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Article ; Online: An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses.

Whittington, Ashley M / Turner, Frances S / Baark, Friedrich / Templeman, Sam / Kirwan, Daniela E / Roufosse, Candice / Krishnan, Nitya / Robertson, Brian D / Chong, Deborah L W / Porter, Joanna C / Gilman, Robert H / Friedland, Jon S

PLoS pathogens

2023 Volume 19, Issue 7, Page(s) e1011495

Abstract: Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is ... ...

Abstract	Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients.
MeSH term(s)	Humans ; Animals ; Mice ; Tuberculosis/microbiology ; Macrophages/metabolism ; Mycobacterium tuberculosis ; Signal Transduction ; Extracellular Matrix/metabolism
Language	English
Publishing date	2023-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011495
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Article ; Online: A case of neck abscess caused by rare hypervirulent Klebsiella pneumoniae, capsular type K20 and sequence type 420.

McHardy, John Alexander / Selvaganeshapillai, Vathshalan / Khanna, Priya / Whittington, Ashley Michael / Turton, Jane / Gopal Rao, Guduru

Annals of clinical microbiology and antimicrobials

2021 Volume 20, Issue 1, Page(s) 46

Abstract: Background: This case report describes a neck abscess caused by a strain of Hypervirulent Klebsiella pneumoniae in a middle aged man with diabetes without a history of travel to East and South East Asia. This case report is of notable significance as ... ...

Abstract	Background: This case report describes a neck abscess caused by a strain of Hypervirulent Klebsiella pneumoniae in a middle aged man with diabetes without a history of travel to East and South East Asia. This case report is of notable significance as Hypervirulent Klebsiella pneumoniae neck abscesses are rarely seen in the UK and are very infrequently documented in individuals who have not first travelled to the high prevalence areas of East and South East Asia. Case presentation: This case report describes a 53 year old diabetic man who contracted a Hypervirulent Klebsiella pneumoniae neck abscess which led to the development of sepsis. Klebsiella pneumoniae was cultured from blood cultures and fluid aspirated from the abscess grew the pathogen with same antimicrobial susceptibility. Hypervirulence was demonstrated after the samples were analysed, at the Antimicrobial Resistance and Healthcare Associated Infections Reference Unit Public Health England Colindale, and found to contain the K20 (rmp)A and rmpA2 virulence genes. Discussion: Hypervirulent Klebsiella pneumoniae is a Gram-negative, encapsulated, non-motile bacillus notable for its ability to metastatically spread and cause potentially life threatening infections in otherwise healthy adults, but especially in those with diabetes. Genes responsible for the production of hyperviscous mucoid polysaccharide capsules and siderophores, such as those isolated in this case, enable the bacteria to more efficiently evade the hosts immune system and disseminate and invade surrounding and distant tissues. Data from Public Health England shows Hypervirulent Klebsiella pneumoniae are rare in the UK. A review of current literature also showed Hypervirulent Klebsiella pneumoniae almost exclusively occur in those who have traveled to East and South East Asia. Conclusions: This case reported a rare Hypervirulent Klebsiella pneumoniae neck abscess outside of, and without travel to, East and South East Asia. This raises concerns about future, potentially life threatening, Hypervirulent Klebsiella pneumoniae infections becoming more widespread without the need for endemic travel. This concern is further exacerbated by the growing global challenge of antimicrobial resistance.
MeSH term(s)	Abscess/diagnosis ; Abscess/microbiology ; Cross Infection ; Diabetes Complications ; Diabetes Mellitus ; Drug Resistance, Bacterial ; Humans ; Klebsiella Infections/diagnosis ; Klebsiella Infections/microbiology ; Klebsiella pneumoniae/isolation & purification ; Male ; Microbial Sensitivity Tests ; Middle Aged ; Neck ; Sepsis/diagnosis ; Sepsis/microbiology ; United Kingdom ; Virulence ; Virulence Factors
Chemical Substances	Virulence Factors
Language	English
Publishing date	2021-06-22
Publishing country	England
Document type	Case Reports ; Journal Article
ZDB-ID	2097873-X
ISSN	1476-0711 ; 1476-0711
ISSN (online)	1476-0711
ISSN	1476-0711
DOI	10.1186/s12941-021-00453-8
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Article: The first three reported cases of

