Faculty Bibliography
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124
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2019:116(17):8493-8498.DOI: 10.1073/pnas.1818522116
Regenerative therapy based on miRNA-302 mimics for enhancing host recovery from pneumonia caused by Streptococcus pneumoniae
Bacterial pneumonia remains a leading cause of morbidity and mortality worldwide. A defining feature of pneumonia is lung injury, leading to protracted suffering and vulnerability long after bacterial clearance. Little is known about which cells are damaged during bacterial pneumonia and if the regenerative process can be harnessed to promote tissue repair and host recovery. Here, we show that infection of mice with Streptococcus pneumoniae (Sp) caused substantial damage to alveolar epithelial cells (AEC), followed by a slow process of regeneration. Concurrent with AEC regeneration, the expression of miRNA-302 is elevated in AEC. Treatment of Sp-infected mice with miRNA-302 mimics improved lung functions, host recovery, and survival. miRNA-302 mediated its therapeutic effects, not by inhibiting apoptosis and preventing damage, but by promoting proliferation of local epithelial progenitor cells to regenerate AEC. These results demonstrate the ability of microRNA-based therapy to promote AEC regeneration and enhance host recovery from bacterial pneumonia.
PMID: 30971494
ISSN: 1091-6490
CID: 3809282
Fast and flexible bacterial genomic epidemiology with PopPUNK
The routine use of genomics for disease surveillance provides the opportunity for high-resolution bacterial epidemiology. Current whole-genome clustering and multilocus typing approaches do not fully exploit core and accessory genomic variation, and they cannot both automatically identify, and subsequently expand, clusters of significantly similar isolates in large data sets spanning entire species. Here, we describe PopPUNK (Population Partitioning Using Nucleotide
PMID: 30679308
ISSN: 1549-5469
CID: 3610722
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2019:116(5):1745-1754.DOI: 10.1073/pnas.1814265116
Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus
The past two decades have witnessed an alarming expansion of staphylococcal disease caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The factors underlying the epidemic expansion of CA-MRSA lineages such as USA300, the predominant CA-MRSA clone in the United States, are largely unknown. Previously described virulence and antimicrobial resistance genes that promote the dissemination of CA-MRSA are carried by mobile genetic elements, including phages and plasmids. Here, we used high-resolution genomics and experimental infections to characterize the evolution of a USA300 variant plaguing a patient population at increased risk of infection to understand the mechanisms underlying the emergence of genetic elements that facilitate clonal spread of the pathogen. Genetic analyses provided conclusive evidence that fitness (manifest as emergence of a dominant clone) changed coincidently with the stepwise emergence of (i) a unique prophage and mutation of the regulator of the pyrimidine nucleotide biosynthetic operon that promoted abscess formation and colonization, respectively, thereby priming the clone for success; and (ii) a unique plasmid that conferred resistance to two topical microbiocides, mupirocin and chlorhexidine, frequently used for decolonization and infection prevention. The resistance plasmid evolved through successive incorporation of DNA elements from non-S. aureus spp. into an indigenous cryptic plasmid, suggesting a mechanism for interspecies genetic exchange that promotes antimicrobial resistance. Collectively, the data suggest that clonal spread in a vulnerable population resulted from extensive clinical intervention and intense selection pressure toward a pathogen lifestyle that involved the evolution of consequential mutations and mobile genetic elements.
