Publications by authors named "Alessandra Soares-Schanoski"

34 Publications

Antibody Responses to SARS-CoV-2 Following an Outbreak Among Marine Recruits With Asymptomatic or Mild Infection.

Front Immunol 2021 9;12:681586. Epub 2021 Jun 9.

Naval Medical Research Center, Silver Spring, MD, United States.

We investigated serological responses following a SARS-CoV-2 outbreak in spring 2020 on a US Marine recruit training base. 147 participants that were isolated during an outbreak of respiratory illness were enrolled in this study, with visits approximately 6 and 10 weeks post-outbreak (PO). This cohort is comprised of young healthy adults, ages 18-26, with a high rate of asymptomatic infection or mild symptoms, and therefore differs from previously reported longitudinal studies on humoral responses to SARS-CoV-2, which often focus on more diverse age populations and worse clinical presentation. 80.9% (119/147) of the participants presented with circulating IgG antibodies against SARS-CoV-2 spike (S) receptor-binding domain (RBD) at 6 weeks PO, of whom 97.3% (111/114) remained positive, with significantly decreased levels, at 10 weeks PO. Neutralizing activity was detected in all sera from SARS-CoV-2 IgG positive participants tested (n=38) at 6 and 10 weeks PO, without significant loss between time points. IgG and IgA antibodies against SARS-CoV-2 RBD, S1, S2, and the nucleocapsid (N) protein, as well neutralization activity, were generally comparable between those participants that had asymptomatic infection or mild disease. A multiplex assay including S proteins from SARS-CoV-2 and related zoonotic and human endemic betacoronaviruses revealed a positive correlation for polyclonal cross-reactivity to S after SARS-CoV-2 infection. Overall, young adults that experienced asymptomatic or mild SARS-CoV-2 infection developed comparable humoral responses, with no decrease in neutralizing activity at least up to 10 weeks after infection.
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http://dx.doi.org/10.3389/fimmu.2021.681586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220197PMC
July 2021

SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study.

Lancet Respir Med 2021 07 15;9(7):712-720. Epub 2021 Apr 15.

Naval Medical Research Center, Silver Spring, MD, USA.

Background: Whether young adults who are infected with SARS-CoV-2 are at risk of subsequent infection is uncertain. We investigated the risk of subsequent SARS-CoV-2 infection among young adults seropositive for a previous infection.

Methods: This analysis was performed as part of the prospective COVID-19 Health Action Response for Marines study (CHARM). CHARM included predominantly male US Marine recruits, aged 18-20 years, following a 2-week unsupervised quarantine at home. After the home quarantine period, upon arrival at a Marine-supervised 2-week quarantine facility (college campus or hotel), participants were enrolled and were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein ELISA. Participants also completed a questionnaire consisting of demographic information, risk factors, reporting of 14 specific COVID-19-related symptoms or any other unspecified symptom, and brief medical history. SARS-CoV-2 infection was assessed by PCR at weeks 0, 1, and 2 of quarantine and participants completed a follow-up questionnaire, which included questions about the same COVID-19-related symptoms since the last study visit. Participants were excluded at this stage if they had a positive PCR test during quarantine. Participants who had three negative swab PCR results during quarantine and a baseline serum serology test at the beginning of the supervised quarantine that identified them as seronegative or seropositive for SARS-CoV-2 then went on to basic training at Marine Corps Recruit Depot-Parris Island. Three PCR tests were done at weeks 2, 4, and 6 in both seropositive and seronegative groups, along with the follow-up symptom questionnaire and baseline neutralising antibody titres on all subsequently infected seropositive and selected seropositive uninfected participants (prospective study period).

Findings: Between May 11, 2020, and Nov 2, 2020, we enrolled 3249 participants, of whom 3168 (98%) continued into the 2-week quarantine period. 3076 (95%) participants, 2825 (92%) of whom were men, were then followed up during the prospective study period after quarantine for 6 weeks. Among 189 seropositive participants, 19 (10%) had at least one positive PCR test for SARS-CoV-2 during the 6-week follow-up (1·1 cases per person-year). In contrast, 1079 (48%) of 2247 seronegative participants tested positive (6·2 cases per person-year). The incidence rate ratio was 0·18 (95% CI 0·11-0·28; p<0·001). Among seropositive recruits, infection was more likely with lower baseline full-length spike protein IgG titres than in those with higher baseline full-length spike protein IgG titres (hazard ratio 0·45 [95% CI 0·32-0·65]; p<0·001). Infected seropositive participants had viral loads that were about 10-times lower than those of infected seronegative participants (ORF1ab gene cycle threshold difference 3·95 [95% CI 1·23-6·67]; p=0·004). Among seropositive participants, baseline neutralising titres were detected in 45 (83%) of 54 uninfected and in six (32%) of 19 infected participants during the 6 weeks of observation (ID50 difference p<0·0001).

Interpretation: Seropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralisation activity or immunity against subsequent infection. These findings might be relevant for optimisation of mass vaccination strategies.

Funding: Defense Health Agency and Defense Advanced Research Projects Agency.
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http://dx.doi.org/10.1016/S2213-2600(21)00158-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049591PMC
July 2021

H7N9 pandemic preparedness: A large-scale production of a split inactivated vaccine.

Biochem Biophys Res Commun 2021 03 4;545:145-149. Epub 2021 Feb 4.

