scholarly journals FRI0262 INCREASED PLASMA LEVELS OF HSP90 ARE ASSOCIATED WITH MORE SEVERE LUNG AND SKIN INVOLVEMENT IN PATIENTS WITH SYSTEMIC SCLEROSIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 715-716
Author(s):  
H. Štorkánová ◽  
S. Oreska ◽  
M. Špiritović ◽  
B. Heřmánková ◽  
K. Bubova ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Plasma Levels ◽  
Dependent Manner ◽  
Healthy Controls ◽  
Skin Involvement ◽  
Dermal Fibrosis ◽  
Potential Association ◽  
One Year

Background:Our previous study demonstrated that Hsp90 is overexpressed in the skin of patients with systemic sclerosis (SSc), in cultured SSc fibroblasts and preclinical models of SSc in a TGF-β dependent manner. We showed that Hsp90 is a new regulator of canonical TGF-β signaling and its inhibition prevents the stimulatory effects of TGF-β on collagen synthesis and dermal fibrosis1.Objectives:The aim of this study was to evaluate plasma Hsp90 of SSc patients and characterize its potential association with skin changes and SSc-related features.Methods:A total of 92 patients (79 females; mean age 52.7; disease duration 6.0 years; diffuse cutaneous (dc)SSc / limited cutaneous (lc)SSc = 38/54) and 92 age- and sex- matched healthy individuals were included. Plasma Hsp90 levels were measured by ELISA (eBioscience, Vienna, Austria). Data are presented as median (IQR).Results:Plasma Hsp90 levels were increased in SSc patients compared to healthy controls [12.5 (9.6–17.9) vs. 9.8 (7.7–12.4) ng/mL, p=0.0001]. Hsp90 levels in all patients positively correlated with CRP (r=0.271, p=0.015). Furthermore, Hsp90 concentrations were negatively associated with functional parameters of ILD: FVC (r=-0.291, p=0.013), FEV1 (r=-0.248, p=0.036), DLCO (r=-0.290, p=0.012) and SpO2(r=-0.317, p=0.038). When adjusted for CRP, these correlations still remained significant in multivariate analysis. Higher Hsp90 concentrations were associated with presence of synovitis [17.6 (15.4 – 24.0) vs. 12.2 (9.3 – 17.3), p=0.039]. In addition, only in patients with dcSSc, Hsp90 levels positively correlated with the mRSS (r=0.437, p=0.006). In a prospective analysis of patients with progressive SSc-ILD treated with 6 (n=21 patients) or 12 (n=14 patients) monthly i.v. pulses of cyclophosphamide (CPA, 10 mg/kg) we did not observe any significant differences between the baseline sample (month 0) and blood drawn after 1, 6 and 12 months. However, baseline Hsp90 was able to predict long-term response after one year of CPA treatment (DLCOm12-m0; r=-0.494, p=0.037). Moreover, change in Hsp90 after one month of CPA treatment (Hsp90m1-m0) was able to predict the short-term inflammatory response (CRPm3-m0, r=-0.495, p=0.019; ESRm3-m0, r=-0.496, p=0.031). Concentrations of extracellular Hsp90 were not significantly affected by other main clinical parameters of SSc.Conclusion:We demonstrated higher plasma levels of Hsp90 in SSc patients compared to healthy controls. Concentrations of extracellular Hsp90 increase with higher inflammatory activity, with deteriorated lung functions in ILD and also with the extent and severity of the skin involvement in patients with diffuse cutaneous SSc. These data further highlight the role of Hsp90 as a significant regulator of fibroblast activation and tissue fibrosis in SSc. In addition, Hsp90 could become a predictor of treatment response.References:[1]Tomcik M et al., Ann Rheum Dis.2014;73(6):1215-22.Acknowledgments:Supported by AZV-16-33542A, MHCR 023728 and SVV – 260373.Disclosure of Interests:Hana Štorkánová: None declared, Sabina Oreska: None declared, Maja Špiritović: None declared, Barbora Heřmánková: None declared, Kristyna Bubova: None declared, Martin Komarc: None declared, Karel Pavelka Consultant of: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Speakers bureau: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Jiří Vencovský: None declared, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim, Ladislav Šenolt: None declared, Radim Bečvář Consultant of: Actelion, Roche, Michal Tomcik: None declared

