Pretreatment With Fluticasone Propionate Increases Antibiotic Efficacy During Treatment of Late-Stage Primary Pneumonic Plague

Severe and late-stage pneumonias are often difficult to treat with antibiotics alone due to overwhelming host inflammatory responses mounted to clear infection. These host responses contribute to pulmonary damage leading to acute lung injury, acute respiratory distress syndrome, and death. In order to effectively treat severe and late-stage pneumonias, use of adjunctive therapies must be considered to reduce pulmonary damage when antimicrobial agents can be administered. Pneumonic plague, a severe pneumonia caused by inhalation of Yersinia pestis , is a fatal disease that causes death within six days without antibiotic intervention. Late-stage pneumonic plague is difficult to treat, as antibiotics must be delivered within 24 hours after onset of symptoms to be effective. Here, we use a murine model of primary pneumonic plague to examine how host inflammatory responses impact antibiotic treatment of late-stage pneumonic plague. We developed a murine infection model demonstrating the poor outcomes associated with delayed delivery of antibiotics. We show that pretreatment of mice with intranasal fluticasone propionate increased efficacy of delayed antibiotic delivery and enhanced murine survival. Mice receiving fluticasone propionate also showed decreased bacterial burden and reduced inflammatory pathology in the lungs. Further, we show that treatment and survival correlated with decreased levels of IL-6 and reduced neutrophil infiltration to the lungs. This work demonstrates how host inflammatory responses complicate treatment of late-stage pneumonic plague, and suggests that targeting of host inflammatory responses may improve treatment of severe, late-stage pneumonia.

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STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters

Nature Communications ◽

10.1038/s41467-020-19684-y ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Robbert Boudewijns ◽

Hendrik Jan Thibaut ◽

Suzanne J. F. Kaptein ◽

Rong Li ◽

Valentijn Vergote ◽

...

Keyword(s):

Inflammatory Responses ◽

Severe Pneumonia ◽

Neutrophil Infiltration ◽

Innate Immune ◽

Micro Ct ◽

Virus Dissemination ◽

The One ◽

Interferon Responses ◽

New Strategies ◽

Severe Lung

AbstractEmergence of SARS-CoV-2 causing COVID-19 has resulted in hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that Syrian hamsters, in contrast to mice, are highly permissive to SARS-CoV-2 and develop bronchopneumonia and strong inflammatory responses in the lungs with neutrophil infiltration and edema, further confirmed as consolidations visualized by micro-CT alike in clinical practice. Moreover, we identify an exuberant innate immune response as key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.

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Between Amyloids and Aggregation Lies a Connection with Strength and Adhesion

New Journal of Science ◽

10.1155/2014/815102 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 14

Author(s):

Peter N. Lipke ◽

Caleen Ramsook ◽

Melissa C. Garcia-Sherman ◽

Desmond N. Jackson ◽

Cho X. J. Chan ◽

...

Keyword(s):

Inflammatory Responses ◽

Human Infection ◽

Fiber Formation ◽

Host Responses ◽

Infection Model ◽

High Avidity ◽

Force Microscopy ◽

Atomic Force ◽

Fungal Adhesins

We tell of a journey that led to discovery of amyloids formed by yeast cell adhesins and their importance in biofilms and host immunity. We begin with the identification of the adhesin functional amyloid-forming sequences that mediate fiber formation in vitro. Atomic force microscopy and confocal microscopy show 2-dimensional amyloid “nanodomains” on the surface of cells that are activated for adhesion. These nanodomains are arrays of adhesin molecules that bind multivalent ligands with high avidity. Nanodomains form when adhesin molecules are stretched in the AFM or under laminar flow. Treatment with anti-amyloid perturbants or mutation of the amyloid sequence prevents adhesion nanodomain formation and activation. We are now discovering biological consequences. Adhesin nanodomains promote formation and maintenance of biofilms, which are microbial communities. Also, in abscesses within candidiasis patients, we find adhesin amyloids on the surface of the fungi. In both human infection and a Caenorhabditis elegans infection model, the presence of fungal surface amyloids elicits anti-inflammatory responses. Thus, this is a story of how fungal adhesins respond to extension forces through formation of cell surface amyloid nanodomains, with key consequences for biofilm formation and host responses.

