scholarly journals The cGAS/STING Pathway Detects Streptococcus pneumoniae but Appears Dispensable for Antipneumococcal Defense in Mice and Humans

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Juan Sebastian Ruiz-Moreno ◽  
Lutz Hamann ◽  
Lei Jin ◽  
Leif E. Sander ◽  
Monika Puzianowska-Kuznicka ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Type I Ifns ◽  
Mouse Macrophages ◽  
Upper Respiratory ◽  
Sting Pathway ◽  
And Control ◽  
Wall Components

ABSTRACT Streptococcus pneumoniae is a frequent colonizer of the upper respiratory tract and a leading cause of bacterial pneumonia. The innate immune system senses pneumococcal cell wall components, toxin, and nucleic acids, which leads to production of inflammatory mediators to initiate and control antibacterial defense. Here, we show that the cGAS (cyclic GMP-AMP [cGAMP] synthase)-STING pathway mediates detection of pneumococcal DNA in mouse macrophages to primarily stimulate type I interferon (IFN) responses. Cells of human individuals carrying HAQ TMEM173 , which encodes a common hypomorphic variant of STING, were largely or partly defective in inducing type I IFNs and proinflammatory cytokines upon infection. Subsequent analyses, however, revealed that STING was dispensable for restricting S. pneumoniae during acute pneumonia in mice. Moreover, explorative analyses did not find differences in the allele frequency of HAQ TMEM173 in nonvaccinated pneumococcal pneumonia patients and healthy controls or an association of HAQ TMEM173 carriage with disease severity. Together, our results indicate that the cGAS/STING pathway senses S. pneumoniae but plays no major role in antipneumococcal immunity in mice and humans.

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.

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 Nasal Tissue Extraction Is Essential for Characterization of the Murine Upper Respiratory Tract Microbiota

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
L. Patrick Schenck ◽  
Joshua J. C. McGrath ◽  
Daphnée Lamarche ◽  
Martin R. Stämpfli ◽  
Dawn M. E. Bowdish ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Research Design ◽  
Respiratory Infections ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Nasal Tissue ◽  
Colonization Success ◽  
Upper Respiratory ◽  
Nasal Microbiota

ABSTRACT Respiratory infections are a leading cause of morbidity and mortality worldwide. Bacterial pathogens often colonize the upper respiratory tract (nose or mouth) prior to causing lower respiratory infections or invasive disease. Interactions within the upper respiratory tract between colonizing bacteria and the resident microbiota could contribute to colonization success and subsequent transmission. Human carriage studies have identified associations between pathogens such as Streptococcus pneumoniae and members of the resident microbiota, although few mechanisms of competition and cooperation have been identified and would be aided by the use of animal models. Little is known about the composition of the murine nasal microbiota; thus, we set out to improve assessment, including tissue sampling, composition, and comparison between mouse sources. Nasal washes were efficient in sampling the nasopharyngeal space but barely disrupted the nasal turbinates. Nasal tissue extraction increased the yield of cultivable bacterial compared to nasal washes, revealing distinct community compositions. Experimental pneumococcal colonization led to dominance by the colonizing pathogen in the nasopharynx and nasal turbinates, but the composition of the microbiota, and interactions with resident microbes, differed depending on the sampling method. Importantly, vendor source has a large impact on microbial composition. Bacterial interactions, including cooperation and colonization resistance, depend on the biogeography of the nose and should be considered during research design of experimental colonization with pathogens. IMPORTANCE The nasal microbiota is composed of species that play a role in the colonization success of pathogens, including Streptococcus pneumoniae and Staphylococcus aureus. Murine models provide the ability to explore disease pathogenesis, but little is known about the natural murine nasal microbiota. This study established techniques to allow the exploration of the bacterial members of the nasal microbiota. The mouse nasal microbiota included traditional respiratory bacteria, including Streptococcus, Staphylococcus, and Moraxella species. Analyses were affected by different sampling methods as well as the commercial source of the mice, which should be included in future research design of infectious disease research.

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 Efficacy of Aminomethyl Spectinomycins against Complex Upper Respiratory Tract Bacterial Infections

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Amy Iverson ◽  
Christopher J. Meyer ◽  
Peter Vogel ◽  
Samanthi Waidyarachchi ◽  
Nisha Das ◽  
...  
Keyword(s):  
Single Dose ◽  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Otitis Media ◽  
Respiratory Infections ◽  
Acute Otitis Media ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Upper Respiratory

ABSTRACT The most frequent ailment for which antibiotics are prescribed is otitis media (ear infections), which is most commonly caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Treatment of otitis media is complicated by the fact that the bacteria in the middle ear typically form biofilms, which can be recalcitrant to antibiotic treatment. Furthermore, bacterial respiratory infections can be greatly exacerbated by viral coinfection, which is particularly evidenced by the synergy between influenza and S. pneumoniae. In this study, we sought to ascertain the in vivo efficacy of aminomethyl spectinomycin lead 1950, an effective antibacterial agent both in vitro and in vivo against Streptococcus pneumoniae in the context of complex respiratory infections and acute otitis media. A single dose of 1950 significantly reduced bacterial burden in the respiratory tract for all three pathogens, even when species were present in a coinfection model. Additionally, a single dose of 1950 effectively reduced pneumococcal acute otitis media from the middle ear. The agent 1950 also proved efficacious in the context of influenza-pneumococcal super infection. These data further support the development of this family of compounds as potential therapeutic agents against the common causes of complex upper respiratory tract infections and acute otitis media.