Barnacle, James R / Chow, Yimmy J / Borman, Andrew M / Wyllie, Steven / Dominguez, Valentin / Russell, Katherine / Roberts, Helen / Armstrong-James, Darius / Whittington, Ashley M

Medical mycology case reports

2022 Volume 39, Page(s) 14–17

Abstract: An epidemic of cat-transmitted sporotrichosis caused ... ...

Abstract	An epidemic of cat-transmitted sporotrichosis caused by
Language	English
Publishing date	2022-12-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2670415-8
ISSN	2211-7539
ISSN	2211-7539
DOI	10.1016/j.mmcr.2022.12.004
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Article ; Online: Monocyte Adhesion, Migration, and Extracellular Matrix Breakdown Are Regulated by Integrin αVβ3 in

Brilha, Sara / Wysoczanski, Riccardo / Whittington, Ashley M / Friedland, Jon S / Porter, Joanna C

Journal of immunology (Baltimore, Md. : 1950)

2017 Volume 199, Issue 3, Page(s) 982–991

Abstract: In tuberculosis (TB), the innate inflammatory immune response drives tissue destruction, morbidity, and mortality. Monocytes secrete matrix metalloproteinases (MMPs), which have key roles in local tissue destruction and cavitation. We hypothesized that ... ...

Abstract	In tuberculosis (TB), the innate inflammatory immune response drives tissue destruction, morbidity, and mortality. Monocytes secrete matrix metalloproteinases (MMPs), which have key roles in local tissue destruction and cavitation. We hypothesized that integrin signaling might regulate monocyte MMP secretion in pulmonary TB during cell adhesion to the extracellular matrix (ECM). Adhesion to type I collagen and fibronectin by
MeSH term(s)	Cell Adhesion ; Cell Movement ; Collagen Type I/metabolism ; Collagenases/metabolism ; Extracellular Matrix/drug effects ; Extracellular Matrix/metabolism ; Fibronectins/metabolism ; Gene Expression Regulation ; Humans ; Integrin alphaVbeta3/antagonists & inhibitors ; Integrin alphaVbeta3/genetics ; Integrin alphaVbeta3/immunology ; Matrix Metalloproteinase 1/genetics ; Matrix Metalloproteinase 1/metabolism ; Matrix Metalloproteinase 10/immunology ; Matrix Metalloproteinase 10/metabolism ; Matrix Metalloproteinase 7/immunology ; Matrix Metalloproteinase 7/metabolism ; Matrix Metalloproteinase Inhibitors/pharmacology ; Monocytes/immunology ; Monocytes/microbiology ; Monocytes/physiology ; Mycobacterium tuberculosis/immunology ; Signal Transduction ; Sputum/chemistry ; Up-Regulation
Chemical Substances	Collagen Type I ; Fibronectins ; Integrin alphaVbeta3 ; Matrix Metalloproteinase Inhibitors ; Collagenases (EC 3.4.24.-) ; Matrix Metalloproteinase 10 (EC 3.4.24.22) ; Matrix Metalloproteinase 7 (EC 3.4.24.23) ; Matrix Metalloproteinase 1 (EC 3.4.24.7)
Language	English
Publishing date	2017-06-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1700128
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Article ; Online: Cross-sectional observational study of epidemiology of COVID-19 and clinical outcomes of hospitalised patients in North West London during March and April 2020.

Gopal Rao, Guduru / Allen, Alexander / Papineni, Padmasayee / Wang, Liyang / Anderson, Charlotte / McGregor, Alastair / Whittington, Ashley / John, Laurence / Harris, Miriam / Hiles, Stephen / Nicholas, Thomas / Adams, Katherine / Akbar, Ayesha / Blomquist, Paula / Decraene, Valerie / Patel, Bharat / Manuel, Rohini / Chow, Yimmy / Kuper, Martin

BMJ open

2021 Volume 11, Issue 2, Page(s) e044384

Abstract: Objective: The aim of this paper is to describe evolution, epidemiology and clinical outcomes of COVID-19 in subjects tested at or admitted to hospitals in North West London.: Design: Observational cohort study.: Setting: London North West ... ...

