamic Changes in the Streptococcus pneumoniae Transcriptome during Transition from Biofilm Formation to Invasive Disease upon Influenza A Virus Infection

Infection and Immunity ◽

10.1128/iai.02225-14 ◽

2014 ◽

Vol 82 (11) ◽

pp. 4607-4619 ◽

Cited By ~ 55

Author(s):

Melinda M. Pettigrew ◽

Laura R. Marks ◽

Yong Kong ◽

Janneane F. Gent ◽

Hazeline Roche-Hakansson ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Influenza A Virus ◽

Influenza A ◽

Lactate Production ◽

Invasive Disease ◽

Content Type ◽

Induced Changes ◽

Upregulated Genes

ABSTRACTStreptococcus pneumoniaeis a leading cause of infectious disease globally. Nasopharyngeal colonization occurs in biofilms and precedes infection. Prior studies have indicated that biofilm-derived pneumococci are avirulent. However, influenza A virus (IAV) infection releases virulent pneumococci from biofilmsin vitroandin vivo. Triggers of dispersal include IAV-induced changes in the nasopharynx, such as increased temperature (fever) and extracellular ATP (tissue damage). We used whole-transcriptome shotgun sequencing (RNA-seq) to compare theS. pneumoniaetranscriptome in biofilms, bacteria dispersed from biofilms after exposure to IAV, febrile-range temperature, or ATP, and planktonic cells grown at 37°C. Compared with biofilm bacteria, actively dispersedS. pneumoniae, which were more virulent in invasive disease, upregulated genes involved in carbohydrate metabolism. Enzymatic assays for ATP and lactate production confirmed that dispersed pneumococci exhibited increased metabolism compared to those in biofilms. Dispersed pneumococci also upregulated genes associated with production of bacteriocins and downregulated colonization-associated genes related to competence, fratricide, and the transparent colony phenotype. IAV had the largest impact on the pneumococcal transcriptome. Similar transcriptional differences were also observed when actively dispersed bacteria were compared with avirulent planktonic bacteria. Our data demonstrate complex changes in the pneumococcal transcriptome in response to IAV-induced changes in the environment. Our data suggest that disease is caused by pneumococci that are primed to move to tissue sites with altered nutrient availability and to protect themselves from the nasopharyngeal microflora and host immune response. These data help explain pneumococcal virulence after IAV infection and have important implications for studies ofS. pneumoniaepathogenesis.

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Host Physiologic Changes Induced by Influenza A Virus Lead toStaphylococcus aureusBiofilm Dispersion and Transition from Asymptomatic Colonization to Invasive Disease

mBio ◽

10.1128/mbio.01235-16 ◽

2016 ◽

Vol 7 (4) ◽

Cited By ~ 29

Author(s):

Ryan M. Reddinger ◽

Nicole R. Luke-Marshall ◽

Anders P. Hakansson ◽

Anthony A. Campagnari

Keyword(s):

Virus Infection ◽

Viral Infection ◽

Influenza A Virus ◽

Bacterial Pneumonia ◽

Influenza A ◽

Systemic Disease ◽

Invasive Disease ◽

Health Concern ◽

Influenza A Virus Infection ◽

Secondary Bacterial Pneumonia

ABSTRACTStaphylococcus aureusis a ubiquitous opportunistic human pathogen and a major health concern worldwide, causing a wide variety of diseases from mild skin infections to systemic disease.S. aureusis a major source of severe secondary bacterial pneumonia after influenza A virus infection, which causes widespread morbidity and mortality. While the phenomenon of secondary bacterial pneumonia is well established, the mechanisms behind the transition from asymptomatic colonization to invasive staphylococcal disease following viral infection remains unknown. In this report, we have shown thatS. aureusbiofilms, grown on an upper respiratory epithelial substratum, disperse in response to host physiologic changes related to viral infection, such as febrile range temperatures, exogenous ATP, norepinephrine, and increased glucose. Mice that were colonized withS. aureusand subsequently exposed to these physiologic stimuli or influenza A virus coinfection developed pronounced pneumonia. This study provides novel insight into the transition from colonization to invasive disease, providing a better understanding of the events involved in the pathogenesis of secondary staphylococcal pneumonia.IMPORTANCEIn this study, we have determined that host physiologic changes related to influenza A virus infection causesS. aureusto disperse from a biofilm state. Additionally, we report that these same host physiologic changes promoteS. aureusdissemination from the nasal tissue to the lungs in an animal model. Furthermore, this study identifies important aspects involved in the transition ofS. aureusfrom asymptomatic colonization to pneumonia.

