Daniel P. Miller

Bio: Daniel P. Miller is an academic researcher from University of Louisville. The author has contributed to research in topics: Porphyromonas gingivalis & Phosphorylation. The author has an hindex of 9, co-authored 15 publications receiving 220 citations.

Metabolic crosstalk regulates Porphyromonas gingivalis colonization and virulence during oral polymicrobial infection.

Abstract: Many human infections are polymicrobial in origin, and interactions among community inhabitants shape colonization patterns and pathogenic potential 1 . Periodontitis, which is the sixth most prevalent infectious disease worldwide 2 , ensues from the action of dysbiotic polymicrobial communities 3 . The keystone pathogen Porphyromonas gingivalis and the accessory pathogen Streptococcus gordonii interact to form communities in vitro and exhibit increased fitness in vivo 3,4 . The mechanistic basis of this polymicrobial synergy, however, has not been fully elucidated. Here we show that streptococcal 4-aminobenzoate/para-amino benzoic acid (pABA) is required for maximal accumulation of P. gingivalis in dual-species communities. Metabolomic and proteomic data showed that exogenous pABA is used for folate biosynthesis, and leads to decreased stress and elevated expression of fimbrial adhesins. Moreover, pABA increased the colonization and survival of P. gingivalis in a murine oral infection model. However, pABA also caused a reduction in virulence in vivo and suppressed extracellular polysaccharide production by P. gingivalis. Collectively, these data reveal a multidimensional aspect to P. gingivalis-S. gordonii interactions and establish pABA as a critical cue produced by a partner species that enhances the fitness of P. gingivalis while diminishing its virulence.

Streptococcus gordonii programs epithelial cells to resist ZEB2 induction by Porphyromonas gingivalis

Abstract: The polymicrobial microbiome of the oral cavity is a direct precursor of periodontal diseases, and changes in microhabitat or shifts in microbial composition may also be linked to oral squamous cell carcinoma. Dysbiotic oral epithelial responses provoked by individual organisms, and which underlie these diseases, are widely studied. However, organisms may influence community partner species through manipulation of epithelial cell responses, an aspect of the host microbiome interaction that is poorly understood. We report here that Porphyromonas gingivalis, a keystone periodontal pathogen, can up-regulate expression of ZEB2, a transcription factor which controls epithelial–mesenchymal transition and inflammatory responses. ZEB2 regulation by P. gingivalis was mediated through pathways involving β-catenin and FOXO1. Among the community partners of P. gingivalis, Streptococcus gordonii was capable of antagonizing ZEB2 expression. Mechanistically, S. gordonii suppressed FOXO1 by activating the TAK1-NLK negative regulatory pathway, even in the presence of P. gingivalis. Collectively, these results establish S. gordonii as homeostatic commensal, capable of mitigating the activity of a more pathogenic organism through modulation of host signaling.

Genes Contributing to Porphyromonas gingivalis Fitness in Abscess and Epithelial Cell Colonization Environments

Abstract: Porphyromonas gingivalis is an important cause of serious periodontal diseases, and is emerging as a pathogen in several systemic conditions including some forms of cancer. Initial colonization by P. gingivalis involves interaction with gingival epithelial cells, and the organism can also access host tissues and spread haematogenously. To better understand the mechanisms underlying these properties, we utilized a highly saturated transposon insertion library of P. gingivalis, and assessed the fitness of mutants during epithelial cell colonization and survival in a murine abscess model by high-throughput sequencing (Tn-Seq). Transposon insertions in many genes previously suspected as contributing to virulence showed significant fitness defects in both screening assays. In addition, a number of genes not previously associated with P. gingivalis virulence were identified as important for fitness. We further examined fitness defects of four such genes by generating defined mutations. Genes encoding a carbamoyl phosphate synthetase, a replication-associated recombination protein, a nitrosative stress responsive HcpR transcription regulator, and RNase Z, a zinc phosphodiesterase, showed a fitness phenotype in epithelial cell colonization and in a competitive abscess infection. This study verifies the importance of several well-characterized putative virulence factors of P. gingivalis and identifies novel fitness determinants of the organism.