Abstract	Objective: The aim of this paper is to describe evolution, epidemiology and clinical outcomes of COVID-19 in subjects tested at or admitted to hospitals in North West London. Design: Observational cohort study. Setting: London North West Healthcare NHS Trust (LNWH). Participants: Patients tested and/or admitted for COVID-19 at LNWH during March and April 2020 MAIN OUTCOME MEASURES: Descriptive and analytical epidemiology of demographic and clinical outcomes (intensive care unit (ICU) admission, mechanical ventilation and mortality) of those who tested positive for COVID-19. Results: The outbreak began in the first week of March 2020 and reached a peak by the end of March and first week of April. In the study period, 6183 tests were performed in on 4981 people. Of the 2086 laboratory confirmed COVID-19 cases, 1901 were admitted to hospital. Older age group, men and those of black or Asian minority ethnic (BAME) group were predominantly affected (p<0.05). These groups also had more severe infection resulting in ICU admission and need for mechanical ventilation (p<0.05). However, in a multivariate analysis, only increasing age was independently associated with increased risk of death (p<0.05). Mortality rate was 26.9% in hospitalised patients. Conclusion: The findings confirm that men, BAME and older population were most commonly and severely affected groups. Only older age was independently associated with mortality.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; COVID-19/diagnosis ; COVID-19/epidemiology ; COVID-19/mortality ; Child ; Child, Preschool ; Cohort Studies ; Cross-Sectional Studies ; Female ; Hospitalization ; Humans ; Infant ; Infant, Newborn ; Intensive Care Units ; London/epidemiology ; Male ; Middle Aged ; Respiration, Artificial ; Risk Factors ; Young Adult
Language	English
Publishing date	2021-02-18
Publishing country	England
Document type	Journal Article ; Observational Study
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2020-044384
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Article ; Online: False-negative RT-PCR for COVID-19 and a diagnostic risk score: a retrospective cohort study among patients admitted to hospital.

Gupta-Wright, Ankur / Macleod, Colin Kenneth / Barrett, Jessica / Filson, Sarah Ann / Corrah, Tumena / Parris, Victoria / Sandhu, Gurjinder / Harris, Miriam / Tennant, Rachel / Vaid, Nidhi / Takata, Junko / Duraisingham, Sai / Gandy, Nemi / Chana, Harmeet / Whittington, Ashley / McGregor, Alastair / Papineni, Padmasayee

BMJ open

2021 Volume 11, Issue 2, Page(s) e047110

Abstract: Objective: To describe the characteristics and outcomes of patients with a clinical diagnosis of COVID-19 and false-negative SARS-CoV-2 reverse transcription-PCR (RT-PCR), and develop and internally validate a diagnostic risk score to predict risk of ... ...

