Negative regulation of IMD contributes to disease tolerance during systemic bacterial infection in Drosophila

Disease tolerance is an infection phenotype where hosts show relatively high health despite harbouring elevated pathogen loads. Compared to the mechanisms of immune clearance our knowledge of the mechanisms underlying increased tolerance remains incomplete. Variation in the ability to reduce immunopathology may explain why some hosts can tolerate higher pathogen burdens with reduced pathology. Negative immune regulation would therefore appear to be a clear candidate for a mechanism underlying disease tolerance but this has not been tested directly for bacterial infections. Here, we examined how the negative regulation of the immune deficiency (IMD) pathway affects disease tolerance in Drosophila melanogaster when infected with the gram-negative bacterial pathogen Pseudomonas entomophila. We find that UASRNAi-mediated reduced expression of the negative regulators of IMD (pirk & caudal) severely reduced the ability to tolerate infection in both males and females across a wide range of infectious doses. While flies unable to regulate the IMD response exhibited higher expression of antimicrobial peptides and lower bacterial loads as expected, this was not accompanied by a proportional reduction in mortality. Instead, tolerance (measured as fly survival relative to its microbe load) was drastically reduced, likely due to the combination of increased immunopathology and cytotoxicity of elevated AMP expression. Our results therefore highlight that in addition to regulating an efficient pathogen clearance response, negative regulators of IMD also contribute to disease tolerance.

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A Pyrrhic Victory: The PMN Response to Ocular Bacterial Infections

Microorganisms ◽

10.3390/microorganisms7110537 ◽

2019 ◽

Vol 7 (11) ◽

pp. 537 ◽

Cited By ~ 4

Author(s):

Erin T. Livingston ◽

Md Huzzatul Mursalin ◽

Michelle C. Callegan

Keyword(s):

Bacterial Infections ◽

Bacterial Pathogen ◽

General Information ◽

Ocular Disease ◽

Ocular Infection ◽

The Face ◽

Novel Therapeutic Strategies ◽

Pathogen Clearance ◽

Pyrrhic Victory

Some tissues of the eye are susceptible to damage due to their exposure to the outside environment and inability to regenerate. Immune privilege, although beneficial to the eye in terms of homeostasis and protection, can be harmful when breached or when an aberrant response occurs in the face of challenge. In this review, we highlight the role of the PMN (polymorphonuclear leukocyte) in different bacterial ocular infections that invade the immune privileged eye at the anterior and posterior segments: keratitis, conjunctivitis, uveitis, and endophthalmitis. Interestingly, the PMN response from the host seems to be necessary for pathogen clearance in ocular disease, but the inflammatory response can also be detrimental to vision retention. This “Pyrrhic Victory” scenario is explored in each type of ocular infection, with details on PMN recruitment and response at the site of ocular infection. In addition, we emphasize the differences in PMN responses between each ocular disease and its most common corresponding bacterial pathogen. The in vitro and animal models used to identify PMN responses, such as recruitment, phagocytosis, degranulation, and NETosis, are also outlined in each ocular infection. This detailed study of the ocular acute immune response to infection could provide novel therapeutic strategies for blinding diseases, provide more general information on ocular PMN responses, and reveal areas of bacterial ocular infection research that lack PMN response studies.

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An Investigation of Potential Health Risks from Zoonotic Bacterial Pathogens Associated with Farm Rats

Environmental Health Insights ◽

10.1177/1178630220942240 ◽

2020 ◽

Vol 14 ◽

pp. 117863022094224

Author(s):

Lorina Badger-Emeka ◽

Yasmeen Al-Mulhim ◽

Fatimah Al-Muyidi ◽

Maram Busuhail ◽

Salma Alkhalifah ◽

...

