143 results found
Peng Y, Mentzer AJ, Liu G, et al., 2020, Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19., Nat Immunol
The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide-MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.
Zhou D, Duyvesteyn HME, Chen C-P, et al., 2020, Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient, NATURE STRUCTURAL & MOLECULAR BIOLOGY, ISSN: 1545-9993
Fernandez E, Dejnirattisai W, Cao B, et al., 2020, Human antibodies to the dengue virus E-dimer epitope have therapeutic activity against Zika virus infection (vol 45, pg 917, 2020), NATURE IMMUNOLOGY, Vol: 21, Pages: 354-354, ISSN: 1529-2908
Slon-Campos JL, Dejnirattisai W, Jagger BW, et al., 2019, A protective Zika virus E-dimer-based subunit vaccine engineered to abrogate antibody-dependent enhancement of dengue infection, NATURE IMMUNOLOGY, Vol: 20, Pages: 1291-+, ISSN: 1529-2908
Salazar V, Jagger BW, Mongkolsapaya J, et al., 2019, Dengue and Zika Virus Cross-Reactive Human Monoclonal Antibodies Protect against Spondweni Virus Infection and Pathogenesis in Mice, CELL REPORTS, Vol: 26, Pages: 1585-+, ISSN: 2211-1247
Tsai W-Y, Chen H-L, Tsai J-J, et al., 2018, Potent Neutralizing Human Monoclonal Antibodies Preferentially Target Mature Dengue Virus Particles: Implication for Novel Strategy for Dengue Vaccine, JOURNAL OF VIROLOGY, Vol: 92, ISSN: 0022-538X
Renner M, Flanagan A, Dejnirattisai W, et al., 2018, Characterization of a potent and highly unusual minimally enhancing antibody directed against dengue virus, NATURE IMMUNOLOGY, Vol: 19, Pages: 1248-+, ISSN: 1529-2908
Campos JLS, Mongkolsapaya J, Screaton GR, 2018, The immune response against flaviviruses, NATURE IMMUNOLOGY, Vol: 19, Pages: 1189-1198, ISSN: 1529-2908
Bidmos FA, Nadel S, Screaton GR, et al., 2018, Cross-reactive bactericidal antimeningococcal antibodies can be isolated from convalescing invasive Meningococcal disease patients using reverse vaccinology 2.0, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
The threat from invasive meningococcal disease remains a serious source of concern despite the licensure and availability of vaccines. A limitation of currently-available serogroup B vaccines is the breadth of coverage afforded, resulting from the capacity for extensive variation of the meningococcus and its huge potential for the generation of further diversity. Thus, the continuous search for candidate antigens that will compose supplementary or replacement vaccines is mandated. Here, we describe successful efforts to utilize the reverse vaccinology 2.0 approach to identify novel functionally-immunogenic meningococcal antigens. In this study, eight broadly cross-reactive sequence-specific anti-meningococcal human monoclonal antibodies (hmAbs) were cloned from 4 ml of blood taken from a 7-month old sufferer of invasive meningococcal disease (IMD). Three of these hmAbs possessed human complement-dependent bactericidal activity against meningococcal serogroup B strains of disparate PorA and 4CMenB antigen sequence types, strongly suggesting that the target(s) of these bactericidal hmAbs are not PorA (the immunodominant meningococcal antigen), factor-H binding protein (fHbp) or other components of currently-available meningococcal vaccines. Reactivity of the bactericidal hmAbs was confirmed to a single ca. 35 kDa protein in western blots. Unequivocal identification of this antigen is currently ongoing. Collectively, our results provide proof-of-principle for the use of reverse vaccinology 2.0 as a powerful tool in the search for alternative meningococcal vaccine candidate antigens.