scholarly journals Streptococcus pneumoniae Colonization Disrupts the Microbial Community within the Upper Respiratory Tract of Aging Mice

2016 ◽  
Vol 84 (4) ◽  
pp. 906-916 ◽  
Author(s):  
Netusha Thevaranjan ◽  
Fiona J. Whelan ◽  
Alicja Puchta ◽  
Eta Ashu ◽  
Laura Rossi ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Bacterial Colonization ◽  
The Elderly ◽  
Rrna Gene ◽  
Host Immune System ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Increased Risk ◽  
Upper Respiratory

Nasopharyngeal colonization by the Gram-positive bacteriumStreptococcus pneumoniaeis a prerequisite for pneumonia and invasive pneumococcal diseases. Colonization is asymptomatic, involving dynamic and complex interplay between commensals, the host immune system, and environmental factors. The elderly are at an increased risk of developing pneumonia, which might be due to changes in the respiratory microbiota that would impact bacterial colonization and persistence within this niche. We hypothesized that the composition of the upper respiratory tract (URT) microbiota changes with age and subsequently can contribute to sustained colonization and inefficient clearance ofS. pneumoniae. To test this, we used a mouse model of pneumococcal colonization to compare the composition of the URT microbiota in young, middle-aged, and old mice in the naive state and during the course of colonization using nasal pharyngeal washes. Sequencing of variable region 3 (V3) of the 16S rRNA gene was used to identify changes occurring with age and throughout the course ofS. pneumoniaecolonization. We discovered that age affects the composition of the URT microbiota and that colonization withS. pneumoniaeis more disruptive of preexisting communities in older mice. We have further shown that host-pathogen interactions followingS. pneumoniaecolonization can impact the populations of resident microbes, includingStaphylococcusandHaemophilus. Together, our findings indicate alterations to the URT microbiota could be detrimental to the elderly, resulting in increased colonization ofS. pneumoniaeand decreased efficiency in its clearance.

scholarly journals Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

2016 ◽  
Vol 29 (3) ◽  
pp. 525-552 ◽  
Author(s):  
Lindsay Kim ◽  
Lesley McGee ◽  
Sara Tomczyk ◽  
Bernard Beall
Keyword(s):  
Streptococcus Pneumoniae ◽  
Population Based ◽  
Community Acquired Pneumonia ◽  
Surveillance Program ◽  
Upper Respiratory Tract ◽  
Pneumococcal Infections ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Upper Respiratory ◽  
Underlying Mechanisms

SUMMARYStreptococcus pneumoniaeinflicts a huge disease burden as the leading cause of community-acquired pneumonia and meningitis. Soon after mainstream antibiotic usage, multiresistant pneumococcal clones emerged and disseminated worldwide. Resistant clones are generated through adaptation to antibiotic pressures imposed while naturally residing within the human upper respiratory tract. Here, a huge array of related commensal streptococcal strains transfers core genomic and accessory resistance determinants to the highly transformable pneumococcus. β-Lactam resistance is the hallmark of pneumococcal adaptability, requiring multiple independent recombination events that are traceable to nonpneumococcal origins and stably perpetuated in multiresistant clonal complexes. Pneumococcal strains with elevated MICs of β-lactams are most often resistant to additional antibiotics. Basic underlying mechanisms of most pneumococcal resistances have been identified, although new insights that increase our understanding are continually provided. Although all pneumococcal infections can be successfully treated with antibiotics, the available choices are limited for some strains. Invasive pneumococcal disease data compiled during 1998 to 2013 through the population-based Active Bacterial Core surveillance program (U.S. population base of 30,600,000) demonstrate that targeting prevalent capsular serotypes with conjugate vaccines (7-valent and 13-valent vaccines implemented in 2000 and 2010, respectively) is extremely effective in reducing resistant infections. Nonetheless, resistant non-vaccine-serotype clones continue to emerge and expand.

scholarly journals Microbial Communities of the Upper Respiratory Tract and Otitis Media in Children

mBio ◽  
2011 ◽  
Vol 2 (1) ◽  
Author(s):  
Alison S. Laufer ◽  
Joshua P. Metlay ◽  
Janneane F. Gent ◽  
Kristopher P. Fennie ◽  
Yong Kong ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Microbial Communities ◽  
Otitis Media ◽  
Middle Ear ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Increased Risk ◽  
Causal Pathway ◽  
Upper Respiratory