Keyword(s):

Antimicrobial Susceptibility ◽

Bacterial Infections ◽

Pathogenic Bacteria ◽

Rattus Rattus ◽

Bacterial Pathogen ◽

Automated System ◽

Potential Health ◽

Zoonotic Infections ◽

Wide Range ◽

Significant Difference

Background: The 21st century has seen a wide range of diseases resulting from zoonotic infections, of which bacterial infections have led to outbreaks of food-borne diseases. Aim: The study looks at bacterial pathogen carriage by farm rats and their antimicrobial susceptibility, with the view of providing insights for antimicrobial surveillance. Method: Farm rats of Rattus rattus species where randomly collected alive from farms in Al-Ahsa using food baits. They were anaesthetize with urethane within 4 h of collection and were unconscious for the collection of samples. Basic bacteriological culturing methods were used for culturing of bacterial isolates on selective media while the Vitek 2 compact automated system (BioMerieux, Marcy L’Etoile, France) was used for bacteria identification and antimicrobial susceptibility test. Obtained data were analysed using chi-square and paired t-test with significant difference between sensitive and resistance to antimicrobial susceptibility taken at P < .05. Results: Isolated Gramme-negative pathogenic bacteria included strains of Escherichia coli, Pseudomonas oryzihabitans, strains of Pseudomonas aeruginosa, and Salmonella. For the Gramme-positive bacteria, 4 strains of Staphylococcus aureus were encountered. Other Gramme-positive bacteria were coagulase-negative Staphylococcal species (CoNS) as well as Staphylococcus lugdunensis. There was a 100% resistance to the penicillins and a high resistance to imipenem (71%) by the Staphylococcal isolates. Resistance was also high against the β-lactams by the Gramme-positive bacteria isolates. For the Gramme-negative bacteria, there was a higher than 50% resistance by the isolates against the following antibiotics: ampicillin (78%), amoxicillin/clavulanic acid (67%), cefotaxime (77%), ceftazidime (67%), cefepime (78%), norfloxacin (67%), nitrofurantoin (67%), and trimethoprim/sulfamethoxazole (78%). Conclusion: The results showed high antimicrobial resistance that will need monitoring for control of spread from farm rats to humans.

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Heterocycle Compounds with Antimicrobial Activity

Current Pharmaceutical Design ◽

10.2174/1381612826666200206093815 ◽

2020 ◽

Vol 26 (8) ◽

pp. 867-904 ◽

Cited By ~ 2

Author(s):

Maria Fesatidou ◽

Anthi Petrou ◽

Geronikaki Athina

Keyword(s):

Heterocyclic Compounds ◽

Bacterial Infections ◽

Scientific Community ◽

Antimicrobial Agents ◽

Fungal Infections ◽

Biological Activities ◽

Literature Survey ◽

New Findings ◽

Wide Range ◽

Number Of Microorganisms

Background: Bacterial infections are a growing problem worldwide causing morbidity and mortality mainly in developing countries. Moreover, the increased number of microorganisms, developing multiple resistances to known drugs, due to abuse of antibiotics, is another serious problem. This problem becomes more serious for immunocompromised patients and those who are often disposed to opportunistic fungal infections. Objective: The objective of this manuscript is to give an overview of new findings in the field of antimicrobial agents among five-membered heterocyclic compounds. These heterocyclic compounds especially five-membered attracted the interest of the scientific community not only for their occurrence in nature but also due to their wide range of biological activities. Method: To reach our goal, a literature survey that covers the last decade was performed. Results: As a result, recent data on the biological activity of thiazole, thiazolidinone, benzothiazole and thiadiazole derivatives are mentioned. Conclusion: It should be mentioned that despite the progress in the development of new antimicrobial agents, there is still room for new findings. Thus, research still continues.

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Cortical Excitability across the ALS Clinical Motor Phenotypes

Brain Sciences ◽

10.3390/brainsci11060715 ◽

2021 ◽

Vol 11 (6) ◽

pp. 715

Author(s):

Thanuja Dharmadasa

Keyword(s):