Montoya M, Collins M, Dejnirattisai W, et al., 2018, Longitudinal analysis of antibody cross-neutralization following Zika and dengue virus infection in Asia and the Americas, Journal of Infectious Diseases, Vol: 218, Pages: 536-545, ISSN: 0022-1899
Background:The four denguevirus serotypes(DENV1-4)and Zikavirus(ZIKV) are related mosquito-borne flavivirusesof major importanceglobally.While monoclonal antibodiesand plasma from DENV-immune donors canneutralize or enhance ZIKVin vitroand in small animalmodels,and vice versa,the extent, duration, and significanceof cross-reactivityremains unknown,particularly in flavivirus-endemicregions.Methods:We studied neutralizing antibodiesto ZIKV and DENV1-4inlongitudinal serologic specimens through3 years post-infection from people in Latin America and Asiawith laboratory-confirmed DENV infections.We also evaluated neutralizingantibodiesto ZIKV and DENV1-4 in Zika patients through6 months post-infection. Results:In Zika patients, the highest neutralizing antibody titers were to ZIKV, with low-level cross-reactivity to DENV1-4 that was greater in DENV-immuneindividuals. We found in primary and secondaryDENV infections, neutralizing antibodytiters to ZIKV were markedly lower than to the infecting DENVandheterologous DENV serotypes.Cross-neutralization was greatest in early convalescence,then ZIKV neutralization decreased, remainingat low levelsover time.Conclusions:Patterns of antibody cross-neutralization suggestZIKV lies outside the DENV serocomplex. Neutralizing antibody titers can distinguish ZIKV from DENV infections when all viruses are analyzed simultaneously. These findings haveimplications for understanding natural immunity and vaccines.
López-Camacho C, Abbink P, Larocca RA, et al., 2018, Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors., Nature Communications, Vol: 9, ISSN: 2041-1723
Zika virus (ZIKV) emerged on a global scale and no licensed vaccine ensures long-lasting anti-ZIKV immunity. Here we report the design and comparative evaluation of four replication-deficient chimpanzee adenoviral (ChAdOx1) ZIKV vaccine candidates comprising the addition or deletion of precursor membrane (prM) and envelope, with or without its transmembrane domain (TM). A single, non-adjuvanted vaccination of ChAdOx1 ZIKV vaccines elicits suitable levels of protective responses in mice challenged with ZIKV. ChAdOx1 prME ∆TM encoding prM and envelope without TM provides 100% protection, as well as long-lasting anti-envelope immune responses and no evidence of in vitro antibody-dependent enhancement to dengue virus. Deletion of prM and addition of TM reduces protective efficacy and yields lower anti-envelope responses. Our finding that immunity against ZIKV can be enhanced by modulating antigen membrane anchoring highlights important parameters in the design of viral vectored ZIKV vaccines to support further clinical assessments.
Abbink P, Larocca RA, Dejnirattisai W, et al., 2018, Therapeutic and protective efficacy of a dengue antibody against Zika infection in Rhesus monkeys, Nature Medicine, Vol: 24, Pages: 721-723, ISSN: 1078-8956
Strategies to treat Zika virus (ZIKV) infection in dengue virus (DENV) endemic areas are urgently needed. Here we show that a DENV-specific antibody against the E-dimer epitope (EDE) potent ly cross-neutralizes ZIKV and provides robust therapeutic efficacy as well as prophylactic efficacy against ZIKV in rhesus monkeys. Viral escape was not detected, suggesting a relatively high bar to escape. These data demonstrate the potential for antibody-based therapy and prevention of ZIKV.
Screaton G, Mongkolsapaya J, 2018, Which dengue vaccine approach is the most promising, and should we be concerned about enhanced disease after vaccination? The challenges of a dengue vaccine, Cold Spring Harbor perspectives in biology, Vol: 10, ISSN: 1943-0264
A dengue vaccine has been pursued for more than 50 years and, unlike other flaviviral vaccines such as that against yellow fever, progress has been slow. In this review, we describe progress toward the first licensed dengue vaccine Dengvaxia, which does not give complete protection against disease. The antibody response to the dengue virion is reviewed, highlighting immunodominant yet poorly neutralizing responses in the context of a highly dynamic structurally flexible dengue virus particle. Finally, we review recent evidence for cross-reactivity between antibody responses to Zika and dengue viruses, which may further complicate the development of broadly protective dengue virus vaccines.