BioIndustrial Center, Brazil. Electronic address:

In March 2013 it was reported by the World Health Organization (WHO) the first cases of human infections with avian influenza virus A (H7N9). From 2013 to December 2019, 1568 cases have been reported with 616 deaths. H7N9 infection has been associated with high morbidity and mortality rates, and vaccination is currently the most effective way to prevent infections and consequently flu-related severe illness. Developing and producing vaccines against pandemic influenza viruses is the main strategy for a response to a possible pandemic. This study aims to present the production of three industrial lots under current Good Manufacturing Practices (cGMP) of the active antigen used to produce the pandemic influenza vaccine candidate against A(H7N9). These batches were characterized and evaluated for quality standards and tested for immunogenicity in mice. The average yield was 173.50 ± 7.88 μg/mL of hemagglutinin and all the preparations met all the required specifications. The formulated H7N9 vaccine is poorly immunogenic and needs to be adjuvanted with an oil in water emulsion adjuvant (IB160) to achieve a best immune response, in a prime and in a boost scheme. These data are important for initial production planning and preparedness in the case of a H7N9 pandemic.
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http://dx.doi.org/10.1016/j.bbrc.2021.01.058DOI Listing
March 2021

SARS-CoV-2 Seropositivity among US Marine Recruits Attending Basic Training, United States, Spring-Fall 2020.

Emerg Infect Dis 2021 04 2;27(4):1188-1192. Epub 2021 Feb 2.

In a study of US Marine recruits, seroprevalence of severe acute respiratory syndrome coronavirus 2 IgG was 9.0%. Hispanic and non-Hispanic Black participants and participants from states affected earlier in the pandemic had higher seropositivity rates. These results suggest the need for targeted public health strategies among young adults at increased risk for infection.
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http://dx.doi.org/10.3201/eid2704.204732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007328PMC
April 2021

Experimental Human Challenge Defines Distinct Pneumococcal Kinetic Profiles and Mucosal Responses between Colonized and Non-Colonized Adults.

mBio 2021 01 12;12(1). Epub 2021 Jan 12.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

Colonization of the upper respiratory tract with is the precursor of pneumococcal pneumonia and invasive disease. Following exposure, however, it is unclear which human immune mechanisms determine whether a pathogen will colonize. We used a human challenge model to investigate host-pathogen interactions in the first hours and days following intranasal exposure to Using a novel home sampling method, we measured early immune responses and bacterial density dynamics in the nose and saliva after volunteers were experimentally exposed to pneumococcus. Here, we show that nasal colonization can take up to 24 h to become established. Also, the following two distinct bacterial clearance profiles were associated with protection: nasal clearers with immediate clearance of bacteria in the nose by the activity of pre-existent mucosal neutrophils and saliva clearers with detectable pneumococcus in saliva at 1 h post challenge and delayed clearance mediated by an inflammatory response and increased neutrophil activity 24 h post bacterial encounter. This study describes, for the first time, how colonization with a bacterium is established in humans, signifying that the correlates of protection against pneumococcal colonization, which can be used to inform design and testing of novel vaccine candidates, could be valid for subsets of protected individuals. Occurrence of lower respiratory tract infections requires prior colonization of the upper respiratory tract with a pathogen. Most bacterial infection and colonization studies have been performed in murine and models due to the current invasive sampling methodology of the upper respiratory tract, both of which poorly reflect the complexity of host-pathogen interactions in the human nose. Self-collecting saliva and nasal lining fluid at home is a fast, low-cost, noninvasive, high-frequency sampling platform for continuous monitoring of bacterial encounter at defined time points relative to exposure. Our study demonstrates for the first time that, in humans, there are distinct profiles of pneumococcal colonization kinetics, distinguished by speed of appearance in saliva, local phagocytic function, and acute mucosal inflammatory responses, which may either recruit or activate neutrophils. These data are important for the design and testing of novel vaccine candidates.
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http://dx.doi.org/10.1128/mBio.02020-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844534PMC
January 2021

SARS-CoV-2 Transmission among Marine Recruits during Quarantine.

N Engl J Med 2020 12 11;383(25):2407-2416. Epub 2020 Nov 11.

From the Naval Medical Research Center, Silver Spring (A.G.L., C.G., D.L.W., L.E., W.D.G., R.G., F.J., J.M., E.N., B.L.P., C.P., J.R., E.S.A., M.P.S., V.S., C.W.) and the Infectious Disease Clinical Research Program, Uniformed Services University (E.V.M.), Bethesda - both in Maryland; the Naval Medical Research Unit 6, Lima, Peru (R.L., S.L.); the Departments of Neurology (I.R., Y.G., M.-C.G., A.K., N.M., V.D.N., G.N., S.R., A.S.-S., S.V., S.C.S.) and Genetics and Genomic Sciences (A.O., J.D., E.E., A.S.G.-R., A.G., R.S., H.B.), Icahn Institute for Data Science and Genomic Technology (E.E., R.S., H.B.), the Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai (R.S.), and the Center for Computational Biology, Flatiron Institute (R.S.G.S., O.G.T.) - all in New York; the University of Alabama at Birmingham Center for Exercise Medicine, University of Alabama Medical School, Birmingham (M.M.B.); Sema4, Stamford, CT (R.S.); the Navy Medicine Readiness and Training Command Beaufort, Beaufort, SC (M.T.); and the Lewis-Sigler Institute for Integrative Genomics, Princeton, NJ (O.G.T.).

Background: The efficacy of public health measures to control the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been well studied in young adults.

Methods: We investigated SARS-CoV-2 infections among U.S. Marine Corps recruits who underwent a 2-week quarantine at home followed by a second supervised 2-week quarantine at a closed college campus that involved mask wearing, social distancing, and daily temperature and symptom monitoring. Study volunteers were tested for SARS-CoV-2 by means of quantitative polymerase-chain-reaction (qPCR) assay of nares swab specimens obtained between the time of arrival and the second day of supervised quarantine and on days 7 and 14. Recruits who did not volunteer for the study underwent qPCR testing only on day 14, at the end of the quarantine period. We performed phylogenetic analysis of viral genomes obtained from infected study volunteers to identify clusters and to assess the epidemiologic features of infections.