scholarly journals AB0410 S100A4 PLASMA LEVELS CORRELATE WITH DISEASE ACTIVITY, SKIN FIBROSIS AND INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1233.2-1233
Author(s):  
H. Štorkánová ◽  
L. Andres Cerezo ◽  
S. Oreska ◽  
M. Špiritović ◽  
B. Heřmánková ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Disease Activity ◽  
Lung Disease ◽  
Plasma Levels ◽  
Statistical Significance ◽  
Activity Score ◽  
Dependent Manner ◽  
Healthy Controls ◽  
Peripheral Oxygen Saturation ◽  
Potential Association

Background:In our previous study we demonstrated that S100A4 is overexpressed in scleroderma (SSc) skin, SSc fibroblasts and preclinical models of SSc in a TGF-β dependent manner. We showed that S100A4 is a new regulator of TGF-β signalling and its inhibition prevents the pro-fibrotic effects of TGF-β. Inactivation of S100A4 prevented dermal fibrosis induced by bleomycin and in Tsk-1 miceObjectives:The aim of this study was to evaluate S100A4 in the peripheral blood of SSc patients and characterize its potential association with SSc-related features.Methods:A total of 33 patients (29 females; mean age 52.8; disease duration 4.2 years; dcSSc/lcSSc = 8/25) who met the 2013 EULAR/ACR classification criteria for SSc and 20 healthy age- and sex-matched individuals were included in this study. Plasma levels of S100A4 were measured using ELISA (CUSABIO, Houston, USA). Data are presented as median (IQR).Results:S100A4 plasma levels were significantly increased in SSc patients compared to healthy controls (78.6(32.3-146.5) vs. 43.4(32.3-53.4)ng/mL,p=0.011). Patients with diffuse cutaneous (dc)SSc had significantly higher levels of S100A4 than patients with limited cutaneous (lc)SSc or healthy controls (168.5(81.5-347.5) vs. 63.4(30.9-130.6),p=0.017,p=0.001, respectively). Plasma levels of S100A4 positively correlated with mRSS (r=0.556,p=0.001). Furthermore, S100A4 negatively correlated with forced vital capacity (FVC) and peripheral oxygen saturation (SpO2) (r=- 0.362,p=0.038;r=-0.414,p=0.029, respectively). S100A4 levels positively correlated with ESSG activity score (r=0.750,p<0.001). However, only correlations between S100A4 and mRSS, and ESSG activity score were approved at corrected level of statistical significance after Bonferroni’s correction (p<0.01). In a prospective analysis of patients (n=40) with progressive SSc-ILD treated with 6 (n=24) or 12 (n=16) monthly i.v. pulses of cyclophosphamide (CPA, 500 mg/m2), we observed a significant decrease in plasma S100A4 levels between the baseline samples (month 0) and blood drawn after 6 months of CPA treatment (76.3(52.9–98.6) vs. 73.2(44.4–98.6)ng/mL,p=0.013). Furthermore, baseline S100A4 levels predicted the change (m0-m6) in CRP and ESR levels after 6 months of CPA therapy (r=0.472,p=0.004;r=0.528,p=0.003, respectively).Conclusion:We demonstrate that plasma S100A4 levels are significantly increased in SSc patients compared with healthy controls. Increased S100A4 is associated with the dcSSc subset, skin involvement, deteriorated parameters of interstitial lung disease and higher disease activity. In patients with progressive SSc-ILD, S100A4 declines after 6 months of cyclophosphamide therapy and predicts the systemic inflammatory response. These data further support our previous findings on the role of S100A4 as a regulator of TGF-β induced fibrosis in SSc.Acknowledgements:Supported by MHCR023728, SVV–260373.Disclosure of Interests:None declared

HLA-G Expression in the Skin of Patients with Systemic Sclerosis

2009 ◽  
Vol 36 (6) ◽  
pp. 1230-1234 ◽  
Author(s):  
ISABELA J. WASTOWSKI ◽  
PERCIVAL D. SAMPAIO-BARROS ◽  
ELIANE M.I. AMSTALDEN ◽  
GUSTAVO MARTELLI PALOMINO ◽  
JOÃO FRANCISCO MARQUES-NETO ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Control Sample ◽  
Healthy Controls ◽  
Skin Disorders ◽  
Disease Prognosis ◽  
Laboratory Variables ◽  
Skin Biopsies ◽  
Dermal Cells