Culshaw A, Mongkolsapaya J, Screaton G, 2018, The immunology of Zika virus, F1000Research, Vol: 7, Pages: 203-203, ISSN: 2046-1402
Zika virus (ZIKV) was initially thought to cause only mild, self-limiting symptoms. However, recent outbreaks have been associated with the autoimmune disease Guillain-Barré syndrome and causally linked to a congenital malformation known as microcephaly. This has led to an urgent need for a safe and effective vaccine. A comprehensive understanding of the immunology of ZIKV infection is required to aid in the design of such a vaccine. Whilst details of both innate and adaptive immune responses to ZIKV are emerging, further research is needed. As immunopathogenesis has been implicated in poor outcomes following infection with the related dengue virus, identification of cross-reactive immune responses between flaviviruses and the impact they may have on disease progression is also of high importance.
Screaton G, Mongkolsapaya J, 2017, Evolution of neurovirulent Zika virus A Zika virus mutation leads to increased neurovirulence, Science, Vol: 358, Pages: 863-864, ISSN: 0036-8075
In 2015, Zika virus (ZIKV) became headline news after its association with fetal microcephaly (severely reduced head circumference) in Brazil and was declared a public health emergency by the World Health Organization (WHO) (1). However, ZIKV was not new, it was first isolated from the Zika forest, Uganda in 1947 (2). ZIKV incited little interest compared to other flaviviruses, such as dengue virus (DENV), as it was not thought to cause severe disease. ZIKV infections were largely sporadic, and symptoms were usually mild and flu-like, with self-limiting fever, rash, and conjunctivitis. Around 80% of cases were asymptomatic, and epidemic activity had not been described (3). In 2007, large-scale explosive outbreaks of ZIKV infection were described in Micronesia, and the virus spread across the Pacific, reaching South America in 2015, where it rapidly spread through Brazil and neighboring countries (3–5). On page 933 of this issue, Yuan et al. (6) compared sequences of contemporary ZIKV strains with ancestral ZIKV isolates and describe a mutation that increases the neurovirulence of contemporary strains, which they propose underscores the increased pathogenicity of recent outbreaks.
Fernandez E, Dejnirattisai W, Cao B, et al., 2017, Human antibodies to the dengue virus E-dimer epitope have therapeutic activity against Zika virus infection., Nature Immunology, Vol: 18, Pages: 1261-1269, ISSN: 1529-2908
The Zika virus (ZIKV) epidemic has resulted in congenital abnormalities in fetuses and neonates. Although some cross-reactive dengue virus (DENV)-specific antibodies can enhance ZIKV infection in mice, those recognizing the DENV E-dimer epitope (EDE) can neutralize ZIKV infection in cell culture. We evaluated the therapeutic activity of human monoclonal antibodies to DENV EDE for their ability to control ZIKV infection in the brains, testes, placentas, and fetuses of mice. A single dose of the EDE1-B10 antibody given 3 d after ZIKV infection protected against lethality, reduced ZIKV levels in brains and testes, and preserved sperm counts. In pregnant mice, wild-type or engineered LALA variants of EDE1-B10, which cannot engage Fcg receptors, diminished ZIKV burden in maternal and fetal tissues, and protected against fetal demise. Because neutralizing antibodies to EDE have therapeutic potential against ZIKV, in addition to their established inhibitory effects against DENV, it may be possible to develop therapies that control disease caused by both viruses.
Culshaw A, Ladell K, Gras S, et al., 2017, Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8(+) T cell response., Nature Immunology, Vol: 18, Pages: 1228-1237, ISSN: 1529-2908
Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A*11:01-restricted CD8(+) T cell populations specific for variants of the nonstructural protein epitope NS3133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3133-DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2(+) TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2(+) TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs.
Katzelnick LC, Harris E, 2017, Immune correlates of protection for dengue: State of the art and research agenda, Publisher: ELSEVIER SCI LTD, Pages: 4659-4669, ISSN: 0264-410X
Culshaw A, Mongkolsapaya J, Screaton GR, 2017, The immunopathology of dengue and Zika virus infections., Current Opinion in Immunology, Vol: 48, Pages: 1-6, ISSN: 0952-7915
A large proportion of the world's population live in areas with dengue virus (DENV) transmission resulting in tens of millions of symptomatic dengue cases each year. Serious complications following DENV infection occur more frequently in those suffering from a second or subsequent infection implicating virus-specific immunity as having a role in pathogenesis. In recent years outbreaks of the related Zika virus (ZIKV) have been associated with birth defects and neurological complications. As DENV and ZIKV share a viral vector sequential infections can occur. Given the sequence homology between the two viruses, the generation of cross-reactive immune responses is highly likely. This review examines the role immunopathogenesis plays during DENV infection as well as highlighting recent studies that demonstrate DENV immunity may have an effect on the outcome of ZIKV infection.