Results: A total of 1848 recruits volunteered to participate in the study; within 2 days after arrival on campus, 16 (0.9%) tested positive for SARS-CoV-2, 15 of whom were asymptomatic. An additional 35 participants (1.9%) tested positive on day 7 or on day 14. Five of the 51 participants (9.8%) who tested positive at any time had symptoms in the week before a positive qPCR test. Of the recruits who declined to participate in the study, 26 (1.7%) of the 1554 recruits with available qPCR results tested positive on day 14. No SARS-CoV-2 infections were identified through clinical qPCR testing performed as a result of daily symptom monitoring. Analysis of 36 SARS-CoV-2 genomes obtained from 32 participants revealed six transmission clusters among 18 participants. Epidemiologic analysis supported multiple local transmission events, including transmission between roommates and among recruits within the same platoon.

Conclusions: Among Marine Corps recruits, approximately 2% who had previously had negative results for SARS-CoV-2 at the beginning of supervised quarantine, and less than 2% of recruits with unknown previous status, tested positive by day 14. Most recruits who tested positive were asymptomatic, and no infections were detected through daily symptom monitoring. Transmission clusters occurred within platoons. (Funded by the Defense Health Agency and others.).
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http://dx.doi.org/10.1056/NEJMoa2029717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675690PMC
December 2020

Differential gene expression elicited by ZIKV infection in trophoblasts from congenital Zika syndrome discordant twins.

PLoS Negl Trop Dis 2020 08 3;14(8):e0008424. Epub 2020 Aug 3.

Laboratório de Parasitologia, Instituto Butantan, São Paulo, Brazil.

Zika virus (ZIKV) causes congenital Zika syndrome (CZS), which is characterized by fetal demise, microcephaly and other abnormalities. ZIKV in the pregnant woman circulation must cross the placental barrier that includes fetal endothelial cells and trophoblasts, in order to reach the fetus. CZS occurs in ~1-40% of cases of pregnant women infected by ZIKV, suggesting that mothers' infection by ZIKV during pregnancy is not deterministic for CZS phenotype in the fetus. Therefore, other susceptibility factors might be involved, including the host genetic background. We have previously shown that in three pairs of dizygotic twins discordant for CZS, neural progenitor cells (NPCs) from the CZS-affected twins presented differential in vitro ZIKV susceptibility compared with NPCs from the non-affected. Here, we analyzed human-induced-pluripotent-stem-cell-derived (hiPSC-derived) trophoblasts from these twins and compared by RNA-Seq the trophoblasts from CZS-affected and non-affected twins. Following in vitro exposure to a Brazilian ZIKV strain (ZIKVBR), trophoblasts from CZS-affected twins were significantly more susceptible to ZIKVBR infection when compared with trophoblasts from the non-affected. Transcriptome profiling revealed no differences in gene expression levels of ZIKV candidate attachment factors, IFN receptors and IFN in the trophoblasts, either before or after ZIKVBR infection. Most importantly, ZIKVBR infection caused, only in the trophoblasts from CZS-affected twins, the downregulation of genes related to extracellular matrix organization and to leukocyte activation, which are important for trophoblast adhesion and immune response activation. In addition, only trophoblasts from non-affected twins secreted significantly increased amounts of chemokines RANTES/CCL5 and IP10 after infection with ZIKVBR. Overall, our results showed that trophoblasts from non-affected twins have the ability to more efficiently activate genes that are known to play important roles in cell adhesion and in triggering the immune response to ZIKV infection in the placenta, and this may contribute to predict protection from ZIKV dissemination into fetuses' tissues.
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http://dx.doi.org/10.1371/journal.pntd.0008424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425990PMC
August 2020

SARS-CoV-2 likes it cool.

Nat Rev Immunol 2020 07;20(7):406

Sinai Immunology Review Project, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1038/s41577-020-0341-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224124PMC
July 2020

Evaluation of inactivated Bordetella pertussis as a delivery system for the immunization of mice with Pneumococcal Surface Antigen A.

PLoS One 2020 16;15(1):e0228055. Epub 2020 Jan 16.

Laboratório de Bacteriologia, Instituto Butantan, São Paulo, SP, Brazil.

Pneumococcal Surface Protein A (PspA) has been successfully tested as vaccine candidate against Streptococcus pneumoniae infections. Vaccines able to induce PspA-specific antibodies and Th1 cytokines usually provide protection in mice. We have shown that the whole cell pertussis vaccine (wP) or components from acellular pertussis vaccines, such as Pertussis Toxin or Filamentous Hemagglutinin (FHA), are good adjuvants to PspA, suggesting that combined pertussis-PspA vaccines would be interesting strategies against the two infections. Here, we evaluated the potential of wP as a delivery vector to PspA. Bordetella pertussis strains producing a PspA from clade 4 (PspA4Pro) fused to the N-terminal region of FHA (Fha44) were constructed and inactivated with formaldehyde for the production of wPPspA4Pro. Subcutaneous immunization of mice with wPPspA4Pro induced low levels of anti-PspA4 IgG, even after 3 doses, and did not protect against a lethal pneumococcal challenge. Prime-boost strategies using wPPspA4Pro and PspA4Pro showed that there was no advantage in using the wPPspA4Pro vaccine. Immunization of mice with purified PspA4Pro induced higher levels of antibodies and protection against pneumococcal infection than the prime-boost strategies. Finally, purified Fha44:PspA4Pro induced high levels of anti-PspA4Pro IgG, but no protection, suggesting that the antibodies induced by the fusion protein were not directed to protective epitopes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228055PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964896PMC
May 2020

Nasal Pneumococcal Density Is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens.