Motor Cortex ◽

Cortical Excitability ◽

Phenotypic Variability ◽

Specific Treatment ◽

Underlying Disease ◽

Selective Vulnerability ◽

Clinical Feature ◽

Cortical Hyperexcitability ◽

Wide Range

Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a heterogeneity of underlying pathogenic mechanisms. Corticomotoneuronal dysfunction is increasingly postulated as the harbinger of clinical disease, and neurophysiological exploration of the motor cortex in vivo using transcranial magnetic stimulation (TMS) has suggested that motor cortical hyperexcitability may be a critical pathogenic factor linked to clinical features and survival. Region-specific selective vulnerability at the level of the motor cortex may drive the observed differences of clinical presentation across the ALS motor phenotypes, and thus, further understanding of phenotypic variability in relation to cortical dysfunction may serve as an important guide to underlying disease mechanisms. This review article analyses the cortical excitability profiles across the clinical motor phenotypes, as assessed using TMS, and explores this relationship to clinical patterns and survival. This understanding will remain essential to unravelling central disease pathophysiology and for the development of specific treatment targets across the ALS clinical motor phenotypes.

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Phage Resistance Is Associated with Decreased Virulence in KPC-Producing Klebsiella pneumoniae of the Clonal Group 258 Clade II Lineage

Microorganisms ◽

10.3390/microorganisms9040762 ◽

2021 ◽

Vol 9 (4) ◽

pp. 762

Author(s):

Lucia Henrici De Angelis ◽

Noemi Poerio ◽

Vincenzo Di Pilato ◽

Federica De Santis ◽

Alberto Antonelli ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Parental Strain ◽

Bacterial Infections ◽

Capsular Polysaccharide ◽

Galleria Mellonella ◽

Bacterial Pathogen ◽

Phage Resistance ◽

Infection Model ◽

Lytic Phage ◽

Susceptible Host

Phage therapy is now reconsidered with interest in the treatment of bacterial infections. A major piece of information for this application is the definition of the molecular targets exploited by phages to infect bacteria. Here, the genetic basis of resistance to the lytic phage φBO1E by its susceptible host Klebsiella pneumoniae KKBO-1 has been investigated. KKBO-1 phage-resistant mutants were obtained by infection at high multiplicity. One mutant, designated BO-FR-1, was selected for subsequent experiments, including virulence assessment in a Galleria mellonella infection model and characterization by whole-genome sequencing. Infection with BO-FR-1 was associated with a significantly lower mortality when compared to that of the parental strain. The BO-FR-1 genome differed from KKBO-1 by a single nonsense mutation into the wbaP gene, which encodes a glycosyltransferase involved in the first step of the biosynthesis of the capsular polysaccharide (CPS). Phage susceptibility was restored when BO-FR-1 was complemented with the constitutive wbaP gene. Our results demonstrated that φBO1E infects KKBO-1 targeting the bacterial CPS. Interestingly, BO-FR-1 was less virulent than the parental strain, suggesting that in the context of the interplay among phage, bacterial pathogen and host, the emergence of phage resistance may be beneficial for the host.

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Diversity of Pod Shape in Pisum

Diversity ◽

10.3390/d13050203 ◽

2021 ◽

Vol 13 (5) ◽

pp. 203

Author(s):

Thomas Henry Noel Ellis ◽

Julie M. I. Hofer ◽

Eleni Vikeli ◽

Michael J. Ambrose ◽

Paola Higuera-Poveda ◽

...

Keyword(s):

Allelic Variation ◽

Size Variation ◽

Width Ratio ◽

Negative Regulators ◽

Wide Range ◽

Yield Determination ◽

Organ Specific ◽

Length Width ◽

End Use ◽

Pod Length

The seed-containing pod is the defining structure of plants in the legume family, yet pods exhibit a wide range of morphological variation. Within a species pod characters are likely to be correlated with reproductive strategy, and within cultivated forms will correspond to aspects of yield determination and/or end use. Here variation in pod size, described as pod length: pod width ratio, has been analyzed in pea germplasm represented by 597 accessions. This pod size variation is discussed with respect to population structure and to known classical pod morphology mutants. Variability of the pod length: width ratio can be explained by allelic variation at two genetic loci that may correspond to organ-specific negative regulators of growth.