Objective.To determine HLA-G expression in skin biopsies from patients with systemic sclerosis (SSc), and its association with epidemiological, clinical, and laboratory variables and survival.Methods.Paraffin-embedded skin biopsies obtained from 21 SSc patients (14 limited SSc, 7 diffuse SSc) and from 28 healthy controls were studied. HLA-G expression was evaluated by immunohistochemistry.Results.HLA-G molecules were detected in 57% of skin biopsies from patients with SSc (9 from limited SSc, 3 from diffuse SSc), whereas no control sample expressed HLA-G (p = 0.000004). In patients, HLA-G molecules were consistently observed within epidermal and some dermal cells. HLA-G expression was associated with a lower frequency of vascular cutaneous ulcers (p = 0.0004), telangiectasias (p = 0.008), and inflammatory polyarthralgia (p = 0.02). After a 15-year followup, SSc patients who exhibited HLA-G survived longer than patients who did not.Conclusion.HLA-G is expressed in skin biopsies from patients with SSc, and this is associated with a better disease prognosis. This suggests a modulatory role of HLA-G in SSc, as observed in other skin disorders.

scholarly journals Role of methyleprednisolone succinate in the management of acute spinal cord injury

1970 ◽  
Vol 9 (3) ◽  
pp. 168-172
Author(s):  
NK Karn ◽  
BP Shrestha ◽  
GP Khanal ◽  
R Rijal ◽  
P Chaudhary ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neurological Status ◽  
Acute Spinal Cord Injury ◽  
Cord Injury ◽  
And Gender ◽  
One Year

Objective: To see the role of methyleprednisolone succinate in the management of acute spinal cord injury. Methods: A randomized control trial was done including the patients with acute spinal cord injury. They were divided into age and gender matched two groups. Patients with presence of active infection, associated open fracture, those on long term steroid and those who did not give consent to participate in the trial were excluded. One group received methyleprednisolone succinate within 8 hours of injury and another group did not receive the drug. Both the groups were managed nonoperatively. The neurological status of the patients was assessed at presentation, once spinal shock was over, at 6th week and 6th month and after one year according to ASIA scoring. Frankel grading was also assessed in every follow up. Conclusion: Methylprednisolone succinct prevents secondary cord injury to a great extent and hence its administration within 8 hours of injury results in a better functional (motor and sensory) outcome. Keywords: acute spinal cord injury; methyleprednisolone succinate DOI: http://dx.doi.org/10.3126/hren.v9i3.5585   HR 2011; 9(3): 168-172

A Preliminary Study of Acoustic Radiation Force Impulse Quantification for the Assessment of Skin in Diffuse Cutaneous Systemic Sclerosis

2015 ◽  
Vol 42 (3) ◽  
pp. 449-455 ◽  
Author(s):  
Yong Hou ◽  
Qing-li Zhu ◽  
He Liu ◽  
Yu-xin Jiang ◽  
Liang Wang ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Acoustic Radiation ◽  
Radiation Force ◽  
Acoustic Radiation Force ◽  
Acoustic Radiation Force Impulse ◽  
Skin Thickness ◽  
Healthy Controls ◽  
Skin Involvement ◽  
Skin Score ◽  
Valuable Adjunct

Objective.To investigate skin elasticity using acoustic radiation force impulse (ARFI) quantification in systemic sclerosis (SSc), and compare the modified Rodnan skin score (mRSS) with measured shear wave velocity (SWV) and thickness of the skin.Methods.Fifteen patients with diffuse cutaneous SSc (dcSSc) and 15 age-matched and sex-matched healthy controls were evaluated. The SWV and thickness of skin were measured at 17 sites corresponding to those assessed in the mRSS in each participant. The SWV measurements of skin were compared between patients with dcSSc and healthy controls. The correlations between the mRSS and the skin SWV and thickness were explored using Spearman’s correlation.Results.The SWV values were higher in patients with dcSSc compared with healthy controls at right hand dorsum, right forearm, left hand dorsum, left forearm, right foot dorsum, and left foot dorsum (p < 0.05). In patients with dcSSc, the SWV values of uninvolved skin were higher than those of controls (p < 0.001), and the SWV values increased with increasing skin scores except for skin score 3 (p < 0.05). The sum of the SWV values correlated with total clinical skin score (r = 0.841, p < 0.001), and the sum of the skin thickness correlated with total clinical skin score (r = 0.740, p = 0.002).Conclusion.ARFI quantification is feasible and reliable for assessing the skin involvement in dcSSc. ARFI quantification could identify early skin change that may precede palpable skin involvement, and may be a valuable adjunct to skin evaluation in patients with SSc.