Am J Respir Crit Care Med 2020 02;201(3):335-347

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Pneumococcal pneumonia remains a global health problem. Colonization of the nasopharynx with (Spn), although a prerequisite of infection, is the main source of exposure and immunological boosting in children and adults. However, our knowledge of how nasal colonization impacts on the lung cells, especially on the predominant alveolar macrophage (AM) population, is limited. Using a controlled human infection model to achieve nasal colonization with 6B serotype, we investigated the effect of Spn colonization on lung cells. We collected BAL from healthy pneumococcal-challenged participants aged 18-49 years. Confocal microscopy and molecular and classical microbiology were used to investigate microaspiration and pneumococcal presence in the lower airways. AM opsonophagocytic capacity was assessed by functional assays , whereas flow cytometry and transcriptomic analysis were used to assess further changes on the lung cellular populations. AMs from Spn-colonized individuals exhibited increased opsonophagocytosis to pneumococcus (11.4% median increase) for approximately 3 months after experimental pneumococcal colonization. AMs also had increased responses against other bacterial pathogens. Pneumococcal DNA detected in the BAL samples of Spn-colonized individuals were positively correlated with nasal pneumococcal density ( = 0.71;  = 0.029). Similarly, AM-heightened opsonophagocytic capacity was correlated with nasopharyngeal pneumococcal density ( = 0.61,  = 0.025). Our findings demonstrate that nasal colonization with pneumococcus and microaspiration prime AMs, leading to brisker responsiveness to both pneumococcus and unrelated bacterial pathogens. The relative abundance of AMs in the alveolar spaces, alongside their potential for nonspecific protection, render them an attractive target for novel vaccines.
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http://dx.doi.org/10.1164/rccm.201903-0607OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999099PMC
February 2020

Innate and adaptive nasal mucosal immune responses following experimental human pneumococcal colonization.

J Clin Invest 2019 07 30;129(10):4523-4538. Epub 2019 Jul 30.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Streptococcus pneumoniae (Spn) is a common cause of respiratory infection, but also frequently colonizes the nasopharynx in the absence of disease. We used mass cytometry to study immune cells from nasal biopsy samples collected following experimental human pneumococcal challenge in order to identify immunological mechanisms of control of Spn colonization. Using 37 markers, we characterized 293 nasal immune cell clusters, of which 7 were associated with Spn colonization. B cell and CD8+CD161+ T cell clusters were significantly lower in colonized than in non-colonized subjects. By following a second cohort before and after pneumococcal challenge we observed that B cells were depleted from the nasal mucosa upon Spn colonization. This associated with an expansion of Spn polysaccharide-specific and total plasmablasts in blood. Moreover, increased responses of blood mucosal associated invariant T (MAIT) cells against in vitro stimulation with pneumococcus prior to challenge associated with protection against establishment of Spn colonization and with increased mucosal MAIT cell populations. These results implicate MAIT cells in the protection against pneumococcal colonization and demonstrate that colonization affects mucosal and circulating B cell populations.
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http://dx.doi.org/10.1172/JCI128865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763269PMC
July 2019

Systems analysis of subjects acutely infected with the Chikungunya virus.

PLoS Pathog 2019 06 18;15(6):e1007880. Epub 2019 Jun 18.

Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.

The largest ever recorded epidemic of the Chikungunya virus (CHIKV) broke out in 2004 and affected four continents. Acute symptomatic infections are typically associated with the onset of fever and often debilitating polyarthralgia/polyarthritis. In this study, a systems biology approach was adopted to analyze the blood transcriptomes of adults acutely infected with the CHIKV. Gene signatures that were associated with viral RNA levels and the onset of symptoms were identified. Among these genes, the putative role of the Eukaryotic Initiation Factor (eIF) family genes and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3A) in the CHIKV replication process were displayed. We further compared these signatures with signatures induced by the Dengue virus infection and rheumatoid arthritis. Finally, we demonstrated that the CHIKV in vitro infection of murine bone marrow-derived macrophages induced IL-1 beta production in a mechanism that is significantly dependent on the inflammasome NLRP3 activation. The observations provided valuable insights into virus-host interactions during the acute phase and can be instrumental in the investigation of new and effective therapeutic interventions.
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http://dx.doi.org/10.1371/journal.ppat.1007880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599120PMC
June 2019

Zika Virus Selectively Kills Aggressive Human Embryonal CNS Tumor Cells and .

Cancer Res 2018 06 26;78(12):3363-3374. Epub 2018 Apr 26.

Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo (USP), São Paulo, Brazil.

Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells during early development. Here, we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKV) against human breast, prostate, colorectal, and embryonal CNS tumor cell lines, we verified a selective infection of CNS tumor cells followed by massive tumor cell death. ZIKV was more efficient in destroying embryonal CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKV in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, decreased tumor burden, fewer metastasis, and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level with activated Wnt signaling were more susceptible to the oncolytic effects of ZIKV Furthermore, modulation of Wnt signaling pathway significantly affected ZIKV-induced tumor cell death and viral shedding. Altogether, these preclinical findings indicate that ZIKV could be an efficient agent to treat aggressive forms of embryonal CNS tumors and could provide mechanistic insights regarding its oncolytic effects. Brazilian Zika virus strain kills aggressive metastatic forms of human CNS tumors and could be a potential oncolytic agent for cancer therapy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3201DOI Listing
June 2018

Publisher Correction: Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells.

Nat Commun 2018 03 13;9(1):1114. Epub 2018 Mar 13.

Infectious pediatric laboratory, Medicine School of Jundiaí, Jundiaí - SP, 40170-115, Brazil.