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In Vivo Transcriptional Profiling of Yersinia pestis Reveals a Novel Bacterial Mediator of Pulmonary Inflammation

mBio ◽

10.1128/mbio.02302-14 ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 14

Author(s):

Roger D. Pechous ◽

Christopher A. Broberg ◽

Nikolas M. Stasulli ◽

Virginia L. Miller ◽

William E. Goldman

Keyword(s):

Yersinia Pestis ◽

Inflammatory Responses ◽

Severe Pneumonia ◽

Sudden Onset ◽

Host Factors ◽

Respiratory Pathogen ◽

Bacterial Survival ◽

Pneumonic Plague ◽

Content Type

ABSTRACTInhalation ofYersinia pestisresults in primary pneumonic plague, a highly lethal and rapidly progressing necrotizing pneumonia. The disease begins with a period of extensive bacterial replication in the absence of disease symptoms, followed by the sudden onset of inflammatory responses that ultimately prove fatal. Very little is known about the bacterial and host factors that contribute to the rapid biphasic progression of pneumonic plague. In this work, we analyzed thein vivotranscription kinetics of 288 bacterial open reading frames previously shown by microarray analysis to be dynamically regulated in the lung. Using this approach combined with bacterial genetics, we were able to identify five Y. pestis genes that contribute to the development of pneumonic plague. Deletion of one of these genes,ybtX, did not alter bacterial survival but attenuated host inflammatory responses during late-stage disease. Deletion ofybtXin another lethal respiratory pathogen,Klebsiella pneumoniae, also resulted in diminished host inflammation during infection. Thus, ourin vivotranscriptional screen has identified an important inflammatory mediator that is common to two Gram-negative bacterial pathogens that cause severe pneumonia.IMPORTANCEYersinia pestis is responsible for at least three major pandemics, most notably the Black Death of the Middle Ages. Due to its pandemic potential, ease of dissemination by aerosolization, and a history of its weaponization, Y. pestis is categorized by the Centers for Disease Control and Prevention as a tier 1 select agent most likely to be used as a biological weapon. To date, there is no licensed vaccine against Y. pestis. Importantly, an early “silent” phase followed by the rapid onset of nondescript influenza-like symptoms makes timely treatment of pneumonic plague difficult. A more detailed understanding of the bacterial and host factors that contribute to pathogenesis is essential to understanding the progression of pneumonic plague and developing or enhancing treatment options.

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Biofilm Growth Increases Phosphorylcholine Content and Decreases Potency of Nontypeable Haemophilus influenzae Endotoxins

Infection and Immunity ◽

10.1128/iai.74.3.1828-1836.2006 ◽

2006 ◽

Vol 74 (3) ◽

pp. 1828-1836 ◽

Cited By ~ 42

Author(s):

Shayla West-Barnette ◽

Andrea Rockel ◽

W. Edward Swords

Keyword(s):