scholarly journals Effects of Fire and Large Herbivores on Canopy Nitrogen in a Tallgrass Prairie

2019 ◽  
Vol 11 (11) ◽  
pp. 1364 ◽  
Author(s):  
Bohua Ling ◽  
Edward J. Raynor ◽  
Douglas G. Goodin ◽  
Anthony Joern
Keyword(s):  
Spatial Variability ◽  
Nitrogen Content ◽  
Tallgrass Prairie ◽  
High Nitrogen Content ◽  
High Nitrogen ◽  
Grazing History ◽  
One Year ◽  
Canopy Nitrogen

This study analyzed the spatial heterogeneity of grassland canopy nitrogen in a tallgrass prairie with different treatments of fire and ungulate grazing (long-term bison grazing vs. recent cattle grazing). Variogram analysis was applied to continuous remotely sensed canopy nitrogen images to examine the spatial variability in grassland canopies. Heterogeneity metrics (e.g., the interspersion/juxtaposition index) were calculated from the categorical canopy nitrogen maps and compared among fire and grazing treatments. Results showed that watersheds burned within one year had higher canopy nitrogen content and lower interspersions of high-nitrogen content patches than watersheds with longer fire intervals, suggesting an immediate and transient fire effect on grassland vegetation. In watersheds burned within one year, high-intensity grazing reduced vegetation density, but promoted grassland heterogeneity, as indicated by lower canopy nitrogen concentrations and greater interspersions of high-nitrogen content patches at the grazed sites than at the ungrazed sites. Variogram analyses across watersheds with different grazing histories showed that long-term bison grazing created greater spatial variability of canopy nitrogen than recent grazing by cattle. This comparison between bison and cattle is novel, as few field experiments have evaluated the role of grazing history in driving grassland heterogeneity. Our analyses extend previous research of effects from pyric herbivory on grassland heterogeneity by highlighting the role of grazing history in modulating the spatial and temporal distribution of aboveground nitrogen content in tallgrass prairie vegetation using a remote sensing approach. The comparison of canopy nitrogen properties and the variogram analysis of canopy nitrogen distribution provided by our study are useful for further mapping grassland canopy features and modeling grassland dynamics involving interplays among fire, large grazers, and vegetation communities.

Physiological persona differences based on stress and inflammation between meditators and healthy controls

2019 ◽  
Vol 17 (2) ◽  
Author(s):  
Dipti Magan ◽  
Raj Kumar Yadav
Keyword(s):  
Blood Pressure ◽  
Body Mass Index ◽  
Plasma Levels ◽  
Inflammatory Markers ◽  
Tumor Necrosis ◽  
Healthy Controls ◽  
Short Term ◽  
Tnf Α ◽  
Necrosis Factor

AbstractBackgroundNowadays, yoga is endorsed and advised routinely to stay fit and healthy, as well as control many chronic diseases including diabetes type 2, hypertension, coronary artery diseases, etc. Now, our assumption is that those who do regular yoga have different persona than who do not do yoga regularly. We planned to test our hypothesis scientifically, and therefore baseline physiological characteristics with stress and inflammation levels in long-term and short-term meditators and healthy novice controls were analyzed.MethodsIn this retrospective analysis, 97 male participants were included for their Baseline analysis. Fifteen apparently healthy subjects practicing preksha meditation (since >5 years, at least 5 days a week) were included as long-term meditators (LTMs); 58 subjects who attended one of our short-term yoga-based lifestyle intervention programs for 2 weeks were included as short-term meditators (STMs); 24 male novice subjects, who did not participate in any yogic intervention, were included as healthy controls. Here, we analyzed the Baseline plasma levels of stress and inflammatory markers, cortisol, β-endorphin, interleukin (IL)-6 and tumor necrosis factor (TNF)-α in long-term meditators vs. short-term meditators vs. healthy controls.Outcome measuresThe study parameters body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma levels of stress and immune markers, cortisol, β-endorphin (β-Ed), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), were assessed in all the three groups at baseline.ResultsSignificant (p<0.05) differences were observed at baseline for plasma levels of stress and inflammatory markers as well as body mass index and systolic blood pressure among LTM vs. STM vs. healthy controls.ConclusionsOur observations suggest that the subjects who do regular yoga-meditation practice have better stress & inflammation status than comparable age matched healthy controls.