Abstract	Objective: To describe the characteristics and outcomes of patients with a clinical diagnosis of COVID-19 and false-negative SARS-CoV-2 reverse transcription-PCR (RT-PCR), and develop and internally validate a diagnostic risk score to predict risk of COVID-19 (including RT-PCR-negative COVID-19) among medical admissions. Design: Retrospective cohort study. Setting: Two hospitals within an acute NHS Trust in London, UK. Participants: All patients admitted to medical wards between 2 March and 3 May 2020. Outcomes: Main outcomes were diagnosis of COVID-19, SARS-CoV-2 RT-PCR results, sensitivity of SARS-CoV-2 RT-PCR and mortality during hospital admission. For the diagnostic risk score, we report discrimination, calibration and diagnostic accuracy of the model and simplified risk score and internal validation. Results: 4008 patients were admitted between 2 March and 3 May 2020. 1792 patients (44.8%) were diagnosed with COVID-19, of whom 1391 were SARS-CoV-2 RT-PCR positive and 283 had only negative RT-PCRs. Compared with a clinical reference standard, sensitivity of RT-PCR in hospital patients was 83.1% (95% CI 81.2%-84.8%). Broadly, patients with false-negative RT-PCR COVID-19 and those confirmed by positive PCR had similar demographic and clinical characteristics but lower risk of intensive care unit admission and lower in-hospital mortality (adjusted OR 0.41, 95% CI 0.27-0.61). A simple diagnostic risk score comprising of age, sex, ethnicity, cough, fever or shortness of breath, National Early Warning Score 2, C reactive protein and chest radiograph appearance had moderate discrimination (area under the receiver-operator curve 0.83, 95% CI 0.82 to 0.85), good calibration and was internally validated. Conclusion: RT-PCR-negative COVID-19 is common and is associated with lower mortality despite similar presentation. Diagnostic risk scores could potentially help triage patients requiring admission but need external validation.
MeSH term(s)	Aged ; Aged, 80 and over ; COVID-19/diagnosis ; COVID-19 Nucleic Acid Testing ; False Negative Reactions ; Female ; Hospitalization ; Humans ; London/epidemiology ; Male ; Middle Aged ; Retrospective Studies ; Reverse Transcriptase Polymerase Chain Reaction ; Risk Factors
Language	English
Publishing date	2021-02-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2020-047110
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Article ; Online: Title: Risk factors for severe disease in patients admitted with COVID-19 to a hospital in London, England: a retrospective cohort study

Goodall, Jack W / Reed, Thomas A N / Ardissino, Maddalena / Bassett, Paul / Whittington, Ashley M / Cohen, David L / Vaid, Nidhi

medRxiv

Abstract: COVID-19 has caused a major global pandemic and necessitated unprecedented public health restrictions in almost every country. Understanding risk factors for severe disease in hospitalized patients is critical as the pandemic progresses. This ... ...

Abstract	COVID-19 has caused a major global pandemic and necessitated unprecedented public health restrictions in almost every country. Understanding risk factors for severe disease in hospitalized patients is critical as the pandemic progresses. This observational cohort study aimed to characterize the independent associations between the clinical outcomes of hospitalized patients and their demographics, comorbidities, blood tests and bedside observations. All patients admitted to Northwick Park Hospital, London, United Kingdom between 12 March and 15 April 2020 with COVID-19 were retrospectively identified. The primary outcome was death. Associations were explored using Cox proportional hazards modelling. The study included 981 patients. The mortality rate was 36.0%. Age (adjusted hazard ratio (aHR) 1.53), respiratory disease (aHR 1.37), immunosuppression (aHR 2.23), respiratory rate (aHR 1.28), hypoxia (aHR 1.36), Glasgow Coma Score <15 (aHR 1.92), urea (aHR 2.67), alkaline phosphatase (aHR 2.53), C-reactive protein (aHR 1.15), lactate (aHR 2.67), platelet count (aHR 0.77) and infiltrates on chest radiograph (aHR 1.89) were all associated with mortality. These important data will aid clinical risk stratification and provide direction for further research.
Keywords	covid19
Language	English
Publishing date	2020-09-25
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2020.09.24.20200337
Database	COVID19

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Article ; Online: Predictive Factors for Severe Disease in Patients Hospitalised with COVID-19 in London, England

Goodall, Jack / Reed, Thomas A N / Ardissino, Maddalena / Bassett, Paul / Whittington, Ashley M / Cohen, David L. / Vaid, Nidhi

SSRN Electronic Journal ; ISSN 1556-5068

A Retrospective Cohort Study

2020

Keywords	covid19
Language	English
Publisher	Elsevier BV
Publishing country	us
Document type	Article ; Online
DOI	10.2139/ssrn.3638298
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Extra-pulmonary tuberculosis developing at sites of previous trauma.

Barr, David A / Whittington, Ashley M / White, Beth / Patterson, Benjamin / Davidson, Robert N

The Journal of infection

2013 Volume 66, Issue 4, Page(s) 313–319

Abstract: We describe five individuals in whom extra-pulmonary tuberculosis appeared to localise at a site of previous blunt injury. We review other similar case reports where preceding trauma was blunt and non-penetrating, and discuss a possible mechanism ... ...

