scholarly journals The histone demethylase KDM6B fine-tunes the host response to Streptococcus pneumoniae

2019 ◽  
Author(s):  
Michael G. Connor ◽  
Tiphaine Marie-Noelle Camarasa ◽  
Emma Patey ◽  
Orhan Rasid ◽  
Laura Barrio ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Epithelial Cells ◽  
Respiratory Tract ◽  
Chromatin Remodeling ◽  
Host Response ◽  
Histone Demethylase ◽  
Infection Model ◽  
Dependent Manner ◽  
Upper Respiratory Tract ◽  
Upper Respiratory

AbstractStreptococcus pneumoniae is a natural colonizer of the human upper respiratory tract and an opportunistic pathogen. After colonization, bacteria either remain in the human upper respiratory tract, or may progress to cause pneumococcal disease. Although epithelial cells are among the first to encounter pneumococci, the cellular processes and contribution of epithelial cells to the host response are poorly understood. Here, we show a S. pneumoniae serotype 6B ST90 strain, which does not cause disease in a murine infection model, induces a unique NF-κB signature response distinct from an invasive disease causing isolate of serotype 4 (TIGR4). This signature is characterized by activation of p65 (RelA) and requires a histone demethylase, KDM6B. At the molecular level, we show that interaction of the 6B strain with epithelial cells leads to chromatin remodeling within the IL-11 promoter in a KDM6B dependent manner, where KDM6B specifically demethylates histone H3 lysine 27 di-methyl. Chromatin remodeling of the IL-11 locus facilitates p65 access to three NF-κB sites, which are otherwise inaccessible when stimulated by IL-1β or TIGR4. Finally, we demonstrate through chemical inhibition of KDM6B, with GSK-J4 inhibitor, and through exogenous addition of IL-11 that the host responses to 6B ST90 and TIGR4 strains can be interchanged both in vitro and in a murine model of infection in vivo. Our studies hereby reveal how a chromatin modifier governs cellular responses during infection.

scholarly journals Demonstration of N , N -Dimethyldithiocarbamate as a Copper-Dependent Antibiotic against Multiple Upper Respiratory Tract Pathogens

2021 ◽  
Author(s):  
Sanjay V. Menghani ◽  
Angela Rivera ◽  
Miranda Neubert ◽  
James R. Hagerty ◽  
Lourdes Lewis ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Dependent Manner ◽  
Upper Respiratory Tract ◽  
Coccidioides Posadasii ◽  
Content Type ◽  
Upper Respiratory

With the rise of antibiotic resistance, approaches that add new antimicrobials to the current repertoire are vital. Here, we investigate putative and known copper ionophores in an attempt to intoxicate bacteria and use ionophore/copper synergy, and we ultimately find success with N , N -dimethyldithiocarbamate (DMDC). We show that DMDC has in vitro efficacy in a copper-dependent manner and kills pathogens across three different kingdoms, Streptococcus pneumoniae ( Sr. pneumoniae ), Coccidioides posadasii , and Schistosoma mansoni , and in vivo efficacy against Sr . pneumoniae .

scholarly journals Isolation of an obligately anaerobic Streptococcus pneumoniae from blood culture

1977 ◽  
Vol 6 (2) ◽  
pp. 181-182
Author(s):  
j a Yatabe ◽  
K L baldwin ◽  
W J Martin
Keyword(s):  
Streptococcus Pneumoniae ◽  
Tract Infection ◽  
Blood Culture ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Upper Respiratory Tract Infection ◽  
Upper Respiratory Tract ◽  
Obligately Anaerobic ◽  
Upper Respiratory

An obligately anaerobic strain of Streptococcus pneumoniae was isolated from blood culture in a 14-month-old child with an upper respiratory tract infection.

scholarly journals Upper respiratory tract colonization with Streptococcus pneumoniae in adults

2020 ◽  
Vol 19 (4) ◽  
pp. 353-366 ◽  
Author(s):  
Adriano Arguedas ◽  
Krzysztof Trzciński ◽  
Katherine L. O’Brien ◽  
Daniela M. Ferreira ◽  
Anne L. Wyllie ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Upper Respiratory Tract ◽  
Upper Respiratory ◽  
Respiratory Tract Colonization

scholarly journals Identification of Pneumococcal Factors Affecting Pneumococcal Shedding Shows that thedltLocus Promotes Inflammation and Transmission

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
M. Ammar Zafar ◽  
Alexandria J. Hammond ◽  
Shigeto Hamaguchi ◽  
Weisheng Wu ◽  
Masamitsu Kono ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Capsular Polysaccharide ◽  
Inflammatory Responses ◽  
Transposon Mutagenesis ◽  
Respiratory Pathogen ◽  
Invasive Infection ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Upper Respiratory