scholarly journals 0790 The Clinical Significance of Hepcidin as a Predictive Value for Treatment Responses in Restless Legs Syndrome

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A300-A301
Author(s):  
H Im
Keyword(s):  
Restless Legs Syndrome ◽  
Iron Homeostasis ◽  
Dependent Manner ◽  
Healthy Controls ◽  
Restless Legs ◽  
Inflammatory Processes ◽  
Drug Naïve ◽  
Therapeutic Responses

Abstract Introduction Restless legs syndrome (RLS) is a common sensory motor neurological disorder that is related to iron-dopamine dysregulation and immune system alteration. Hepcidin is the key regulatory hormone of systemic iron homeostasis and is related to inflammatory processes. We aimed to evaluate the clinical utility of hepcidin as a diagnostic biomarker and index of therapeutic responses in RLS patients after dopaminergic treatment. Methods Non-anemic and drug-naive RLS patients (n=18) and healthy controls (n=15) were enrolled. Hepcidin (pre-prohepcidin) and iron-related values in serum were measured upon the first visit in both groups and 12 weeks later after dopaminergic treatment in 12 RLS patients. Information about sociodemographic characteristics, sleep-related profiles, mood, and anxiety was obtained upon the first visit in all participants as well as after treatment in RLS patients. Results Hepcidin levels exhibited no significant differences between patients with drug-naïve RLS and healthy controls at a diagnosis (7.1 ± 2.4 vs. 7.0 ± 3.2 ng/ml, p = 0.978). Decreased hepcidin levels were significantly associated with decreased RLS severity (β = 0.002, 95% CI = 0.00−0.00, p = 0.005) and improved quality of life (β = 0.002, 95% CI = 0.00−7.01, p = 0.044) in a dose-dependent manner after 12 weeks of treatment with a dopamine agonist. This association was independent of age, sex, inflammatory markers, sleep quality, insomnia, daytime sleepiness, depression, and anxiety. Conclusion This study demonstrates a role of hepcidin as a predictor of therapeutic responses in RLS patients. Support This work was supported by the Korea Health technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, South Korea [grant number HI17C2072].

Long-term changes in rumen fermentation in defaunated sheep

1991 ◽  
Vol 1991 ◽  
pp. 77-77
Author(s):  
P.P. Frumholtz ◽  
R.J. Wallace ◽  
C.J. Newbold ◽  
E.R. Ørskov
Keyword(s):  
Animal Species ◽  
Fish Meal ◽  
Jugular Vein ◽  
Rumen Fermentation ◽  
Bacteria And Fungi ◽  
One Year ◽  
The Stability ◽  
Ciliate Protozoa

The removal of ciliate protozoa, or defaunation, results in the establishment of a new ecosystem in the rumen, consisting only of bacteria and fungi. Although extensive research has been done on ciliate-free ruminants, the role of protozoa in the rumen still provokes considerable debate. The diversity of experimental design, such as animal species, defaunation method, and diet could account for many of the differences observed between defaunation studies. Also it is important to examine the stability of the ciliate-free ecosystem. The aim of this study was to investigate changes in rumen fermentation of ciliate-free sheep over a period of one year.Eight male castrated sheep, weighing 60-70 kg, received twice daily 700 g of a diet of hay, barley, molasses, fish meal and vitamins/minerals (500, 299.5, 100, 91 and 9.5 g/kg DM respectively). Four sheep were defaunated by the rumen washing technique (Jouany and Senaud, 1979) and kept in isolated pens while the other four were left faunated with a mixed type A ciliate protozoa population. Rumen samples were withdrawn via the rumen cannula and blood samples were taken from the jugular vein -1, 0, 1, 2, 4 and 6 h after feeding. There were three sampling periods: one month, six months and one year after defaunation.

