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doi: 10.1128/mBio.02089-17

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ABSTRACT

Streptococcus pneumoniae and Staphylococcus aureus are 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 between S.pneumoniae and S.aureus in the context of colonization and the transition to invasive disease have not been characterized. In this report, we show that S.pneumoniae and S.aureus form stable dual-species biofilms on epithelial cells in vitro . When these biofilms are exposed to physiological changes associated with viral infection, S.pneumoniae disperses from the biofilm, whereas S.aureus dispersal is inhibited. These findings were supported by results of an in vivo study 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 that S.aureus disseminates into the lungs of mice stably colonized with these bacteria following influenza A virus infection, cocolonization with S.pneumoniae in vitro and in vivo inhibits S.aureus dispersal and transition to disease. This study provides novel insight into both the interactions between S.pneumoniae and S.aureus during carriage and the transition from colonization to secondary bacterial pneumonia.

IMPORTANCE In this study, we demonstrate that Streptococcus pneumoniae can modulate the pathogenic potential of Staphylococcus aureus in a model of secondary bacterial pneumonia. We report that host physiological signals related to viral infection cease to elicit a dispersal response from S.aureus while in a dual-species setting with S.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.

IMPORTANCE
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Streptococcus pneumoniae (the pneumococcus), a Gram-positive diplococcus, is one of the most common opportunistic pathogens in the upper respiratory tract. By the age of 2 years, nearly 95% of children are colonized in the nasopharynx, in the form of a bacterial biofilm, by one of the greater than 90 serotypes of S.pneumoniae . Biofilm formation is a crucial step in pathogenesis, as biofilms promote bacterial persistence, competence, immune evasion, and resistance to antibiotics, all while serving as reservoirs for local and invasive disease ( 1 7 ). The pneumococcus, which predominantly causes upper respiratory tract infections, is the primary etiologic agent of both otitis media and secondary bacterial pneumonia ( 5 , 8 ). Pneumococcal pneumonia following influenza A virus (IAV) infection poses a serious health threat to both young and elderly people. Recent studies have shown that host physiological changes in response to IAV infection, such as increased temperature, as well as the release of norepinephrine, glucose, and ATP, cause the pneumococcus to disperse from asymptomatically colonizing biofilms ( 9 , 10 ). The bacteria, once dispersed from the biofilm in response to these stimuli, cause invasive disease, as they express an altered transcriptome and hypervirulent phenotype compared to the biofilm-associated bacteria ( 11 13 ).

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Journal of Hematology Oncology 2013 6 :74

https://doi.org/10.1186/1756-8722-6-74

© Shi et al.; licensee BioMed Central Ltd.2013

Received: 23August2013

Accepted: 30September2013

Published: 30September2013

Abstract

T-cell activation and dysfunction relies on direct and modulated receptors. Based on their functional outcome, co-signaling molecules can be divided as co-stimulators and co-inhibitors, which positively and negatively control the priming, growth, differentiation and functional maturation of a T-cell response. We are beginning to understand the power of co-inhibitors in the context of lymphocyte homeostasis and the pathogenesis of leukemia, which involves several newly described co-inhibitory pathways, including the programmed death-1 (PD-1) and PD-1 ligand (PD-L1) pathway. The aim of this review is to summarize the PD-1 and PD-L1 biological functions and their alterative expression in hematological malignancies. The role of PD-1 and PD-L1 in T-cell immune suppression and the potential for immunotherapy via blocking PD-1 and PD-L1 in hematological malignancies are also reviewed.

Anaplastic Large Cell Lymphoma Primary Anaplastic Large Cell Lymphoma

Leukemia, particularly aggressive refractory hematological malignancies unresponsive to upfront therapy, remains a difficult condition to treat. The focus of therapy is to achieve complete disease remission. Therefore, alternative treatment options that utilize immunotherapy while minimizing toxicity are warranted [ 1 , 2 , 3 ]. It is well known that persistent immunodeficiency is a common feature in patients with leukemia. Moreover, T cell function becomes suppressed with disease progression. Such immune dysfunction may be due to a disorder in thymic output function (in particular in young patients), which results in a lower level of naive T-cells in the peripheral blood available for an immune response to the proliferation and abnormal expression of the T cell receptor (TCR) repertoire. This condition results in an impaired specific antigen response and abnormal TCR signal transduction, which results in lower T cell activation for an immune response [ 4 , 5 , 6 , 7 , 8 , 9 ]. Moreover, increasing data have shown that peripheral T-cell tolerance is an essential property of the specific immune response to tumor cells. T-cell anergy is defined as the state in which T-cells fail to respond to previously encountered antigenic stimulation by functional APCs. Such T-cells lose the ability to autonomously produce IL-2 [ 10 ]. In addition, the low cytotoxicity of T-cells may be related to the high expression level of inhibitory molecules including programmed death-1 (PD-1), LAG-3 and NKG2A in CD8+T cells [ 11 ]. Moreover, it has been shown that the PD-1 ligand (PD-L1) is highly expressed in leukemia cells. In addition, PD-1/PD-L1 interactions contribute to functional T-cell impairment, which fails to elicit minimal residual disease and may be related to leukemia relapse. This phenomenon may be one of the reasons why immature leukemic progenitor cells escape the immune system i.e., by inhibiting T-cell function via the PD-1/PD-L1 pathway [ Free Shipping Looking For Cheap Sale Limited Edition Love Moschino quilted backpack A4Bwo
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Literary Terms

A character is a person, animal, being, creature, or thing in a story. Writers use characters to perform the actions and speak dialogue , moving the story along a line. A story can have only one character ( protagonist ) and still be a complete story. This character’s conflict may be an inner one (within him/herself), or a conflict with something natural, such as climbing a mountain. Most stories have multiple characters interacting, with one of them as the antagonist , causing a conflict for the protagonist.

A popular television series that just ended is the show “Glee.” Each season had popular characters who had to learn to work together to create a good musical production. Various characters underwent a change, making them a dynamic character, such as Noah Puckerman. He appears to carry out the stereotype of a jock (strong but not so smart), but his character changes as it’s revealed that he can be hard working and intelligent.

A movie that features one character throughout most of it is “Castaway” with Tom Hanks. His character is on board a shipping plane when it crashes. He’s the only survivor, trapped on an island for four years. This movie focuses on his psychological (mental) and physical condition as he slowly adapts to a life of isolation, living alone on an island that is off all regular sea and airplane routes. It’s a great example of how a story can work with only one character, although many minor characters appear in the beginning and end.

These are the most important characters in the story. There are two types, of which there may be a couple for each.

Protagonist Antagonist

These are the other characters in a story. They are not as important as the major characters, but still play a large part in the story. Their actions help drive the story forward. They may impact the decisions the protagonist or antagonist make, either helping or interfering with the conflict.

Characters can have different traits. Major characters will usually be more dynamic, changing and growing through the story while minor characters may be more static.

Static Dynamic

Characters are what make stories. Without a character, there is no story to tell, only a lot of scenery. Many characters in literature, television series, and movies have a huge impact on people. Some people like to live their lives through these characters, who appear to have more exciting lives. Also, these characters may seem so real and inspirational, that people forget they are fictional.

Characters become so important to the audience, that cities across the country hold conventions in which people pay a lot of money to dress and act as their favorite characters from multiple types of shows, particularly of the comic magazine genre (type of literature).

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