Yacoub S, Trieu HT, Phung KL, et al., 2017, Cardio-haemodynamic assessment and venous lactate in severe dengue: Relationship with recurrent shock and respiratory distress, PLOS NEGLECTED TROPICAL DISEASES, Vol: 11, ISSN: 1935-2735
BackgroundDengue can cause plasma leakage that may lead to dengue shock syndrome (DSS). In approximately 30% of DSS cases, recurrent episodes of shock occur. These patients have a higher risk of fluid overload, respiratory distress and poor outcomes. We investigated the association of echocardiographically-derived cardiac function and intravascular volume parameters plus lactate levels, with the outcomes of recurrent shock and respiratory distress in severe dengue.Methods/Principle findingsWe performed a prospective observational study in Paediatric and adult ICU, at the Hospital for Tropical Diseases (HTD), Ho Chi Minh City, Vietnam. Patients with dengue were enrolled within 12 hours of admission to paediatric or adult ICU. A haemodynamic assessment and portable echocardiograms were carried out daily for 5 days from enrolment and all interventions recorded.102 patients were enrolled; 22 patients did not develop DSS, 48 had a single episode of shock and 32 had recurrent shock. Patients with recurrent shock had a higher enrolment pulse than those with 1 episode or no shock (median: 114 vs. 100 vs. 100 b/min, P = 0.002), significantly lower Stroke Volume Index (SVI), (median: 21.6 vs. 22.8 vs. 26.8mls/m2, P<0.001) and higher lactate levels (4.2 vs. 2.9 vs. 2.2 mmol/l, P = 0.001). Higher SVI and worse left ventricular function (higher Left Myocardial Performance Index) on study days 3–5 was associated with the secondary endpoint of respiratory distress. There was an association between the total IV fluid administered during the ICU admission and respiratory distress (OR: 1.03, 95% CI 1.01–1.06, P = 0.001). Admission lactate levels predicted patients who subsequently developed recurrent shock (P = 0.004), and correlated positively with the total IV fluid volume received (rho: 0.323, P = 0.001) and also with admission ALT (rho: 0.764, P<0.001) and AST (rho: 0.773, P<0.001).Conclusions/SignificanceEcho-derived intravascular volume assessment and venou
Yacoub S, Lam PK, Huynh TT, et al., 2017, Endothelial nitric oxide pathways in the pathophysiology of dengue: a prospective observational study., Clinical Infectious Diseases, Vol: 65, Pages: 1453-1461, ISSN: 1058-4838
Background: Dengue can cause increased vascular permeability that may lead to hypovolemic shock. Endothelial dysfunction may underlie this; however the association of endothelial nitric oxide pathways with disease severity is unknown. Methods: We performed a prospective observational study in two Vietnamese hospitals, assessing patients presenting early (<72 hours fever) and patients hospitalized with warning signs or severe dengue. The reactive hyperaemic index (RHI), which measures endothelium-dependent vasodilation and is a surrogate marker of endothelial function and NO bioavailability was evaluated using peripheral artery tonometry (EndoPAT) and plasma levels of L-arginine, Arginase-1 and ADMA were measured at serial time-points. The main outcome of interest was plasma leakage severity. Results: 314 patients were enrolled, median age of the participants was 21 (IQR 13-30) years. No difference was found in the endothelial parameters between dengue and other febrile illness (OFI). Considering dengue patients, the RHI was significantly lower for patients with severe plasma leakage compared to those with no leakage (1.46 vs. 2.00, P<0.001), over acute time-points, apparent already in the early febrile phase (1.29 vs. 1.75, P=0.012). RHI correlated negatively with arginase-1, and positively with L-arginine (P=0.001). Endothelial dysfunction/NO bioavailability is associated with worse plasma leakage, occurs early in dengue illness and correlates with hypoargininaemia and high arginase-1 levels.