ABSTRACTStreptococcus pneumoniaeasymptomatically colonizes the upper respiratory tract of children and is a frequent cause of otitis media. Patterns of microbial colonization likely influenceS. pneumoniaecolonization and otitis media susceptibility. This study compared microbial communities in children with and without otitis media. Nasal swabs and clinical and demographic data were collected in a cross-sectional study of Philadelphia, PA, children (6 to 78 months) (n= 108) during the 2008-2009 winter respiratory virus season. Swabs were cultured forS. pneumoniae. DNA was extracted from the swabs; 16S rRNA gene hypervariable regions (V1 and V2) were PCR amplified and sequenced by Roche/454 Life Sciences pyrosequencing. Microbial communities were described using the Shannon diversity and evenness indices. Principal component analysis (PCA) was used to group microbial community taxa into four factors representing correlated taxa. Of 108 children, 47 (44%) were colonized byS. pneumoniae, and 25 (23%) were diagnosed with otitis media. Microbial communities withS. pneumoniaewere significantly less diverse and less even. Two PCA factors were associated with a decreased risk of pneumococcal colonization and otitis media, as follows: one factor included potentially protective flora (CorynebacteriumandDolosigranulum), and the other factor includedPropionibacterium,Lactococcus, andStaphylococcus. The remaining two PCA factors were associated with an increased risk of otitis media. One factor includedHaemophilus, and the final factor includedActinomyces,Rothia,Neisseria, andVeillonella. Generally, these taxa are not considered otitis media pathogens but may be important in the causal pathway. Increased understanding of upper respiratory tract microbial communities will contribute to the development of otitis media treatment and prevention strategies.IMPORTANCEOtitis media (middle ear infection) is the most common reason for pediatric sick visits in the United States.Streptococcus pneumoniaeis a leading otitis media pathogen.S. pneumoniaemust colonize the upper respiratory tract and compete with a complex community of nonpathogenic bacteria before infecting the middle ear. We compared microbial communities in the upper respiratory tract of children who had otitis media and those who did not. Members of the normal flora, i.e.,CorynebacteriumandDolosigranulum, were protective forS. pneumoniaecolonization and otitis media. As expected, the generaHaemophiluswas associated with otitis media. Surprisingly,Actinomyces,Rothia,Neisseria, andVeillonellawere associated with an increased risk of otitis media. These bacteria are not otitis media pathogens but may be associated with antibiotic use or involved in the causal pathway to disease. Increased understanding of upper respiratory tract microbial communities will lead to new ways to prevent middle ear infections, including probiotics.

scholarly journals cGAS–STING and MyD88 Pathways Synergize in Ly6Chi Monocyte to Promote Streptococcus pneumoniae-Induced Late-Stage Lung IFNγ Production

2021 ◽  
Vol 12 ◽  
Author(s):  
Seema Patel ◽  
Heidi R. Tucker ◽  
Himanshu Gogoi ◽  
Samira Mansouri ◽  
Lei Jin
Keyword(s):  
Streptococcus Pneumoniae ◽  
Late Stage ◽  
Early Stage ◽  
Intracellular Cytokine Staining ◽  
Pneumococcal Infection ◽  
Adoptive Cell Transfer ◽  
Type I ◽  
Type I Ifns ◽  
Reporter Mice ◽  
Sting Pathway

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway senses DNA and induces type I interferon (IFN) production. Whether and how the STING pathway crosstalk to other innate immune pathways during pathogen infection, however, remains unclear. Here, we showed that STING was needed for Streptococcus pneumoniae-induced late, not early, stage of lung IFNγ production. Using knockout mice, IFNγ reporter mice, intracellular cytokine staining, and adoptive cell transfer, we showed that cGAS–STING-dependent lung IFNγ production was independent of type I IFNs. Furthermore, STING expression in monocyte/monocyte-derived cells governed IFNγ production in the lung via the production of IL-12p70. Surprisingly, DNA stimulation alone could not induce IL-12p70 or IFNγ in Ly6Chi monocyte. The production of IFNγ required the activation by both DNA and heat-killed S. pneumococcus. Accordingly, MyD88−/− monocyte did not generate IL-12p70 or IFNγ. In summary, the cGAS–STING pathway synergizes with the MyD88 pathway in monocyte to promote late-stage lung IFNγ production during pulmonary pneumococcal infection.

scholarly journals Complete Genome Sequence of Streptococcus pneumoniae Virulent Phage MS1

2017 ◽  
Vol 5 (28) ◽  
Author(s):  
Witold Kot ◽  
Mourad Sabri ◽  
Hélène Gingras ◽  
Marc Ouellette ◽  
Denise M. Tremblay ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Tract Infection ◽  
Respiratory Tract ◽  
Throat Swab ◽  
Open Reading Frames ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Virulent Phage ◽  
Upper Respiratory ◽  
Reading Frames

ABSTRACT The lytic Streptococcus pneumoniae phage MS1 was isolated from a throat swab of a patient with symptoms of upper respiratory tract infection. The genome of this siphophage has 56,075 bp, 42.3% G+C content, and 77 open reading frames, including queuosine biosynthesis genes. Phage MS1 is related to pneumococcal phage Dp-1.

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