The original PDF version of this Article contained errors in the spelling of Luiz Carlos Caires-Júnior, Uirá Souto Melo, Bruno Henrique Silva Araujo, Alessandra Soares-Schanoski, Murilo Sena Amaral, Kayque Alves Telles-Silva, Vanessa van der Linden, Helio van der Linden, João Ricardo Mendes de Oliveira, Nivia Maria Rodrigues Arrais, Joanna Goes Castro Meira, Ana Jovina Barreto Bispo, Esper Abrão Cavalheiro, and Robert Andreata-Santos, which were incorrectly given as Luiz Carlos de Caires Jr., UiráSouto Melo, Bruno Silva Henrique Araujo, Alessandra Soares Schanoski, MuriloSena Amaral, Kayque Telles Alves Silva, Vanessa Van der Linden, Helio Van der Linden, João Mendes Ricardo de Oliveira, Nivia Rodrigues Maria Arrais, Joanna Castro Goes Meira, Ana JovinaBarreto Bispo, EsperAbrão Cavalheiro, and Robert Andreata Santos. Furthermore, in both the PDF and HTML versions of the Article, the top panel of Fig. 3e was incorrectly labeled '10608-1' and should have been '10608-4', and financial support from CAPES and DECIT-MS was inadvertently omitted from the Acknowledgements section. These errors have now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-03497-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849689PMC
March 2018

Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells.

Nat Commun 2018 02 2;9(1):475. Epub 2018 Feb 2.

Infectious pediatric laboratory, Medicine School of Jundiaí, Jundiaí - SP, 13202-550, Brazil.

Congenital Zika syndrome (CZS) causes early brain development impairment by affecting neural progenitor cells (NPCs). Here, we analyze NPCs from three pairs of dizygotic twins discordant for CZS. We compare by RNA-Seq the NPCs derived from CZS-affected and CZS-unaffected twins. Prior to Zika virus (ZIKV) infection the NPCs from CZS babies show a significantly different gene expression signature of mTOR and Wnt pathway regulators, key to a neurodevelopmental program. Following ZIKV in vitro infection, cells from affected individuals have significantly higher ZIKV replication and reduced cell growth. Whole-exome analysis in 18 affected CZS babies as compared to 5 unaffected twins and 609 controls excludes a monogenic model to explain resistance or increased susceptibility to CZS development. Overall, our results indicate that CZS is not a stochastic event and depends on NPC intrinsic susceptibility, possibly related to oligogenic and/or epigenetic mechanisms.
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http://dx.doi.org/10.1038/s41467-017-02790-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797251PMC
February 2018

Mucosal immunization with PspA (Pneumococcal surface protein A)-adsorbed nanoparticles targeting the lungs for protection against pneumococcal infection.

PLoS One 2018 23;13(1):e0191692. Epub 2018 Jan 23.

Laboratório de Bacteriologia, Instituto Butantan, São Paulo, SP, Brazil.

Burden of pneumonia caused by Streptococcus pneumoniae remains high despite the availability of conjugate vaccines. Mucosal immunization targeting the lungs is an attractive alternative for the induction of local immune responses to improve protection against pneumonia. Our group had previously described the development of poly(glycerol adipate-co-ω-pentadecalactone) (PGA-co-PDL) polymeric nanoparticles (NPs) adsorbed with Pneumococcal surface protein A from clade 4 (PspA4Pro) within L-leucine microcarriers (nanocomposite microparticles-NCMPs) for mucosal delivery targeting the lungs (NP/NCMP PspA4Pro). NP/NCMP PspA4Pro was now used for immunization of mice. Inoculation of this formulation induced anti-PspA4Pro IgG antibodies in serum and lungs. Analysis of binding of serum IgG to intact bacteria showed efficient binding to bacteria expressing PspA from clades 3, 4 and 5 (family 2), but no binding to bacteria expressing PspA from clades 1 and 2 (family 1) was observed. Both mucosal immunization with NP/NCMP PspA4Pro and subcutaneous injection of the protein elicited partial protection against intranasal lethal pneumococcal challenge with a serotype 3 strain expressing PspA from clade 5 (PspA5). Although similar survival levels were observed for mucosal immunization with NP/NCMP PspA4Pro and subcutaneous immunization with purified protein, NP/NCMP PspA4Pro induced earlier control of the infection. Conversely, neither immunization with NP/NCMP PspA4Pro nor subcutaneous immunization with purified protein reduced bacterial burden in the lungs after challenge with a serotype 19F strain expressing PspA from clade 1 (PspA1). Mucosal immunization with NP/NCMP PspA4Pro targeting the lungs is thus able to induce local and systemic antibodies, conferring protection only against a strain expressing PspA from the homologous family 2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191692PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779684PMC
February 2018

Impaired expression of CXCL5 and matrix metalloproteinases in the lungs of mice with high susceptibility to Streptococcus pneumoniae infection.

Immun Inflamm Dis 2018 03 9;6(1):128-142. Epub 2017 Nov 9.

Laboratório de Bacteriologia, Instituto Butantan, São Paulo-SP, Brazil.

Introduction: Streptococcus pneumoniae colonizes the nasopharynx of healthy individuals establishing a commensal relationship with the host. In some conditions, bacteria invade the lower respiratory tract and innate immune responses are crucial to avoid diseases such as pneumonia, sepsis, or meningitis.

Methods: Here, we compared the susceptibility to pneumococcal respiratory infection of two outbred mouse lines, AIRmin and AIRmax, selected for low or high acute inflammatory responses, respectively.

Results: AIRmin mice showed increased susceptibility to infection with different pneumococcal serotypes, when compared to AIRmax. Significant higher numbers of alveolar macrophages expressing the CD206 mannose receptor were observed in AIRmin mice when compared to AIRmax mice. Despite this difference, secretion of several cytokines and chemokines in the respiratory tract of AIRmin and AIRmax mice, after infection, was similar. The only exception was CXCL5, which was highly induced after pneumococcal infection in AIRmax mice but not in AIRmin mice. Reduced expression of the matrix metalloproteinases (MMP) 2, 3, 8, and 9, as well as reduced activities of MMPs were also observed in the lungs of AIRmin mice, after infection. Such impaired responses may have contributed to the low influx of neutrophils observed in the airways of these mice. Finally, high percentages of macrophages and neutrophils in apoptosis or necrosis, at the site of infection, were also observed in AIRmin mice, suggesting that leukocyte functionality is also compromised.