Insights into Dynamic Polymicrobial Synergy Revealed by Time-Coursed RNA-Seq.

Abstract: Many bacterial infections involve polymicrobial communities in which constituent organisms are synergistically pathogenic. Periodontitis, a commonly occurring chronic inflammatory disorder, is induced by multispecies bacterial communities. The periodontal keystone pathogen Porphyromonas gingivalis and the accessory pathogen Streptococcus gordonii exhibit polymicrobial synergy in animal models of disease. Mechanisms of co-adhesion and community formation by P. gingivalis and S. gordonii are well-established; however, little is known regarding the basis for increased pathogenicity. In this study we used time-coursed RNA-Seq to comprehensively and quantitatively examine the dynamic transcriptional landscape of P. gingivalis in a model consortium with S. gordonii. Genes encoding a number of potential virulence determinants had higher relative mRNA levels in the context of dual species model communities than P. gingivalis alone, including adhesins, the Type IX secretion apparatus, and tetratricopeptide repeat (TPR) motif proteins. In contrast, genes encoding conjugation systems and many of the stress responses showed lower levels of expression in P. gingivalis. A notable exception to reduced abundance of stress response transcripts was the genes encoding components of the oxidative stress-related OxyR regulon, indicating an adaptation of P. gingivalis to detoxify peroxide produced by the streptococcus. Collectively, the results are consistent with evolutionary adaptation of P. gingivalis to a polymicrobial oral environment, one outcome of which is increased pathogenic potential.

The oral microbiota: dynamic communities and host interactions.

Abstract: The dynamic and polymicrobial oral microbiome is a direct precursor of diseases such as dental caries and periodontitis, two of the most prevalent microbially induced disorders worldwide. Distinct microenvironments at oral barriers harbour unique microbial communities, which are regulated through sophisticated signalling systems and by host and environmental factors. The collective function of microbial communities is a major driver of homeostasis or dysbiosis and ultimately health or disease. Despite different aetiologies, periodontitis and caries are each driven by a feedforward loop between the microbiota and host factors (inflammation and dietary sugars, respectively) that favours the emergence and persistence of dysbiosis. In this Review, we discuss current knowledge and emerging mechanisms governing oral polymicrobial synergy and dysbiosis that have both enhanced our understanding of pathogenic mechanisms and aided the design of innovative therapeutic approaches for oral diseases.

The annual meeting of the federation of american societies for experimental biology

Abstract: HOBOKEN, N.J.--(BUSINESS WIRE)--John Wiley and Sons Inc. (NYSE:JWA) (NYSE:JWB), in partnership with the Federation of American Societ ies for Experimental Biology (FASEB), is pleased to announce a new peer-reviewed, open access journal, FASEB BioAdvances. Launching in 2018 as part of the Wiley Open Access portfolio, FASEB BioAdvances will be edited by Jasna Markovac, Ph.D., of the University of Michigan and California Inst itute of Technology. Dr. Markovac will serve as the publicat ion’s Founding Editor and will lead the effort for the journal on publishing mult i / transdisciplinary research reports from the international community.

On ‘On binding’