Haemophilus Influenzae ◽

Inflammatory Responses ◽

Opportunistic Pathogen ◽

Host Responses ◽

Toll Like Receptor ◽

Nontypeable Haemophilus Influenzae ◽

Toll Like Receptor 4 ◽

Biofilm Growth ◽

Bacterial Endotoxins ◽

Cell Layers

ABSTRACT Nontypeable Haemophilus influenzae (NTHI) is a common respiratory commensal and opportunistic pathogen. NTHI is normally contained within the airways by host innate defenses that include recognition of bacterial endotoxins by Toll-like receptor 4 (TLR4). NTHI produces lipooligosaccharide (LOS) endotoxins which lack polymeric O side chains and which may contain host glycolipids. We recently showed that NTHI biofilms contain variants with sialylated LOS glycoforms that are essential to biofilm formation. In this study, we show that NTHI forms biofilms on epithelial cell layers. Confocal analysis revealed that sialylated variants were distributed throughout the biofilm, while variants expressing phosphorylcholine (PCho) were found within the biofilm. Consistent with this observation, PCho content of LOS purified from NTHI biofilms was increased compared to LOS from planktonic cultures. Hypothesizing that the observed changes in endotoxin composition could affect bioactivity, we compared inflammatory responses to NTHI LOS purified from biofilm and planktonic cultures. Our results show that endotoxins from biofilms induced weaker host innate responses. While we observed a minimal effect of sialylation on LOS bioactivity, there was a significant decrease in bioactivity associated with PCho substitutions. We thus conclude that biofilm growth increases the proportion of PCho+ variants in an NTHI population, resulting in a net decrease in LOS bioactivity. Thus, in addition to their well-documented resistance phenotypes, our data show that biofilm communities of NTHI bacteria contain variants that evoke less potent host responses.

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Study of the effect exerted by fructo-oligosaccharides from yacon (Smallanthus sonchifolius) root flour in an intestinal infection model with Salmonella Typhimurium

British Journal Of Nutrition ◽

10.1017/s0007114512004230 ◽

2012 ◽

Vol 109 (11) ◽

pp. 1971-1979 ◽

Cited By ~ 11

Author(s):

Eva Velez ◽

Natalia Castillo ◽

Oscar Mesón ◽

Alfredo Grau ◽

María E. Bibas Bonet ◽

...

Keyword(s):

Mouse Model ◽

Protective Effect ◽

Salmonella Enteritidis ◽

Inflammatory Responses ◽

Intestinal Barrier ◽

Secretory Iga ◽

Infection Model ◽

Enteric Infection ◽

Smallanthus Sonchifolius ◽

Iga Production

Beneficial effects of prebiotics like inulin and fructo-oligosaccharides (FOS) have been proven in health and nutrition. Yacon (Smallanthus sonchifolius), an Andean crop, contains FOS (50–70 % of its dry weight) and, therefore, is considered a prebiotic. Commercial FOS can up-regulate total secretory IgA (S-IgA) in infant mice, prevent infection with Salmonella in swine or enhance immune response for Salmonella vaccine in a mouse model. Previously, we found that administration of yacon root flour regulates gut microbiota balance and has immunomodulatory effects without inflammatory responses. The aim of the present paper is to analyse if yacon prevents enteric infection caused by a strain of Salmonella enteritidis serovar Typhimurium (S. Typhimurium) in a mouse model. BALB/c mice were supplemented with yacon flour (45 d), challenged with S. Typhimurium and killed to study pathogen translocation, total and specific IgA production by ELISA, presence of IgA and other cytokines and Toll-like receptor 4 (TLR4) and clustor of differentiation 206 (CD206) receptors positive cells by immunofluorescence and histological changes. Yacon flour administration had a protective effect from 15 to 30 d of treatment. We found a peak of total S-IgA production without translocation of the pathogen for these periods. At 30 d, there was an increase in IL-6 and macrophage inflammatory proteins-1α+ cells and expression of the receptors CD206 and TLR4. Yacon flour did not have incidence in pathogen-specific S-IgA production. Longer periods (45 d) of administration had no protective effect. Therefore, yacon can prevent enteric infection caused by S. Typhimurium when given up to 30 d; this effect would be mediated by enhancing non-specific immunity, such as total S-IgA, that improves the immunological intestinal barrier.

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In VivoEfficacy of Anuran Trypsin Inhibitory Peptides against Staphylococcal Skin Infection and the Impact of Peptide Cyclization

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04324-14 ◽

2015 ◽

Vol 59 (4) ◽

pp. 2113-2121 ◽

Cited By ~ 9

Author(s):

U. Malik ◽

O. N. Silva ◽

I. C. M. Fensterseifer ◽

L. Y. Chan ◽

R. J. Clark ◽

...