Scherwitzl I, Mongkolsapaja J, Screaton G, 2017, Recent advances in human flavivirus vaccines., Current Opinion in Virology, Vol: 23, Pages: 95-101, ISSN: 1879-6265
Dengue (DENV), West Nile (WNV) and Zika (ZIKV) viruses are mosquito-transmitted flaviviruses that cause thousands of human deaths and millions of illnesses each year. In the last decades, epidemic outbreaks of all three flaviviruses emerged and caused a major health and economical problem in many parts of the world. The increasing and expanding burden of flaviviruses has highlighted the need for effective human vaccines against all three viruses. This review provides an overview of the recent progress in DENV, WNV and ZIKV vaccines development with specific focus on candidates in human clinical development.
Lebre MC, Vieira PL, Tang MW, et al., 2016, Synovial IL-21/TNF-producing CD4(+) T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast-like synoviocytes, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 101, Pages: 775-783, ISSN: 0741-5400
Tuberculosis (TB) remains a major public health problem internationally, causing 9.6 million new cases and 1.5 milliondeaths worldwide in 2014. The Bacillus Calmette-Guérin vaccine is the only licensed vaccine against TB, but itsprotective effect does not extend to controlling the development of infectious pulmonary disease in adults. Thedevelopment of a more effective vaccine against TB is therefore a pressing need for global health. Although it isestablished that cell-mediated immunity is necessary for the control of latent infection, the presupposition that suchimmunity is sufficient for vaccine-induced protection has recently been challenged. A greater understanding ofprotective immunity against TB is required to guide future vaccine strategies against TB. In contrast to cell-mediatedimmunity, the human antibody response against M.tb is conventionally thought to exert little immune control over thecourse of infection. Humoral responses are prominent during active TB disease, and have even been postulated tocontribute to immunopathology. However, there is evidence to suggest that specific antibodies may limit thedissemination of M.tb, and potentially also play a role in prevention of infection via mucosal immunity. Further,antibodies are now understood to confer protection against a range of intracellular pathogens by modulating immunityvia Fc-receptor mediated phagocytosis. In this review, we will explore the evidence that antibody-mediated immunitycould be reconsidered in the search for new vaccine strategies against TB.
Barba-Spaeth G, Dejnirattisai W, Rouvinski A, et al., 2016, Structural basis of potent Zika-dengue virus antibody cross-neutralization, Nature, Vol: 536, Pages: 48-53, ISSN: 1476-4687
Zika virus is a member of the flavivirus genus that had not been associated with severe disease in humans until the recent outbreaks, when it was linked to microcephaly in newborns in Brazil and to Guillain-Barré syndrome in adults in French Polynesia. Zika virus is related to dengue virus, and we report here that a category of antibodies isolated from dengue patients and targeting a conformational epitope potently neutralize Zika virus. The crystal structure of two of these antibodies in complex with the envelope protein of Zika virus reveals the details of a conserved epitope, which is also the site of interaction of the envelope protein dimer with the precursor prM protein during virus maturation. Comparison of the Zika and dengue virus immunocomplexes provides a lead for rational, epitope-focused design of a universal vaccine capable of eliciting potent cross-neutralizing antibodies to protect against Zika and dengue viruses simultaneously.
van Wilgenburg B, Scherwitzl I, Hutchinson EC, et al., 2016, MAIT cells are activated during human viral infections, Nature Communications, Vol: 7, ISSN: 2041-1723
Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo. MAIT cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus. This activation-driving cytokine release and Granzyme B upregulation-is TCR-independent but dependent on IL-18 in synergy with IL-12, IL-15 and/or interferon-α/β. IL-18 levels and MAIT cell activation correlate with disease severity in acute dengue infection. Furthermore, HCV treatment with interferon-α leads to specific MAIT cell activation in vivo in parallel with an enhanced therapeutic response. Moreover, TCR-independent activation of MAIT cells leads to a reduction of HCV replication in vitro mediated by IFN-γ. Together these data demonstrate MAIT cells are activated following viral infections, and suggest a potential role in both host defence and immunopathology.