Abstract: In 'On binding', Chomsky reformulates the Propositional Island Condition and the Specified Subject Condition as conditions on logical form, called the Nominative Island Condition (NIC) and the Opacity Condition (OC), respectively. He also replaces cyclic nodes by 'bounding' nodes in the formulation of the Subjacency Condition. An investigation of NIC and OC shows that the claim that they are universal is virtually empty and that they cannot be regarded as natural conditions. Furthermore, they account for a quite limited range of data and the mechanisms that have been proposed to supplement them are ad hoc or problematic in other ways. Subjacency is no more satisfactory. It seems unable to account for various relevant facts. A consideration of these issues suggests that some of Chomsky's most basic assumptions should be abandoned and that more concrete frameworks are likely to prove more adequate. On binding' (Chomsky, 1980) represents an important new stage in the development of the ideas that Chomsky has been exploring since 'Conditions on transformations' (Chomsky, 1973). It introduces two important innovations. One, which forms the central theme of the paper, is the reformulation of the Propositional Island Condition (PIC) and the Specified Subject Condition (SSC) as conditions on logical form, called the Nominative Island Condition (NIC) and the Opacity Condition (OC), respectively. The other, which is rather less prominent but of comparable importance, is the replacement of cyclic nodes by 'bounding' nodes in the formulation of the Subjacency Condition. In this paper, we will take a critical look at the theoretical framework which Chomsky outlines in his paper. Chomsky suggests that the On binding' framework constitutes 'a highly unified theory, with a few abstract principles governing a wide range of phenomena' (1980: 10). We will argue that this assessment is Linguistics 19 (1981), 1133-1164. 0024-3949/81/0019-1133 $2.00 © Mouton Publishers 1134 R. D. Borsley and G. M. H rn untenable. We will develop a number of criticisms of NIC and OC, and the Subjacency Condition. These criticisms not only argue against Chomsky's assessment of the On binding' theory but also cast doubt on the general approach to syntax which Chomsky is pursuing. In our view, this approach compares unfavourably with the less abstract approaches developed in Bresnan (1978) and Horn (1979, to appear). We cannot discuss this matter in detail here but we will touch on it in a number of places. Since On binding' was written, numerous papers have appeared which revise and extend Chomsky's proposals. We will make no attempt to survey this literature. We will, however, consider some of the changes which Chomsky himself proposes in his Lectures on Government and Binding (Chomsky, 1981). In this work, which appeared when the present paper was largely complete, Chomsky develops a somewhat different framework, which he calls the government binding theory. Some of the criticisms that we advance against the On binding' theory are not applicable to the new theory. Others, however, remain valid. We will comment on this matter where appropriate. The paper is organised as follows. In section 1, we will consider the basic nature of the conditions. We will argue that the claim that they are universal is virtually unfalsifiable and that they cannot be regarded as natural conditions. In section 2, we will consider the supposed motivation for the conditions. We will show that they leave many facts unaccounted for and that the additional mechanisms that have been proposed to supplement them are ad hoc or problematic in other ways. Finally, in section 3, we will consider the Subjacency Condition. We will show that it too is effectively unfalsifiable and, more importantly, that it cannot provide an illuminating account of the various facts that it is supposed to handle. 1. The nature of NIC and OC In essence, the reformulation of PIC and SSC as conditions on logical form is an attempt to make concrete the view advanced in Chomsky (1977) that they should be seen not as general conditions on rule application but as conditions on anaphora. The new conditions are formulated as follows: (1) The Nominative Island Condition: A nominative anaphor cannot be free in S. (2) The Opacity Condition: If α is in the domain of the subject of β, β minimal, then α cannot be free in β.

Oral Microbiome and SARS-CoV-2: Beware of Lung Co-infection

Abstract: The new coronavirus SARS-CoV-2, the cause of COVID-19, has become a public health emergency of global concern. Like the SARS and influenza pandemics, there have been a large number of cases coinfected with other viruses, fungi, and bacteria, some of which originate from the oral cavity. Capnocytophaga, Veillonella, and other oral opportunistic pathogens were found in the BALF of the COVID-19 patients by mNGS. Risk factors such as poor oral hygiene, cough, increased inhalation under normal or abnormal conditions, and mechanical ventilation provide a pathway for oral microorganisms to enter the lower respiratory tract and thus cause respiratory disease. Lung hypoxia, typical symptoms of COVID-19, would favor the growth of anaerobes and facultative anaerobes originating from the oral microbiota. SARS-CoV-2 may aggravate lung disease by interacting with the lung or oral microbiota via mechanisms involving changes in cytokines, T cell responses, and the effects of host conditions such as aging and the oral microbiome changes due to systemic diseases. Because the oral microbiome is closely associated with SARS-CoV-2 co-infections in the lungs, effective oral health care measures are necessary to reduce these infections, especially in severe COVID-19 patients. We hope this review will draw attention from both the scientific and clinical communities on the role of the oral microbiome in the current global pandemic.