28 results found
Tan LKK, Reglinski M, Teo D, et al., 2021, Vaccine-induced, but not natural immunity, against the Streptococcal Inhibitor of complement protects against invasive disease, npj Vaccines, Vol: 6, Pages: 1-9, ISSN: 2059-0105
Highly pathogenic emm1 Streptococcus pyogenes strains secrete the multidomain Streptococcal inhibitor of complement (SIC) that binds and inactivates components of the innate immune response. We aimed to determine if naturally occurring or vaccine-induced antibodies to SIC are protective against invasive S. pyogenes infection. Immunisation with full-length SIC protected mice against systemic bacterial dissemination following intranasal or intramuscular infection with emm1 S. pyogenes. Vaccine-induced rabbit anti-SIC antibodies, but not naturally occurring human anti-SIC antibodies, enhanced bacterial clearance in an ex vivo whole-blood assay. SIC vaccination of both mice and rabbits resulted in antibody recognition of all domains of SIC, whereas naturally occurring human anti-SIC antibodies recognised the proline-rich region of SIC only. We, therefore, propose a model whereby natural infection with S. pyogenes generates non-protective antibodies against the proline-rich region of SIC, while vaccination with full-length SIC permits the development of protective antibodies against all SIC domains.
Mallet F, Perret M, Tran T, et al., 2019, Early herpes and TTV DNAemia in septic shock patients: a pilot study., Intensive Care Med Exp, Vol: 7, ISSN: 2197-425X
BACKGROUND: Septic shock patients exhibit an increased incidence of viral reactivation. Precise timing of such reactivation-as an early marker of immune suppression, or as a consequence of the later-is not known precisely. Here, using a fully designed nucleic acid extraction automated procedure together with tailored commercial PCR kits, we focused on the description of early reactivation within the first week of ICU admission of several herpes viruses and Torque Teno virus (TTV) in 98 septic shock patients. RESULTS: Most of septic shock patients had at least one viremia event during the first week (88%). TTV and herpesviruses were detected in 56% and 53% of septic shock patient, respectively. The two most frequent herpesviruses detected within the first week were EBV (35%) and HSV1 (26%). Different kinetic were observed among herpesviruses, faster for EBV and HSV1 than for CMV and HHV6. Although no association was found between herpes viremia and secondary infections, patients with herpesviridae-related viremia were more severe, e.g., higher SOFA scores and plasma lactate levels. While reactivating only 1 virus was not associated with mortality, patients with multiple viremia events had higher ICU mortality. Surprisingly, EBV + TTV early reactivation seemed associated with a lower D28 mortality. No clear association was observed between viremia and immune biomarkers. CONCLUSION: Applying a semi-automated process of viral DNAemia determination to this cohort of 98 patients with septic shock, we observed that the number of patients with positive viremia increased during the first week in the ICU. Of note, there was no improvement in predicting the outcome when using viremia status. Nevertheless, this pilot study, introducing standardized procedures from extraction to detection, provides the basis for future standardized diagnostic criteria. A prospective longitudinal clinical study using these procedures will enable determination of whether such viremia
Lamb LE, Siggins MK, Scudamore C, et al., 2018, Impact of contusion injury on intramuscular emm1 group A-Streptococcus infection and Lymphatic spread, Virulence, Vol: 9, Pages: 1074-1084, ISSN: 2150-5594
Invasive group A Streptococcus (iGAS) is frequently associated with emm1 isolates, with an attendant mortality of around 20%. Cases occasionally arise in previously healthy individuals with a history of upper respiratory tract infection, soft tissue contusion, and no obvious portal of entry. Using a new murine model of contusion, we determined the impact of contusion on iGAS bacterial burden and phenotype. Calibrated mild blunt contusion did not provide a focus for initiation or seeding of GAS that was detectable following systemic GAS bacteremia, but instead enhanced GAS migration to the local draining lymph node following GAS inoculation at the same time and site of contusion. Increased migration to lymph node was associated with emergence of mucoid bacteria, although was not specific to mucoid bacteria. In one study, mucoid colonies demonstrated a significant increase in capsular hyaluronan that was not linked to a covRS or rocA mutation, but to a deletion in the promoter of the capsule synthesis locus, hasABC, resulting in a strain with increased fitness for lymph node migration. In summary, in the mild contusion model used, we could not detect seeding of muscle by GAS. Contusion promoted bacterial transit to the local lymph node. The consequences of contusion-associated bacterial lymphatic migration may vary depending on the pathogen and virulence traits selected.