Abstract	We describe five individuals in whom extra-pulmonary tuberculosis appeared to localise at a site of previous blunt injury. We review other similar case reports where preceding trauma was blunt and non-penetrating, and discuss a possible mechanism involving transport of mycobacteria in monocytes to sites of injury during "latent" tuberculosis infection. This challenges the conventional model proposed for mycobacteria dissemination in tuberculosis disease.
MeSH term(s)	Adolescent ; Adult ; Aged ; Female ; Humans ; Latent Tuberculosis/epidemiology ; Latent Tuberculosis/microbiology ; Latent Tuberculosis/pathology ; Male ; Middle Aged ; Monocytes/microbiology ; Mycobacterium tuberculosis/pathogenicity ; Wounds, Nonpenetrating/complications ; Young Adult
Language	English
Publishing date	2013-04
Publishing country	England
Document type	Case Reports ; Journal Article
ZDB-ID	424417-5
ISSN	1532-2742 ; 0163-4453
ISSN (online)	1532-2742
ISSN	0163-4453
DOI	10.1016/j.jinf.2012.08.010
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Zs.A 1501: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis.

Fox, Katharine A / Kirwan, Daniela E / Whittington, Ashley M / Krishnan, Nitya / Robertson, Brian D / Gilman, Robert H / López, José W / Singh, Shivani / Porter, Joanna C / Friedland, Jon S

American journal of respiratory and critical care medicine

2018 Volume 198, Issue 2, Page(s) 245–255

Abstract: Rationale: Platelets may interact with the immune system in tuberculosis (TB) to regulate human inflammatory responses that lead to morbidity and spread of infection.: Objectives: To identify a functional role of platelets in the innate inflammatory ... ...

Abstract	Rationale: Platelets may interact with the immune system in tuberculosis (TB) to regulate human inflammatory responses that lead to morbidity and spread of infection. Objectives: To identify a functional role of platelets in the innate inflammatory and matrix-degrading response in TB. Methods: Markers of platelet activation were examined in plasma from 50 patients with TB before treatment and 50 control subjects. Twenty-five patients were followed longitudinally. Platelet-monocyte interactions were studied in a coculture model infected with live, virulent Mycobacterium tuberculosis (M.tb) and dissected using qRT-PCR, Luminex multiplex arrays, matrix degradation assays, and colony counts. Immunohistochemistry detected CD41 (cluster of differentiation 41) expression in a pulmonary TB murine model, and secreted platelet factors were measured in BAL fluid from 15 patients with TB and matched control subjects. Measurements and main results: Five of six platelet-associated mediators were upregulated in plasma of patients with TB compared with control subjects, with concentrations returning to baseline by Day 60 of treatment. Gene expression of the monocyte collagenase MMP-1 (matrix metalloproteinase-1) was upregulated by platelets in M.tb infection. Platelets also enhanced M.tb-induced MMP-1 and -10 secretion, which drove type I collagen degradation. Platelets increased monocyte IL-1 and IL-10 and decreased IL-12 and MDC (monocyte-derived chemokine; also known as CCL-22) secretion, as consistent with an M2 monocyte phenotype. Monocyte killing of intracellular M.tb was decreased. In the lung, platelets were detected in a TB mouse model, and secreted platelet mediators were upregulated in human BAL fluid and correlated with MMP and IL-1β concentrations. Conclusions: Platelets drive a proinflammatory, tissue-degrading phenotype in TB.
MeSH term(s)	Adult ; Apoptosis/immunology ; Apoptosis/physiology ; Blood Platelets/immunology ; Cell Proliferation/physiology ; Female ; Humans ; Male ; Mycobacterium tuberculosis/pathogenicity ; Pneumonia/immunology ; Pneumonia/physiopathology ; Tuberculosis/immunology ; Tuberculosis/physiopathology
Language	English
Publishing date	2018-02-07
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.201710-2102OC
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