Conclusions: Our results indicate that CXCL5 and MMPs contribute to the resistance to pneumococcal infection in mice.
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http://dx.doi.org/10.1002/iid3.205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818448PMC
March 2018

Outbreak of chikungunya virus in a vulnerable population of Sergipe, Brazil-A molecular and serological survey.

J Clin Virol 2017 12 3;97:44-49. Epub 2017 Nov 3.

Laboratory of Molecular Evolution and Bioinformatics, Department of Microbiology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil. Electronic address:

Background: Chikungunya virus (CHIKV) is a re-emerging arbovirus that is causing outbreaks in several countries of the Americas. The virus was introduced in Brazil in 2014, and since then, several Brazilian states have notified autochthonous cases.

Objectives: Provide additional evidence on a CHIKV outbreak and an outline of the laboratory and clinical profile of symptomatic patients in Sergipe, Brazil.

Study Design: In February 2016, we collected 142 serum samples from symptomatic patients for arboviruses in Sergipe, Brazil. All samples were submitted to qRT-PCR for the emerging arboviruses circulating in Brazil - ZIKV, CHIKV, and DENV - and later submitted to the immunoenzymatic assay. RNA positive samples were randomly selected and sequenced for characterization of the genotype involved in the outbreak.

Results: Our study had 75.35% (107/142) positivity for CHIKV infection, with all age groups and genera being equally infected. The virus was identified in 11 of the 13 cities studied in that state, including the ECSA genotype. Importantly, fever was the only statistically significant symptoms for CHIKV infection (p<0.05), while asthenia was significantly associated with symptomatic patients that were CHIKV-negative (p<0.05).

Conclusions: Our findings support the importance of fever as a clinical marker and contribute to molecular and serological surveillance data, which may help in the understanding of CHIKV circulation, emergence and clinical description.
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http://dx.doi.org/10.1016/j.jcv.2017.10.015DOI Listing
December 2017

Viral Load and Cytokine Response Profile Does Not Support Antibody-Dependent Enhancement in Dengue-Primed Zika Virus-Infected Patients.

Clin Infect Dis 2017 10;65(8):1260-1265

São José do Rio Preto School of Medicine.

Background: The pathogenesis of severe dengue disease involves immune components as biomarkers. The mechanism by which some dengue virus (DENV)-infected individuals progress to severe disease is poorly understood. Most studies on the pathogenesis of severe dengue disease focus on the process of antibody-dependent enhancement (ADE) as a primary risk factor. With the circulation of Zika virus (ZIKV) in DENV-endemic areas, many people infected by ZIKV were likely exposed to DENV. The influence of such exposure on Zika disease outcomes remains unknown.

Methods: We investigated whether patients previously exposed to DENV exhibited higher viremia when exposed to a subsequent, heterologous dengue or Zika infection than those patients not previously exposed to dengue. We measured viral loads and cytokine profile during patients' acute infections.

Results: Neither dengue nor Zika viremia was higher in patients with prior DENV infection, although the power to detect such a difference was only adequate in the ZIKV analysis. Of the 10 cytokines measured, only 1 significant difference was detected: Levels of interleukin 1β (IL-1β) were lower in dengue-infected patients who had experienced a previous dengue infection than patients infected with dengue for the first time. However, power to detect differences between groups was low. In Zika-infected patients, levels of IL-1β showed a significant, positive correlation with viral load.

Conclusions: No signs of ADE were observed in vivo in patients with acute ZIKV infection who had prior exposure to DENV.
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http://dx.doi.org/10.1093/cid/cix558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849103PMC
October 2017

MMP9 integrates multiple immunoregulatory pathways that discriminate high suppressive activity of human mesenchymal stem cells.

Sci Rep 2017 04 13;7(1):874. Epub 2017 Apr 13.

Laboratory of Immunology, Heart Institute (InCor), School of Medicine, University of São Paulo, São Paulo, Brazil.

The mechanisms underlying mesenchymal stem cells' (MSC) suppressive potency are largely unknown. We here show that highly suppressive human adipose tissue-derived MSC (AdMSC) display and induce a differential immunologic profile, upon ongoing AdMSC suppressive activity, promoting: (i) early correlated inhibition of IFN-γ and TNF-α production, along IL-10 increase, (ii) CD73Foxp3Treg subset expansion, and (iii) specific correlations between gene expression increases, such as: MMP9 correlated with CCL22, TNF, FASL, RUNX3, and SEMAD4 in AdMSC and, in T cells, MMP9 upregulation correlated with CCR4, IL4 and TBX21, among others, whereas MMP2 correlated with BCL2 and LRRC31. MMP9 emerged as an integrating molecule for both AdMSC and T cells in molecular networks built with our gene expression data, and we confirmed upregulation of MMP9 and MMP2 at the protein level, in AdMSC and T cells, respectively. MMP2/9 inhibition significantly decreased AdMSC suppressive effect, confirming their important role in suppressive acitivity. We conclude that MMP9 and 2 are robust new players involved in human MSC immunoregulatory mechanisms, and the higher suppressive activity correlates to their capacity to trigger a coordinated action of multiple specific molecules, mobilizing various immunoregulatory mechanisms.
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http://dx.doi.org/10.1038/s41598-017-00923-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429835PMC
April 2017

Design, Immune Responses and Anti-Tumor Potential of an HPV16 E6E7 Multi-Epitope Vaccine.