Rol M-L, Venet F, Rimmele T, et al., 2017, The REAnimation Low Immune Status Markers (REALISM) project: a protocol for broad characterisation and follow-up of injury-induced immunosuppression in intensive care unit (ICU) critically ill patients., BMJ Open, Vol: 7
INTRODUCTION: The host response to septic shock is dynamic and complex. A sepsis-induced immunosuppression phase has recently been acknowledged and linked to bad outcomes and increased healthcare costs. Moreover, a marked suppression of the immune response has also been partially described in patients hospitalized in intensive care unit (ICU) for severe trauma or burns. It has been hypothesized that immune monitoring could enable identification of patients who might most benefit from novel, adjunctive immune-stimulating therapies. However, there is currently neither a clear definition for such injury-induced immunosuppression nor a stratification biomarker compatible with clinical constraints. METHODS AND ANALYSIS: We set up a prospective, longitudinal single-centre clinical study to determine the incidence, severity and persistency of innate and adaptive immune alterations in ICU patients. We optimized a workflow to describe and follow the immunoinflammatory status of 550 patients (septic shock, severe trauma/burn and major surgery) during the first 2 months after their initial injury. On each time point, two immune functional tests will be performed to determine whole-blood TNF-α production in response to ex vivo lipopolysaccharide stimulation and the T lymphocyte proliferation in response to phytohaemagglutinin. In addition, a complete immunophenotyping using flow cytometry including monocyte HLA-DR expression and lymphocyte subsets will be obtained. New markers (ie, levels of expression of host mRNA and viral reactivation) will be also evaluated. Reference intervals will be determined from a cohort of 150 age-matched healthy volunteers. This clinical study will provide, for the first time, data describing the immune status of severe ICU patients over time. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the institutional review board (no 69HCL15_0379) and the French National Security agency for drugs and health-related products. Results w
Hamilton C, Tan L, Miethke T, et al., 2017, Immunity to uropathogens: the emerging roles of inflammasomes, Nature Reviews Urology, Vol: 14, Pages: 284-295, ISSN: 1759-4812
Urinary tract infections (UTIs) cause a huge burden of morbidity worldwide with recurrence of UTIs becoming significantly frequent due to the emergence of antibiotic-resistant bacterial strains. Recent research has focussed on interactions between the innate and adaptive immune responses to pathogens colonizing the urinary tract. Inflammasomes are part of the innate immune defense and respond rapidly to several infectious diseases. Assembly of the multiprotein inflammasome complex activates Caspase-1, processes proinflammatory cytokines IL-1β and IL-18, and induces pyroptosis. These effector pathways, in turn, act at different levels to either prevent or resolve infection, or eliminate the infectious agent itself. Whilst in certain instances inflammasome activation promotes tissue pathology, the precise functions of inflammasomes in UTIs remain unexplored. In this review, we discuss recent studies on the roles of inflammasomes in UTIs with a particular focus on common infections of the urinary tract. An improved understanding of inflammasomes may provide valuable novel approaches for the design of diagnostics and therapeutics for complicated UTIs, thus enabling us to counteract the challenge of drug resistance.