PMID: 30635416
ISSN: 1091-6490
CID: 3580072
Pneumococcal quorum sensing drives an asymmetric owner-intruder competitive strategy during carriage via the competence regulon
Competition among microorganisms is a key determinant of successful host colonization and persistence. For Streptococcus pneumoniae, lower than predicted rates of co-colonizing strains suggest a competitive advantage for resident bacteria over newcomers. In light of evolutionary theory, we hypothesized that S. pneumoniae use owner-intruder asymmetries to settle contests, leading to the disproportionate success of the initial resident 'owner', regardless of the genetic identity of the 'intruder'. We investigated the determinants of within-host competitive success utilizing S. pneumoniae colonization of the upper respiratory tract of infant mice. Within 6 h, colonization by the resident inhibited colonization by an isogenic challenger. The competitive advantage of the resident was dependent on quorum sensing via the competence (Com) regulon and downstream choline binding protein D (CbpD) and on the competence-induced bacteriocins A and B (CibAB) implicated in fratricide. CbpD and CibAB are highly conserved across pneumococcal lineages, indicating evolutionary advantages for asymmetric competitive strategies within the species. Mathematical modelling supported a significant role for quorum sensing via the Com regulon in competition, even for strains with different competitive advantages. Our study suggests that asymmetric owner-intruder competitive strategies do not require complex cognition and are used by a major human pathogen to determine 'ownership' of human hosts.
PMID: 30546100
ISSN: 2058-5276
CID: 3554882
An Infant Mouse Model of Influenza Virus Transmission Demonstrates the Role of Virus-Specific Shedding, Humoral Immunity, and Sialidase Expression by Colonizing Streptococcus pneumoniae
The pandemic potential of influenza A viruses (IAV) depends on the infectivity of the host, transmissibility of the virus, and susceptibility of the recipient. While virus traits supporting IAV transmission have been studied in detail using ferret and guinea pig models, there is limited understanding of host traits determining transmissibility and susceptibility because current animal models of transmission are not sufficiently tractable. Although mice remain the primary model to study IAV immunity and pathogenesis, the efficiency of IAV transmission in adult mice has been inconsistent. Here we describe an infant mouse model that supports efficient transmission of IAV. We demonstrate that transmission in this model requires young age, close contact, shedding of virus particles from the upper respiratory tract (URT) of infected pups, the use of a transmissible virus strain, and a susceptible recipient. We characterize shedding as a marker of infectiousness that predicts the efficiency of transmission among different influenza virus strains. We also demonstrate that transmissibility and susceptibility to IAV can be inhibited by humoral immunity via maternal-infant transfer of IAV-specific immunoglobulins and modifications to the URT milieu, via sialidase activity of colonizing Streptococcus pneumoniae Due to its simplicity and efficiency, this model can be used to dissect the host's contribution to IAV transmission and explore new methods to limit contagion.IMPORTANCE This study provides insight into the role of the virus strain, age, immunity, and URT flora on IAV shedding and transmission efficiency. Using the infant mouse model, we found that (i) differences in viral shedding of various IAV strains are dependent on specific hemagglutinin (HA) and/or neuraminidase (NA) proteins, (ii) host age plays a key role in the efficiency of IAV transmission, (iii) levels of IAV-specific immunoglobulins are necessary to limit infectiousness, transmission, and susceptibility to IAV, and (iv) expression of sialidases by colonizing S. pneumoniae antagonizes transmission by limiting the acquisition of IAV in recipient hosts. Our findings highlight the need for strategies that limit IAV shedding and the importance of understanding the function of the URT bacterial composition in IAV transmission. This work reinforces the significance of a tractable animal model to study both viral and host traits affecting IAV contagion and its potential for optimizing vaccines and therapeutics that target disease spread.
PMID: 30563897
ISSN: 2150-7511
CID: 3556562
pyseer: a comprehensive tool for microbial pangenome-wide association studies
Summary/UNASSIGNED:Genome-wide association studies (GWAS) in microbes have different challenges to GWAS in eukaryotes. These have been addressed by a number of different methods. pyseer brings these techniques together in one package tailored to microbial GWAS, allows greater flexibility of the input data used, and adds new methods to interpret the association results. Availability and implementation/UNASSIGNED:pyseer is written in python and is freely available at https://github.com/mgalardini/pyseer, or can be installed through pip. Documentation and a tutorial are available at http://pyseer.readthedocs.io. Supplementary information/UNASSIGNED:Supplementary data are available at Bioinformatics online.