ABSTRACTHost-to-host transmission is a necessary but poorly understood aspect of microbial pathogenesis. Herein, we screened a genomic library of mutants of the leading respiratory pathogenStreptococcus pneumoniaegenerated by mariner transposon mutagenesis (Tn-Seq) to identify genes contributing to its exit or shedding from the upper respiratory tract (URT), the limiting step in the organism’s transmission in an infant mouse model. Our analysis focused on genes affecting the bacterial surface that directly impact interactions with the host. Among the multiple factors identified was thedltlocus, which addsd-alanine onto lipoteichoic acids (LTA) and thereby increases Toll-like receptor 2-mediated inflammation and resistance to antimicrobial peptides. The more robust proinflammatory response in the presence ofd-alanylation promotes secretions that facilitate pneumococcal shedding and allows for transmission. Expression of thedltlocus is controlled by the CiaRH system, which senses cell wall stress in response to antimicrobial activity, including in response to lysozyme, the most abundant antimicrobial along the URT mucosa. Accordingly, in alysM−/−host, there was no longer an effect of thedltlocus on pneumococcal shedding. Thus, our findings demonstrate how a pathogen senses the URT milieu and then modifies its surface characteristics to take advantage of the host response for transit to another host.IMPORTANCEStreptococcus pneumoniae(the pneumococcus) is a common cause of respiratory tract and invasive infection. The overall effectiveness of immunization with the organism’s capsular polysaccharide depends on its ability to block colonization of the upper respiratory tract and thereby prevent host-to-host transmission. Because of the limited coverage of current pneumococcal vaccines, we carried out an unbiasedin vivotransposon mutagenesis screen to identify pneumococcal factors other than its capsular polysaccharide that affect transmission. One such candidate was expressed by thedltlocus, previously shown to addd-alanine onto the pneumococcal lipoteichoic acid present on the bacterial cell surface. This modification protects against host antimicrobials and augments host inflammatory responses. The latter increases secretions and bacterial shedding from the upper respiratory tract to allow for transmission. Thus, this study provides insight into a mechanism employed by the pneumococcus to successfully transit from one host to another.

scholarly journals Type I Interferon Signaling Is a Common Factor Driving Streptococcus pneumoniae and Influenza A Virus Shedding and Transmission

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tonia Zangari ◽  
Mila B. Ortigoza ◽  
Kristen L. Lokken-Toyli ◽  
Jeffrey N. Weiser
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Influenza A Virus ◽  
Influenza A ◽  
Common Factor ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Infant Mouse ◽  
Upper Respiratory

ABSTRACT The dynamics underlying respiratory contagion (the transmission of infectious agents from the airways) are poorly understood. We investigated host factors involved in the transmission of the leading respiratory pathogen Streptococcus pneumoniae. Using an infant mouse model, we examined whether S. pneumoniae triggers inflammatory pathways shared by influenza A virus (IAV) to promote nasal secretions and shedding from the upper respiratory tract to facilitate transit to new hosts. Here, we show that amplification of the type I interferon (IFN-I) response is a critical host factor in this process, as shedding and transmission by both IAV and S. pneumoniae were decreased in pups lacking the common IFN-I receptor (Ifnar1−/− mice). Additionally, providing exogenous recombinant IFN-I to S. pneumoniae-infected pups was sufficient to increase bacterial shedding. The expression of IFN-stimulated genes (ISGs) was upregulated in S. pneumoniae-infected wild-type (WT) but not Ifnar1−/− mice, including genes involved in mucin type O-glycan biosynthesis; this correlated with an increase in secretions in S. pneumoniae- and IAV-infected WT compared to Ifnar1−/− pups. S. pneumoniae stimulation of ISGs was largely dependent on its pore-forming toxin, pneumolysin, and coinfection with IAV and S. pneumoniae resulted in synergistic increases in ISG expression. We conclude that the induction of IFN-I signaling appears to be a common factor driving viral and bacterial respiratory contagion. IMPORTANCE Respiratory tract infections are a leading cause of childhood mortality and, globally, Streptococcus pneumoniae is the leading cause of mortality due to pneumonia. Transmission of S. pneumoniae primarily occurs through direct contact with respiratory secretions, although the host and bacterial factors underlying transmission are poorly understood. We examined transmission dynamics of S. pneumoniae in an infant mouse model and here show that S. pneumoniae colonization of the upper respiratory tract stimulates host inflammatory pathways commonly associated with viral infections. Amplification of this response was shown to be a critical host factor driving shedding and transmission of both S. pneumoniae and influenza A virus, with infection stimulating expression of a wide variety of genes, including those involved in the biosynthesis of mucin, a major component of respiratory secretions. Our findings suggest a mechanism facilitating S. pneumoniae contagion that is shared by viral infection.

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