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Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry

European Respiratory Journal ◽

10.1183/13993003.01592-2016 ◽

2017 ◽

Vol 49 (2) ◽

pp. 1601592 ◽

Cited By ~ 70

Author(s):

Helen E. Jo ◽

Ian Glaspole ◽

Christopher Grainge ◽

Nicole Goh ◽

Peter M.A. Hopkins ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Disease Severity ◽

Large Population ◽

Underlying Disease ◽

National Registry ◽

Hazard Ratio ◽

Wide Range ◽

Baseline Characteristics

The prevalence of idiopathic pulmonary fibrosis (IPF), a fatal and progressive lung disease, is estimated at 1.25–63 out of 100 000, making large population studies difficult. Recently, the need for large longitudinal registries to study IPF has been recognised.The Australian IPF Registry (AIPFR) is a national registry collating comprehensive longitudinal data of IPF patients across Australia. We explored the characteristics of this IPF cohort and the effect of demographic and physiological parameters and specific management on mortality.Participants in the AIPFR (n=647, mean age 70.9±8.5 years, 67.7% male, median follow up 2 years, range 6 months–4.5 years) displayed a wide range of age, disease severity and co-morbidities that is not present in clinical trial cohorts. The cumulative mortality rate in year one, two, three and four was 5%, 24%, 37% and 44% respectively. Baseline lung function (forced vital capacity, diffusing capacity of the lung for carbon monoxide, composite physiological index) and GAP (gender, age, physiology) stage (hazard ratio 4.64, 95% CI 3.33–6.47, p<0.001) were strong predictors of mortality. Patients receiving anti-fibrotic medications had better survival (hazard ratio 0.56, 95% CI 0.34–0.92, p=0.022) than those not on anti-fibrotic medications, independent of underlying disease severity.The AIPFR provides important insights into the understanding of the natural history and clinical management of IPF.

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Evidence for the Non-Infectious Etiology of Early Postoperative Fever

Infection Control ◽

10.1017/s0195941700061749 ◽

1985 ◽

Vol 6 (7) ◽

pp. 273-277 ◽

Cited By ~ 85

Author(s):

Richard A. Garibaldi ◽

Susan Brodine ◽

Sego Matsumiya ◽

Miki Coleman

Keyword(s):

General Surgery ◽

Underlying Disease ◽

Therapeutic Interventions ◽

Empiric Antibiotic Therapy ◽

Postoperative Fever ◽

Wide Range ◽

Severe Underlying Disease ◽

Empiric Antibiotic ◽

Sources Of Infection ◽

A Prospective Study

AbstractIn a prospective study of infections in 871 general surgery patients, we identified 81 patients who developed unexplained postoperative fevers. The majority of these episodes (72%) occurred early (within the first 48 hours) following surgery. Patients who developed early, unexplained fevers differed significantly from patients who developed documented postoperative infections. Patients with unexplained fevers were younger, had less severe underlying disease and underwent less extensive surgeries than patients who subsequently developed infections. In these respects, they were more similar to non-infected, non-febrile patients.We concluded that episodes of early, unexplained postoperative fever occur frequently in a wide range of general surgery patients. Most of these episodes are non-infectious in origin. Patients with early postoperative fevers should be evaluated to identify any obvious sources of infection. If no focus is identified, empiric antibiotic therapy should not be initiated nor should prophylactic antibiotics be extended for prolonged durations. Unexplained fevers will resolve in time without specific therapeutic interventions.

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CRYOGLOBULIN TEST AND CRYOGLOBULINEMIA HEPATITIS C-VIRUS RELATED

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2017.007 ◽

2016 ◽

Vol 9 (1) ◽

pp. e2017007 ◽

Cited By ~ 2

Author(s):