Keyword(s):

Antimicrobial Agents ◽

Cyclic Peptide ◽

Sequence Similarity ◽

Infection Model ◽

Content Type ◽

Wide Range ◽

Inhibitory Activities ◽

The Impact

ABSTRACTStaphylococcus aureusis a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weakin vitroinhibitory activities againstS. aureus, but several had strong antibacterial activities againstS. aureusin anin vivomurine wound infection model. pYR, an immunomodulatory peptide fromRana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg−1. Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.

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Circulating microbial cell-free DNA is associated with inflammatory host-responses in severe pneumonia

Thorax ◽

10.1136/thoraxjnl-2020-216013 ◽

2021 ◽

pp. thoraxjnl-2020-216013

Author(s):

Haopu Yang ◽

Ghady Haidar ◽

Nameer S Al-Yousif ◽

Haris Zia ◽

Daniel Kotok ◽

...

Keyword(s):

Large Scale ◽

Inflammatory Responses ◽

Severe Pneumonia ◽

Systemic Circulation ◽

Microbial Cell ◽

Metagenomic Sequencing ◽

Cell Free Dna ◽

Free Dna ◽

Culture Positive ◽

Culture Negative

Host inflammatory responses predict worse outcome in severe pneumonia, yet little is known about what drives dysregulated inflammation. We performed metagenomic sequencing of microbial cell-free DNA (mcfDNA) in 83 mechanically ventilated patients (26 culture-positive, 41 culture-negative pneumonia, 16 uninfected controls). Culture-positive patients had higher levels of mcfDNA than those with culture-negative pneumonia and uninfected controls (p<0.005). Plasma levels of inflammatory biomarkers (fractalkine, procalcitonin, pentraxin-3 and suppression of tumorigenicity-2) were independently associated with mcfDNA levels (adjusted p<0.05) among all patients with pneumonia. Such host–microbe interactions in the systemic circulation of patients with severe pneumonia warrant further large-scale clinical and mechanistic investigations.

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3-methyadenine inhibits lipopolysaccharides-induced pulmonary inflammation at the early stage of silicosis via blocking NF-κB signaling pathway

Toxicology and Industrial Health ◽

10.1177/07482337211039426 ◽

2021 ◽

pp. 074823372110394

Author(s):

Yujing Zhang ◽

Shuai Huang ◽

Shiyi Tan ◽

Mingke Chen ◽

Shang Yang ◽

...

Keyword(s):

Lung Injury ◽

Late Stage ◽

Caspase 3 ◽

Inflammatory Responses ◽

Early Stage ◽

Pulmonary Inflammation ◽

Mechanism Study ◽

Silica Dust ◽

Tnf Α

Occupational exposure to silica dust is related to pulmonary inflammation and silicosis. Lipopolysaccharides (LPSs) could aggravate apoptosis in alveolar macrophages (AMs) of human silicosis through autophagy, yet how the reduction of autophagy attenuated LPS-induced lung injury and the related mechanisms need to be investigated. In the study, we aim to understand the role of 3-methyladenine (3-MA), an inhibitor of autophagy, in LPS-mediated inflammatory responses and fibrosis. We collected AMs from observers/silicosis patients. The results showed that LPS induced NF-κB-related pulmonary inflammation in observers and silicosis patients, as confirmed by an increase in the expression of IL-1β, IL-6, TNF-α, and p65, which could be inhibited by 3-MA treatment. In mice models, at the early stage (7d) of silicosis, but not the late (28d) stage, blocking autophagy reversed the increased levels of IL-1β, IL-6, TNF-α, and p65 caused by LPS. Mechanism study revealed that LPS triggered the expression of LC3 II, p62, and cleaved caspase-3 at the early stage exposed to silica, which could be restored by 3-MA, while there was no difference in the expression of LAMP1 either at the early or late stage of silicosis in different groups. Similarly, 3-MA treatment did not prevent fibrosis characterized by destroyed alveoli, collagen deposition, and increased expression of α-SMA and Col-1 induced by LPS at the late stage of silicosis. The results suggested that 3-MA has a role in the protection of lung injury at the early stage of silicosis and provided an experimental basis for preventive strategies of pulmonary inflammation and silicosis.