PLoS One 2015 21;10(9):e0138686. Epub 2015 Sep 21.

Laboratório de Biotecnologia Molecular I, Instituto Butantan, Av. Vital Brasil 1500, São Paulo-SP, Brazil.

Cervical cancer is a common type of cancer among women worldwide and infection with high-risk human papillomavirus (HPVs) types represents the major risk factor for the etiopathogenesis of the disease. HPV-16 is the most frequently identified HPV type in cervical lesions and expression of E6 and E7 oncoproteins is required for the uncontrolled cellular proliferation. In the present study we report the design and experimental testing of a recombinant multi-epitope protein containing immunogenic epitopes of HPV-16 E6 and E7. Tumor preventive assays, based on the engraftment of TC-1 cells in mice, showed that the E6E7 multi-epitope protein induced a full preventive anti-tumor protection in wild-type mice, as well as in mice deficient in expression of CD4+ T cells and TLR4 receptor. Nonetheless, no anti-tumor protection was observed in mice deficient in CD8+ T cells. Also, the vaccine promoted high activation of E6/E7-specific T cells and in a therapeutic-approach, E6E7 protein conferred full anti-tumor protection in mice. These results show a potential use of this E6E7 multi-epitope antigen as a new and promising antigen for the development of a therapeutic vaccine against tumors induced by HPV.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138686PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577214PMC
May 2016

Impaired antigen presentation and potent phagocytic activity identifying tumor-tolerant human monocytes.

Biochem Biophys Res Commun 2012 Jun 31;423(2):331-7. Epub 2012 May 31.

Laboratory of TumorImmunology, IdiPAZ, La Paz Hospital, Madrid, Spain.

Monocyte exposure to tumor cells induces a transient state in which these cells are refractory to further exposure to cancer. This phenomenon, termed "tumor tolerance", is characterized by a decreased production of proinflammatory cytokines in response to tumors. In the past, we found that this effect comprises IRAK-M up regulation and TLR4 and CD44 activation. Herein we have established a human model of tumor tolerance and have observed a marked down-regulation of MHCII molecules as well as the MHCII master regulator, CIITA, in monocytes/macrophages. These cells combine an impaired capability for antigen presentation with potent phagocytic activity and exhibit an M2-like phenotype. In addition circulating monocytes isolated from Chronic Lymphocytic Leukemia patients exhibited the same profile as tumor tolerant cells after tumor ex vivo exposition.
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http://dx.doi.org/10.1016/j.bbrc.2012.05.124DOI Listing
June 2012

Role of MMPs in orchestrating inflammatory response in human monocytes via a TREM-1-PI3K-NF-κB pathway.

J Leukoc Biol 2012 Jun 29;91(6):933-45. Epub 2012 Mar 29.

Laboratory of Tumor Immunology, IdiPAZ, La Paz Hospital, Madrid, Spain

The MMPs constitute a family of endopeptidases that can cleavage extracellular proteins. They are involved in a number of events; some of these include inflammatory processes. One of its targets is the TREM-1, which has emerged as an important modulator of innate immune responses in mammals. This transmembrane glycoprotein possesses an Ig-like ectodomain readily shed by MMPs to generate sTREM-1. Whereas membrane-anchored TREM-1 amplifies inflammatory responses, sTREM-1 exhibits anti-inflammatory properties. Here we show that sustained cell surface expression of TREM-1 in human monocytes, through metalloproteinase inhibition, counteracts the well-characterized down-regulation of several proinflammatory cytokines during the ET time-frame, also known as M2 or alternative activation. In addition to the cytokines profile, other features of the ET phenotype were underdeveloped when TREM-1 was stabilized at the cell surface. These events were mediated by the signal transducers PI3Ks and Syk. We also show that sTREM-1 counteracts the proinflammatory response obtained by membrane TREM-1 stabilization but failed to induce ET on naïve human monocytes. As the sustained TREM-1 expression at the cell surface suffices to block the progress of a refractory state in human monocytes, our data indicate that TREM-1 and MMPs orchestrate an "adaptive" form of innate immunity by modulating the human monocytes response to endotoxin.
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http://dx.doi.org/10.1189/jlb.0711340DOI Listing
June 2012

Potent phagocytic activity with impaired antigen presentation identifying lipopolysaccharide-tolerant human monocytes: demonstration in isolated monocytes from cystic fibrosis patients.

J Immunol 2009 May;182(10):6494-507

Research Unit, Laboratory of Tumor Immunology, La Paz Hospital, Madrid, Spain.

Monocyte exposure to LPS induces a transient state in which these cells are refractory to further endotoxin stimulation. This phenomenon, termed endotoxin tolerance (ET), is characterized by a decreased production of cytokines in response to the proinflammatory stimulus. We have established a robust model of ET and have determined the time frame and features of LPS unresponsiveness in cultured human monocytes. A large number of genes transcribed in tolerant monocytes were classified as either "tolerizable" or "nontolerizable" depending on their expression levels during the ET phase. Tolerant monocytes exhibit rapid IL-1R-associated kinase-M (IRAK-M) overexpression, high levels of triggering receptor expressed on myeloid cells-1 (TREM-1) and CD64, and a marked down-regulation of MHC molecules and NF-kappaB2. These cells combine potent phagocytic activity with impaired capability for Ag presentation. We also show that circulating monocytes isolated from cystic fibrosis patients share all the determinants that characterize cells locked in an ET state. These findings identify a new mechanism that contributes to impaired inflammation in cystic fibrosis patients despite a high frequency of infections. Our results indicate that a tolerant phenotype interferes with timing, efficiency, and outcome of the innate immune responses against bacterial infections.
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http://dx.doi.org/10.4049/jimmunol.0803350DOI Listing
May 2009

Contribution of globular death domains and unstructured linkers to MyD88.IRAK-4 heterodimer formation: an explanation for the antagonistic activity of MyD88s.