Umberto Basile

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Confounding Factor ◽

Underlying Disease ◽

Clinical Syndrome ◽

Laboratory Techniques ◽

Preanalytical Phase ◽

Wide Range

Cryoglobulins are immunoglobulins that precipitate in serum at temperatures below 37°C and resolubilize upon warming. The clinical syndrome of cryoglobulinemia usually includes purpura, weakness, and arthralgia, but the underlying disease may also contribute other symptoms. Blood samples for cryoglobulin are collected, transported, clotted and spun at 37°C, before the precipitate is allowed to form when serum is stored at 4°C in a Wintrobe tube for at least seven days. The most critical and confounding factor affecting the cryoglobulin test is when the preanalytical phase is not fully completed at 37°C. The easiest way to quantify cryoglobulins is the cryocrit estimate. However, this approach has low accuracy and sensitivity. Furthermore, the precipitate should be resolubilized by warming to confirm that it is truly formed of cryoglobulins. The characterization of cryoglobulins requires the precipitate is several times washed, before performing immunofixation, a technique by which cryoglobulins can be classified depending on the characteristics of the detected immunoglobulins. These features imply a pathogenic role of these molecules which are consequently associated with a wide range of symptoms and manifestations. According to the Brouet classification, Cryoglobulins are grouped into three types by the immunochemical properties of immunoglobulins in the cryoprecipitate. The aim of this paper is to review the major aspects of cryoglobulinemia and the laboratory techniques used to detect and characterize cryoglobulins, taking into consideration the presence and consequences of cryoglobulinemia in Hepatitis C Virus (HCV) infection.

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Cross-Reactivity of Drug-Dependent Antibodies in Patients with Immune Thrombocytopenia Induced By Beta-Lactam Antibiotics

Blood ◽

10.1182/blood-2019-131375 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2350-2350

Author(s):

Matthew John Slaught ◽

Daniel W. Bougie ◽

Richard H. Aster

Keyword(s):

Bacterial Infections ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Cross Reactivity ◽

Beta Lactam ◽

Cross Reactions ◽

Beta Lactam Antibiotics ◽

Wide Range ◽

Group 2 ◽

Group 1

More than 50 beta lactam (BL) antibiotics are now in active use for treatment of a wide range of bacterial infections. BL antibiotics are among the most common drugs capable of inducing antibodies (DDAbs) that cause drug-induced immune thrombocytopenia (DITP). Most DDAbs are highly specific for the sensitizing drug but beta lactams all have a common core structure and many similarities among side groups that are added to augment potency and modify specificity, raising the possibility that a DDAb specific for one BL may cross-react with another. We studied DDAbs from 33 patients with DITP induced by 9 commonly used BL drugs to determine whether patterns of cross-reactivity exist that might influence the choice of an alternative antibiotic in a patient with BL-induced DITP. DDAbs were demonstrated in a flow cytometric assay considered to be "positive" when immunoglobulins in patient serum but not normal serum react with normal platelets in the presence, but not in the absence of drug (Blood 2018;131:1486). DDAbs detected in the 33 patients were specific for 9 different BL drugs that were divided into two groups, "penicillins" (Group 1) and cephalosporins (Group 2) on the basis of structural similarities (Figure 1). In Group 1 were 19 DDAbs specific for amoxicillin (2), nafcillin (4) and piperacillin (13). Structurally similar ampicillin and penicillin were also tested with these abs. In Group 2 were 14 DDAbs specific for cefadroxil (1), cefepime (2), ceftazidime (2), ceftizoxime (1), ceftriaxone (7) and cephalexin 1). Cross-reactions identified within these groups of DDAbs are shown in Tables 1 and 2. Cross-reactions, many quite strong (S) were observed among DDAbs specific for drugs in both structural groups (Tables 1 and 2). Particularly noteworthy were cross-reactions of the 19 Group 1 DDAbs with ampicillin (6) and penicillin (6) (Table 1) and of the 14 Group 2 DDAbs with cefepime (6), ceftizoxazole (6) and ceftriaxone (3) (Table 2). The findings show that platelet-specific DDAbs induced by beta lactam antibiotics, in contrast with those induced by medications like quinine, sulfamethoxazole and vancomycin, commonly cross-react with other antibiotics of this class. In patients with immune thrombocytopenia induced by a beta lactam antibiotic, it may be prudent to avoid switching to another beta lactam or, if this is necessary, to monitor platelet counts carefully. Disclosures No relevant conflicts of interest to declare.

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