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Gut Microbiota, Fusobacteria, and Colorectal Cancer

Diseases ◽

10.3390/diseases6040109 ◽

2018 ◽

Vol 6 (4) ◽

pp. 109 ◽

Cited By ~ 17

Author(s):

Dervla Kelly ◽

Liying Yang ◽

Zhiheng Pei

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Inflammatory Responses ◽

Tumor Development ◽

Host Responses ◽

Future Research ◽

Bacterial Microbiota ◽

Promote Tumor Growth ◽

Tumor Environment ◽

Protective Strategies

The gut microbiota has emerged as an environmental contributor to colorectal cancer (CRC) in both animal models and human studies. It is now generally accepted that bacteria are ubiquitous colonizers of all exposed human body surfaces, including the entire alimentary tract (5). Recently, the concept that a normal bacterial microbiota is essential for the development of inflammation-induced carcinoma has emerged from studies of well-known colonic bacterial microbiota. This review explores the evidence for a role of fusobacteria, an anaerobic gram-negative bacterium that has repeatedly been detected at colorectal tumor sites in higher abundance than surrounding histologically normal tissue. Mechanistic studies provide insight on the interplay between fusobacteria, other gut microbiota, barrier functions, and host responses. Studies have shown that fusobacteria activate host inflammatory responses designed to protect against pathogens that promote tumor growth. We discuss how future research identifying the pathophysiology underlying fusobacteria colon colonization during colorectal cancer may lead to new therapeutic targets for cancer. Furthermore, disease-protective strategies suppressing tumor development by targeting the local tumor environment via bacteria represent another exciting avenue for researchers and are highlighted in this review.

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Heparanase Mediates Intestinal Inflammation and Injury in a Mouse Model of Sepsis

Journal of Histochemistry & Cytochemistry ◽

10.1369/0022155417692536 ◽

2017 ◽

Vol 65 (4) ◽

pp. 241-249 ◽

Cited By ~ 12

Author(s):

Song Chen ◽

Ying He ◽

Ziwei Hu ◽

Siyu Lu ◽

Xiaohan Yin ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Cecal Ligation ◽

Neutrophil Infiltration ◽

Intestinal Injury ◽

Mucosal Surfaces ◽

Type Plasminogen Activator ◽

Effective Inhibition ◽

Factor Α

Heparanase, a heparan sulfate (HS)–specific endoglycosidase, plays an important role in inflammation and mediates acute pulmonary and renal injuries during sepsis. To explore its role in septic intestinal injury, a non-anticoagulant heparanase inhibitor, N-desulfated/re- N-acetylated heparin (NAH), was administrated to a mouse sepsis model induced by cecal ligation and puncture (CLP). Immunohistochemical staining revealed massive shedding of HS from the intestinal mucosal surfaces after CLP, and effective inhibition of heparanase by NAH was confirmed by markedly reduced HS shedding. Following CLP, intestinal expression of heparanase was increased, whereas pretreatment with NAH reduced the sepsis-induced upregulation of heparanase expression. Meanwhile, CLP led to shedding of syndecan-1 and upregulated expression of proteases such as matrix metalloprotease-9 and urokinase-type plasminogen activator in the intestine, whereas NAH markedly suppressed syndecan-1 shedding and protease upregulation following CLP. In addition, pretreatment with NAH attenuated intestinal injury, inhibited neutrophil infiltration and suppressed the production of inflammatory cytokines (tumor necrosis factor–α, interleukin-1β, and interleukin-6) in the intestine during sepsis, and it also significantly reduced the elevation of inflammatory cytokines in the serum 24 hr after CLP. Our findings demonstrate that the activation of intestinal heparanase contributes to intestinal injury during early sepsis by facilitating the destruction of mucosal epithelial glycocalyx and promoting inflammatory responses.

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