Lamb L, McDonald W, Scudamore C, et al., 2015, The effect of trauma on invasive group A streptococcal disease, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 60-60, ISSN: 0140-6736
Lamb LEM, Sriskandan S, Tan LKK, 2014, Bromine, bear-claw scratch fasciotomies, and the Eagle effect: management of group A streptococcal necrotising fasciitis and its association with trauma, The Lancet Infectious Diseases, Vol: 15, Pages: 109-121, ISSN: 1474-4457
Necrotising fasciitis is a rare, but potentially fatal, soft-tissue infection. Historical depictions of the disease have been described since classical times and were mainly recorded in wartime reports of battle injuries. Although several different species of bacteria can cause necrotising fasciitis, perhaps the most widely known is group A streptococcus (GAS). Infection control, early surgical debridement, and antibiotic therapy are now the central tenets of the clinical management of necrotising fasciitis; these treatment approaches all originate from those used in wars in the past 150 years. We review reports from the 19th century, early 20th century, and mid-20th century onwards to show how the management of necrotising fasciitis has progressed in parallel with prevailing scientific thought and medical practice. Historically, necrotising fasciitis has often, but not exclusively, been associated with penetrating trauma. However, along with a worldwide increase in invasive GAS disease, recent reports have cited cases of necrotising fasciitis following non-combat-related injuries or in the absence of antecedent events. We also investigate the specific association between GAS necrotising fasciitis and trauma. In the 21st century, molecular biology has improved our understanding of GAS pathogenesis, but has not yet affected attributable mortality.
Tan LKK, Sriskandan S, 2014, Step on the GAS: Are We Almost There for Clindamycin and Intravenous Immunoglobulin?, Clinical Infectious Diseases, Vol: 59, Pages: 366-368, ISSN: 1537-6591
Tan LKK, Eccersley LRJ, Sriskandan S, 2014, Current views of haemolytic streptococcal pathogenesis., Current opinion in infectious diseases, Vol: 27, Pages: 155-164, ISSN: 0951-7375
<h4>Purpose of review</h4>Increasing disease caused by beta-haemolytic streptococci indicates the need for improved understanding of pathogenesis.<h4>Recent findings</h4>Streptococcus pyogenes, or group A Streptococcus (GAS), causes significant disease worldwide. The closely related Streptococcus dysgalactiae subspecies equisimilis (SDSE) is increasingly recognized as causing a similar disease spectrum. Whole-genome sequencing applied to the study of outbreaks may reveal factors that contribute to pathogenesis and changes in epidemiology. The role of quorum sensing in biofilm formation, and interspecies communication with other streptococci, is discussed. GAS has evolved multiple mechanisms to evade the humoral arm of innate immunity, including complement, which is well known in protecting the host from bacteria, and the coagulation-fibrinolytic system, which is increasingly recognized as an innate immune effector.<h4>Summary</h4>Molecular biology has enhanced our understanding of the intricate balance of host-pathogen interactions that result in clearance or establishment of invasive streptococcal infection. Although the skin and oropharynx remain the usual ecological niche of GAS and SDSE, occasionally the bacteria find themselves within deeper tissues and blood. Recent research has armed us with better knowledge of bacterial adaptations to this alternative environment. However, the challenge is to translate this knowledge into clinical practice, through the development of novel therapeutic options and ultimately a vaccine against GAS.
Jongerius I, Lavender H, Tan L, et al., 2013, Distinct Binding and Immunogenic Properties of the Gonococcal Homologue of Meningococcal Factor H Binding Protein, PLOS PATHOGENS, Vol: 9, ISSN: 1553-7366
Price H, Dunn D, Pillay D, et al., 2013, Suppression of HBV by Tenofovir in HBV/HIV Coinfected Patients: A Systematic Review and Meta-Analysis, PLOS ONE, Vol: 8, ISSN: 1932-6203
Johnson S, Tan L, van der Veen S, et al., 2012, Design and Evaluation of Meningococcal Vaccines through Structure-Based Modification of Host and Pathogen Molecules, PLOS PATHOGENS, Vol: 8, ISSN: 1553-7366