PMCID:6289128
PMID: 30535304
ISSN: 1367-4811
CID: 3556312
Age-related differences in IL-1 signaling and capsule serotype affect persistence of Streptococcus pneumoniae colonization
Young age is a risk factor for prolonged colonization by common pathogens residing in their upper respiratory tract (URT). Why children present with more persistent colonization is unknown and there is relatively little insight into the host-pathogen interactions that contribute to persistent colonization. To identify factors permissive for persistent colonization during infancy, we utilized an infant mouse model of Streptococcus pneumoniae colonization in which clearance from the mucosal surface of the URT requires many weeks to months. Loss of a single bacterial factor, the pore-forming toxin pneumolysin (Ply), and loss of a single host factor, IL-1α, led to more persistent colonization. Exogenous administration of Ply promoted IL-1 responses and clearance, and intranasal treatment with IL-1α was sufficient to reduce colonization density. Major factors known to affect the duration of natural colonization include host age and pneumococcal capsular serotype. qRT-PCR analysis of the uninfected URT mucosa showed reduced baseline expression of genes involved in IL-1 signaling in infant compared to adult mice. In line with this observation, IL-1 signaling was important in initiating clearance in adult mice but had no effect on early colonization of infant mice. In contrast to the effect of age, isogenic constructs of different capsular serotype showed differences in colonization persistence but induced similar IL-1 responses. Altogether, this work underscores the importance of toxin-induced IL-1α responses in determining the outcome of colonization, clearance versus persistence. Our findings about IL-1 signaling as a function of host age may provide an explanation for the increased susceptibility and more prolonged colonization during early childhood.
PMID: 30379943
ISSN: 1553-7374
CID: 3400412
Streptococcus pneumoniae: transmission, colonization and invasion
Streptococcus pneumoniae has a complex relationship with its obligate human host. On the one hand, the pneumococci are highly adapted commensals, and their main reservoir on the mucosal surface of the upper airways of carriers enables transmission. On the other hand, they can cause severe disease when bacterial and host factors allow them to invade essentially sterile sites, such as the middle ear spaces, lungs, bloodstream and meninges. Transmission, colonization and invasion depend on the remarkable ability of S. pneumoniae to evade or take advantage of the host inflammatory and immune responses. The different stages of pneumococcal carriage and disease have been investigated in detail in animal models and, more recently, in experimental human infection. Furthermore, widespread vaccination and the resulting immune pressure have shed light on pneumococcal population dynamics and pathogenesis. Here, we review the mechanistic insights provided by these studies on the multiple and varied interactions of the pneumococcus and its host.
PMCID:5949087
PMID: 29599457
ISSN: 1740-1534
CID: 3011602
The neonatal window of opportunity-early priming for life [Editorial]
PMID: 29247715
ISSN: 1097-6825
CID: 3027142
Capsule prolongs survival of Streptococcus pneumoniae during starvation
Person-to-person transmission of Streptococcus pneumoniae (the pneumococcus) may occur via environmental sources in close contact with carriers. Pneumococcal polysaccharide capsules, the determinant of serotype (or type), are heterogeneous in structure and amount and these differences affect rates of transmission. In this study, we examined the contribution of capsule and its variations to the maintenance of pneumococcal viability under starvation conditions. S. pneumoniae retained its ability to colonize infant mice even after incubation for 24hrs in PBS at 25°C. The expression of capsule by the cps locus prolonged survival under these and other nutrient-poor conditions. Analysis of capsule-switch constructs showed that strain-to-strain differences in survival were due to capsule type rather than genetic background. The addition of glucose was sufficient to rescue the survival defect of the capsule-deficient derivative demonstrating that in the absence of capsule survival depends upon nutrient availability. During starvation, there was a decrease in capsule size and amount of capsular polysaccharide that was dependent on bacterial viability and the presence of the cps locus. These observations suggest that pneumococci catabolize their own capsular polysaccharide using the genes involved in its biosynthesis to maintain viability when other carbon sources are unavailable. Our findings describe a new role of the pneumococcal capsule; the prolongation of viability under nutrient limiting conditions as would be encountered during periods when the organism is between hosts.
PMCID:5820961
PMID: 29311231
ISSN: 1098-5522
CID: 2906512