Dejnirattisai W, Supasa P, Wongwiwat W, et al., 2016, Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus, Nature Immunology, Vol: 17, Pages: 1102-1108, ISSN: 1529-2916
Zika virus (ZIKV) was discovered in 1947 and was thought to lead to relatively mild disease. The recent explosive outbreak of ZIKV in South America has led to widespread concern, with reports of neurological sequelae ranging from Guillain Barré syndrome to microcephaly. ZIKV infection has occurred in areas previously exposed to dengue virus (DENV), a flavivirus closely related to ZIKV. Here we investigated the serological cross-reaction between the two viruses. Plasma immune to DENV showed substantial cross-reaction to ZIKV and was able to drive antibody-dependent enhancement (ADE) of ZIKV infection. Using a panel of human monoclonal antibodies (mAbs) to DENV, we showed that most antibodies that reacted to DENV envelope protein also reacted to ZIKV. Antibodies to linear epitopes, including the immunodominant fusion-loop epitope, were able to bind ZIKV but were unable to neutralize the virus and instead promoted ADE. Our data indicate that immunity to DENV might drive greater ZIKV replication and have clear implications for disease pathogenesis and future vaccine programs for ZIKV and DENV.
Yacoub S, Lam PK, Vu LH, et al., 2016, Association of microvascular function and endothelial biomarkers with clinical outcome in dengue: an observational study, Journal of Infectious Diseases, Vol: 214, Pages: 697-706, ISSN: 1537-6613
Background. The hallmark of severe dengue is increased microvascular permeability however alterations in the microcirculation and their evolution over the course of dengue are unknown.Methods. We conducted a prospective observational study to evaluate the sublingual microcirculation using sidestream dark field imaging in patients presenting early (<72 hours fever) and patients hospitalized with warning signs or severe dengue in Vietnam. Clinical, microvascular function, global haemodynamics assessed by echocardiograms and serological markers of endothelial activation were performed at 4 time points.Results. 165 patients were enrolled. No difference was found between the microcirculatory parameters comparing dengue with other febrile illnesses. Proportion of perfused vessels (PPV) and Mean Flow Index (MFI) were lower in dengue patients with plasma leakage (PPV: 88.1% vs. 90.6%, P=0.010 and MFI: 2.1 vs. 2.4, P=0.007) most marked during the critical phase. PPV and MFI correlated with the endothelial activation markers, VCAM-1 (P<0.001 for both) and Angiopoietin-2 (P<0.001 and P=0.001 respectively) with a negative association.Conclusion. Modest microcirculatory alterations occur in dengue, are associated with plasma leakage and correlate with molecules of endothelial activation, Angiopoietin-2 and VCAM-1.
Jonsson P, Southcombe JH, Santos AM, et al., 2016, Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 5682-5687, ISSN: 1091-6490
The αβ T-cell coreceptor CD4 enhances immune responses more than 1 million-fold in some assays, and yet the affinity of CD4 for its ligand, peptide-major histocompatibility class II (pMHC II) on antigen-presenting cells, is so weak that it was previously unquantifiable. Here, we report that a soluble form of CD4 failed to bind detectably to pMHC II in surface plasmon resonance-based assays, establishing a new upper limit for the solution affinity at 2.5 mM. However, when presented multivalently on magnetic beads, soluble CD4 bound pMHC II-expressing B cells, confirming that it is active and allowing mapping of the native coreceptor binding site on pMHC II. Whereas binding was undetectable in solution, the affinity of the CD4/pMHC II interaction could be measured in 2D using CD4- and adhesion molecule-functionalized, supported lipid bilayers, yielding a 2D Kd of ∼5,000 molecules/μm2. This value is two to three orders of magnitude higher than previously measured 2D Kd values for interacting leukocyte surface proteins. Calculations indicated, however, that CD4/pMHC II binding would increase rates of T-cell receptor (TCR) complex phosphorylation by threefold via the recruitment of Lck, with only a small, 2–20% increase in the effective affinity of the TCR for pMHC II. The affinity of CD4/pMHC II therefore seems to be set at a value that increases T-cell sensitivity by enhancing phosphorylation, without compromising ligand discrimination.
Yacoub S, Mongkolsapaya J, Screaton G, 2016, Recent advances in understanding dengue, F1000 Research, Vol: 5, ISSN: 2046-1402
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