Eccersley L, Tan L, 2012, The impact of twice-daily consultant ward rounds on the length of stay in two general medical wards - effect on training?, CLINICAL MEDICINE, Vol: 12, Pages: 186-187, ISSN: 1470-2118
Lucidarme J, Tan L, Exley RM, et al., 2011, Characterization of Neisseria meningitidis Isolates That Do Not Express the Virulence Factor and Vaccine Antigen Factor H Binding Protein, CLINICAL AND VACCINE IMMUNOLOGY, Vol: 18, Pages: 1002-1014, ISSN: 1556-6811
Lionel T, Joe C, Li Y, et al., 2010, THE VACCINE ANTIGEN FACTOR H BINDING PROTEIN FROM NEISSERIA MENINGITIDIS CAN BE MODIFIED TO REDUCE BINDING TO FACTOR H WITH NO CHANGE IN IMMUNOGENICITY, Publisher: W B SAUNDERS CO LTD, Pages: 516-517, ISSN: 0163-4453
Scourfield A, Tan LKK, Nelson M, 2010, Severe septic-shock like reaction to co-trimoxazole in an HIV-positive man, INTERNATIONAL JOURNAL OF STD & AIDS, Vol: 21, Pages: 521-523, ISSN: 0956-4624
LKK T, Carlone GM, Borrow R, 2010, CURRENT CONCEPTS Advances in the Development of Vaccines against Neisseria meningitidis, NEW ENGL J MED, Vol: 362, Pages: 1511-1520, ISSN: 0028-4793
Tan L, Schneider M, Caesar J, et al., 2009, THE INTERACTION BETWEEN FACTOR H AND NEISSERIA MENINGITIDIS, Publisher: W B SAUNDERS CO LTD, Pages: S438-S438, ISSN: 0163-4453
Tan LKK, Gilleece Y, Mandalia S, et al., 2009, Reduced glomerular filtration rate but sustained virologic response in HIV/hepatitis B co-infected individuals on long-term tenofovir, JOURNAL OF VIRAL HEPATITIS, Vol: 16, Pages: 471-478, ISSN: 1352-0504
Stebbing J, Wong N, Tan L, et al., 2009, The Relationship Between Prolonged Antiretroviral Therapy and Cryptogenic Liver Disease, JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, Vol: 50, Pages: 554-556, ISSN: 1525-4135
Tan LKK, Yacoub S, Scott S, et al., 2008, Acute lung injury and other serious complications of Plasmodium vivax malaria, LANCET INFECT DIS, Vol: 8, Pages: 449-454, ISSN: 1473-3099
Plasmodium vivax infection is classified among the so-called benign malarias, but it is increasingyly recognised that serious and even life-threatening complications may occur. We present the case of a returning traveller with P vivax infection who developed acute lung injury 3 days into treatment, and discuss the serious complications of this infection. The case highlights the fact that P vivax infection is benign by name but not always by nature.
Wong THN, Tan L, Wing C, et al., 2008, Cryptogenic liver disease in HIV infected patients treated with anti-retroviral drugs, British Infection Society 10th Annual Meeting, Pages: 307-307, ISSN: 0163-4453
Tan LK, Nelson M, 2008, Maraviroc: a CCR5 antagonist, Future HIV therapy, Vol: 2, Pages: 111-123
HIV requires binding to both the CD4 molecule and a coreceptor to enable entry into the cell. CCR5 is a chemokine receptor that is utilized as a coreceptor by the majority of virus in early asymptomatic HIV infection. Maraviroc is a novel small molecule CCR5 antagonist which, in Phase IIb/III clinical trials up to 48 weeks, has been shown to be efficacious as part of an optimized antiretroviral regimen against CCR5 tropic HIV-1 in treatment-experienced patients. A further trial has demonstrated its noninferiority to efavirenz in achieving a HIV viral load less than 400 copies/ml as part of highly active antiretroviral therapy in treatment-naive individuals. It has recently received regulatory approval for use in North America and Europe in treatment-experienced patients. With increasing use, the role of maraviroc in the treatment of HIV-infected patients will be more clearly defined.
Tan LKK, Lacey S, Mandalia S, et al., 2008, Hospital-based study of viridans streptococcal bacteraemia in children and adults, JOURNAL OF INFECTION, Vol: 56, Pages: 103-107, ISSN: 0163-4453
Tan L, Lacey S, Melzer M, 2007, The clinical significance of Viridans streptococcal bacteraemia in patients at a district general hospital, 17th European Congress of Clinical Microbiology and Infectious Diseases/25th International Congress of Chemotherapy, Publisher: ELSEVIER SCIENCE BV, Pages: S630-S630, ISSN: 0924-8579
Tan LKK, 2006, Good news for treating HIV and tuberculosis co-infection?, Thorax, Vol: 61, Pages: 816-816, ISSN: 0040-6376
Tan L, 2005, Teaching medicine in a developing country, BMJ, Vol: 331, Pages: s130-s131, ISSN: 0959-8138
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