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Faculty Opinions recommendation of Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1097147.553145 ◽

2007 ◽

Author(s):

Joseph Mizgerd

Keyword(s):

Influenza A Virus ◽

Bacterial Pneumonia ◽

Influenza A ◽

1918 Influenza ◽

Secondary Bacterial Pneumonia

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In Vitro and In Vivo Activities of DA-7867, a New Oxazolidinone, against Aerobic Gram-Positive Bacteria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.6.2498-2500.2005 ◽

2005 ◽

Vol 49 (6) ◽

pp. 2498-2500 ◽

Cited By ~ 7

Author(s):

Eun Jeong Yoon ◽

Yeong Woo Jo ◽

Sung Hak Choi ◽

Tae Ho Lee ◽

Jae Keol Rhee ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Streptococcus Pneumoniae ◽

Gram Positive ◽

Methicillin Resistant ◽

Gram Positive Bacteria ◽

Vancomycin Resistant Enterococci ◽

Infection Models ◽

Vancomycin Resistant

ABSTRACT In vitro and in vivo activities of DA-7867 were assessed against methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. All isolates were inhibited by DA-7867 at ≤0.78 μg/ml, a four-times-lower concentration than that of inhibition by linezolid. For murine infection models, DA-7867 also exhibited greater efficacy than linezolid against all isolates tested.

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Antiviral activity of Ladania067, an extract from wild black currant leaves against influenza A virus in vitro and in vivo

Frontiers in Microbiology ◽

10.3389/fmicb.2014.00171 ◽

2014 ◽

Vol 5 ◽

Cited By ~ 12

Author(s):

Emanuel Haasbach ◽

Carmen Hartmayer ◽

Alice Hettler ◽

Alicja Sarnecka ◽

Ulrich Wulle ◽

...

Keyword(s):

Antiviral Activity ◽

Influenza A Virus ◽

Influenza A ◽

Black Currant

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Exacerbation of Influenza A Virus Disease Severity by Respiratory Syncytial Virus Co-Infection in a Mouse Model

Viruses ◽

10.3390/v13081630 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1630 ◽

Cited By ~ 1

Author(s):

Junu A. George ◽

Shaikha H. AlShamsi ◽

Maryam H. Alhammadi ◽

Ahmed R. Alsuwaidi

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

Influenza A Virus ◽

Influenza A ◽

Immune Cell ◽

Virus Disease ◽

Viral Loads ◽

Syncytial Virus

Influenza A virus (IAV) and respiratory syncytial virus (RSV) are leading causes of childhood infections. RSV and influenza are competitive in vitro. In this study, the in vivo effects of RSV and IAV co-infection were investigated. Mice were intranasally inoculated with RSV, with IAV, or with both viruses (RSV+IAV and IAV+RSV) administered sequentially, 24 h apart. On days 3 and 7 post-infection, lung tissues were processed for viral loads and immune cell populations. Lung functions were also evaluated. Mortality was observed only in the IAV+RSV group (50% of mice did not survive beyond 7 days). On day 3, the viral loads in single-infected and co-infected mice were not significantly different. However, on day 7, the IAV titer was much higher in the IAV+RSV group, and the RSV viral load was reduced. CD4 T cells were reduced in all groups on day 7 except in single-infected mice. CD8 T cells were higher in all experimental groups except the RSV-alone group. Increased airway resistance and reduced thoracic compliance were demonstrated in both co-infected groups. This model indicates that, among all the infection types we studied, infection with IAV followed by RSV is associated with the highest IAV viral loads and the most morbidity and mortality.

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GP96 drives exacerbation of secondary bacterial pneumonia following influenza A virus infection

10.1101/2020.09.14.297192 ◽

2020 ◽

Author(s):

Tomoko Sumitomo ◽

Masanobu Nakata ◽

Satoshi Nagase ◽

Yuki Takahara ◽

Mariko Honda-Ogawa ◽

...

Keyword(s):

Epithelial Cells ◽

Influenza A Virus ◽

Transcriptional Repression ◽

Bacterial Pneumonia ◽

Influenza A ◽

Surface Expression ◽

Lung Pathology ◽

Direct Binding ◽

Novel Therapeutic Strategies ◽

Secondary Bacterial Pneumonia

AbstractInfluenza A virus (IAV) infection predisposes the host to secondary bacterial pneumonia, known as a major cause of morbidity and mortality during influenza epidemics. Analysis of interactions between IAV-infected human epithelial cells and Streptococcus pneumoniae revealed that infected cells ectopically exhibited the endoplasmic reticulum chaperon GP96 on the surface. Importantly, efficient pneumococcal adherence to epithelial cells was imparted by interactions with extracellular GP96 and integrin αV, with the surface expression mediated by GP96 chaperone activity. Furthermore, abrogation of adherence was gained by chemical inhibition or genetic knockout of GP96, as well as addition of RGD peptide. Direct binding of extracellular GP96 and pneumococci was shown to be mediated by pneumococcal oligopeptide permease components. Additionally, IAV infection induced activation of calpains and Snail1, which are responsible for degradation and transcriptional repression of junctional proteins in the host, respectively, indicating increased bacterial translocation across the epithelial barrier. Notably, treatment of IAV-infected mice with the GP96 inhibitor enhanced pneumococcal clearance from lung tissues and ameliorated lung pathology. Taken together, the present findings indicate a viral-bacterial synergy in relation to disease progression and suggest a paradigm for developing novel therapeutic strategies tailored to inhibit pneumococcal colonization in an IAV-infected respiratory tract.

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