scholarly journals Vitamin D status and metabolism in an ovine pregnancy model: effect of long-term, high-altitude hypoxia

2016 ◽  
Vol 310 (11) ◽  
pp. E1062-E1071 ◽  
Author(s):  
Ravi Goyal ◽  
Tara L. Billings ◽  
Trina Mansour ◽  
Courtney Martin ◽  
David J. Baylink ◽  
...  
Keyword(s):  
Vitamin D ◽  
High Altitude ◽  
Plasma Levels ◽  
Vitamin D Status ◽  
Molecular Determinants ◽  
Near Term ◽  
Specific Regulation ◽  
Circulating Levels

Vitamin D status increases during healthy mammalian pregnancy, but the molecular determinants remain uncharacterized. The first objective of this study was to determine the effects of pregnancy, and the second objective was to examine the role of chronic hypoxia on vitamin D status and metabolism in an ovine model. We analyzed the plasma levels of cholecalciferol, 25-OH-D, and 1α,25-(OH)2D in nonpregnant ewes, near-term pregnant ewes, and their fetuses exposed to normoxia (low altitude) or hypoxia (high-altitude) for 100 days. Hypoxic sheep had increased circulating levels of 25-OH-D and 1α,25-(OH)2D compared with normoxic sheep. Hypoxia increases in 25-OH-D were associated with increased expression of renal 25-hydroxylases CYP2R1 and CYP2J. Pregnancy did not increase further the plasma levels of 25-OH-D, but it significantly increased those of the active metabolite, 1α,25-(OH)2D, in both normoxic and hypoxic ewes. Increased bioactivation of vitamin D correlated with increased expression of the vitamin D-activating enzyme CYP27b1 and decreased expression of the inactivating enzyme CYP24a1 in maternal kidneys and placentas. Hypoxia increased parathyroid hormone levels and further increased renal CYP27b1. Pregnancy and hypoxia decreased the expression of vitamin D receptor (VDR) in maternal kidney and lung, with opposite effects on placental VDR. We conclude that ovine pregnancy is a model of increased vitamin D status, and long-term hypoxia further improves vitamin D status due to pregnancy- and hypoxia-specific regulation of VDR and metabolic enzymes.

scholarly journals Role of LAMP1 Binding and pH Sensing by the Spike Complex of Lassa Virus

2016 ◽  
Vol 90 (22) ◽  
pp. 10329-10338 ◽  
Author(s):  
Hadas Cohen-Dvashi ◽  
Hadar Israeli ◽  
Orly Shani ◽  
Aliza Katz ◽  
Ron Diskin
Keyword(s):  
Membrane Fusion ◽  
Molecular Mechanisms ◽  
Cell Entry ◽  
Lassa Virus ◽  
Dependent Manner ◽  
Acidic Ph ◽  
Ph Sensing ◽  
Positively Charged

ABSTRACTTo effectively infect cells, Lassa virus needs to switch in an endosomal compartment from its primary receptor, α-dystroglycan, to a protein termed LAMP1. A unique histidine triad on the surface of the receptor-binding domain from the glycoprotein spike complex of Lassa virus is important for LAMP1 binding. Here we investigate mutated spikes that have an impaired ability to interact with LAMP1 and show that although LAMP1 is important for efficient infectivity, it is not required for spike-mediated membrane fusionper se. Our studies reveal important regulatory roles for histidines from the triad in sensing acidic pH and preventing premature spike triggering. We further show that LAMP1 requires a positively charged His230 residue to engage with the spike complex and that LAMP1 binding promotes membrane fusion. These results elucidate the molecular role of LAMP1 binding during Lassa virus cell entry and provide new insights into how pH is sensed by the spike.IMPORTANCELassa virus is a devastating disease-causing agent in West Africa, with a significant yearly death toll and severe long-term complications associated with its infection in survivors. In recent years, we learned that Lassa virus needs to switch receptors in a pH-dependent manner to efficiently infect cells, but neither the molecular mechanisms that allow switching nor the actual effects of switching were known. Here we investigate the activity of the viral spike complex after abrogation of its ability to switch receptors. These studies inform us about the role of switching receptors and provide new insights into how the spike senses acidic pH.

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