Biochem Biophys Res Commun 2009 Feb 22;380(1):183-7. Epub 2009 Jan 22.

Cardiovascular Research Center and Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.

Homotypic interactions of death domains (DD) mediate complex formation between MyD88 and IL-1 receptor-associated kinases (IRAKs). A truncated splice variant of MyD88, MyD88s, cannot recruit IRAK-4 and fails to elicit inflammatory responses. We have generated recombinant DD of MyD88 and IRAK-4, both alone and extended by the linkers to TIR or kinase domains. We show that both MyD88 DD variants bind to the linker-extended IRAK-4 DD and pull-down full-length IRAK-4 from monocyte extracts. By contrast, residues up to Glu(116) from the DD-kinase connector of IRAK-4 are needed for strong interactions with the adaptor. Our findings indicate that residues 110-120, which form a C-terminal extra helix in MyD88, but not the irregular linker between DD and TIR domains, are required for IRAK-4 recruitment, and provide a straightforward explanation for the negative regulation of innate immune responses mediated by MyD88s.
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http://dx.doi.org/10.1016/j.bbrc.2009.01.069DOI Listing
February 2009

Monocytes from cystic fibrosis patients are locked in an LPS tolerance state: down-regulation of TREM-1 as putative underlying mechanism.

PLoS One 2008 Jul 16;3(7):e2667. Epub 2008 Jul 16.

Research Unit, La Paz Hospital, Madrid, Spain.

Cystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the gene that codes for the chloride channel, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CF patients are frequently colonized by several pathogens, but the mechanisms that allow colonization in spite of apparently functional immune systems are incompletely understood. In this paper we show that blood peripheral monocytes isolated from CF patients are found in an endotoxin tolerance state, yet this is not due to a deficient TLR activation. On the other hand, levels of the amplifier of inflammatory responses, TREM-1 (Triggering Receptor Expressed on Myeloid cells), are notably down-regulated in monocytes from patients, in comparison to those extracted from healthy volunteers. Furthermore, the soluble form of TREM-1 (sTREM-1) was not detected in the sera of patients. Additionally, and in strict contrast to patients who suffer from Chronic Obstructive Pulmonary Disease (COPD), CF monocytes challenged ex vivo with LPS neither up-regulated membrane-anchored TREM-1 nor sTREM-1. Finally, similar levels of PGE(2) expression and p65 translocation into the nucleus were found in both patients and healthy volunteers, thus suggesting that TREM-1 regulation is neither controlled by PGE(2) levels nor by p65 activation in this case. However, PU.1 translocation into the nucleus was significantly higher in CF monocytes than in controls, suggesting a role for this transcription factor in the control of TREM-1 expression. We conclude that down-regulation of TREM-1 expression in cystic fibrosis patients is at least partly responsible for the endotoxin tolerance state in which their monocytes are locked.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002667PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2442190PMC
July 2008

Position-dependent expression of GADD45alpha in rat brain tumours.

Med Oncol 2007 ;24(4):436-44

Department of Applied Mathematics, Faculty of Mathematics, Complutense University, Madrid, Spain.

Although the complex and multifactorial process of tumour growth has been extensively studied for decades, our understanding of the fundamental relationship between tumour growth dynamics and genetic expression profile remains incomplete. Recent studies of tumour dynamics indicate that gene expression in solid tumours would depend on the distance from the centre of the tumour. Since tumour proliferative activity is mainly localised to its external zone, and taking into account that generation and expansion of genetic mutations depend on the number of cell divisions, important differences in gene expression between central and peripheral sections of the same tumour are to be expected. Here, we have studied variations in the genetic expression profile between peripheral and internal samples of the same brain tumour. We have carried out microarray analysis of mRNA expression, and found a differential profile of genetic expression between the two cell subsets. In particular, one major nuclear protein that regulates cell responses to DNA-damaging and stress signals, GADD45alpha, was expressed at much lower levels in the peripheral zone, as compared to tumour core samples. These differences in GADD45alpha mRNA transcription levels have been confirmed by quantitative analysis via real time PCR, and protein levels of GADD45alpha also exhibit the same pattern of differential expression. Our findings suggest that GADD45alpha might play a major role in the regulation of brain tumour invasive potential.
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http://dx.doi.org/10.1007/s12032-007-0025-9DOI Listing
February 2008

Metalloproteinases shed TREM-1 ectodomain from lipopolysaccharide-stimulated human monocytes.

J Immunol 2007 Sep;179(6):4065-73

Research Unit, La Paz Hospital, Madrid, Spain.

Triggering receptors expressed on myeloid cell (TREM) proteins are a family of cell surface receptors that participate in diverse cellular processes such as inflammation, coagulation, and bone homeostasis. TREM-1, in particular, is expressed on neutrophils and monocytes and is a potent amplifier of inflammatory responses. LPS and other microbial products induce up-regulation of cell surface-localized TREM-1 and the release of its soluble form, sTREM-1. Two hypotheses have been advanced to explain the origin of sTREM-1: alternative splicing of TREM-1 mRNA and proteolytic cleavage(s) of mature, membrane-anchored TREM-1. In this report, we present conclusive evidence in favor of the proteolytic mechanism of sTREM-1 generation. No alternative splicing forms of TREM-1 were detected in monocytes/macrophages. Besides, metalloproteinase inhibitors increased the stability of TREM-1 at the cell surface while significantly reducing sTREM-1 release in cultures of LPS-challenged human monocytes and neutrophils. We conclude that metalloproteinases are responsible for shedding of the TREM-1 ectodomain through proteolytic cleavage of its long juxtamembrane linker.
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http://dx.doi.org/10.4049/jimmunol.179.6.4065DOI Listing
September 2007
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