Background: A novel, isothermal nucleic acid amplification method, RT-LAMP, presents potential for nucleic acid amplification-based diagnostics in resource-limited settings. Low-cost HIV-1 viral load monitoring will improve access to ART for HIV-1-infected individuals present in settings where on-site viral load testing is unavailable. Aim: The aim of this dissertation was to develop an RT-LAMP HIV-1 viral load assay by combining the RT-LAMP reaction with colorimetric amplification detection by hydroxy-naphthol blue dye. Methods: Different approaches for HIV RNA extraction from patient plasma and culture supernatant were studied to obtain template for RT-LAMP. Reaction products for 4 different RT-LAMP primer sets were analysed using agarose gel electrophoresis and restriction digestion. Results: The first 3 primers sets produced persistent off-target amplification. The fourth primer set, designed against culture supernatant DU179, produced a target-specific colour change from violet to blue after 1 hour, following optimisation of amounts of Mg2SO4 and AMV RT. Further studies showed HNB detection sensitivity to template copy number. Conclusions: Initial reaction conditions pertaining to an RT-LAMP based, colorimetric HIV-1 viral load assay were established. Further work is required to determine the reaction duration at which the colour change represents a viral load of ≥1000 copies HIV RNA per ml plasma.

HIV-associated sensory neuropathy (HIV-SN) is one of the most common neurological problems of HIV. It is frequently painful and reduces quality of life. HIV-SN can be caused both by HIV itself and by exposure to neurotoxic antiretrovirals such as stavudine. The South African Department of Health now recommends use of tenofovir in place of stavudine as first line treatment. However many people remain on stavudine and or live with the side effects. Stavudine is still prescribed in many other resource-poor countries. This thesis presents the first systematic study of clinical and genetic risk factors for the development of symptomatic HIV-SN in Black Southern Africans. I recruited 404 Black HIV-positive Africans from the Virology Clinic of the Charlotte Maxeke Academic Hospital, Johannesburg and assessed HIV-SN using the AIDS Clinical Trials Group (ACTG) Brief Peripheral Neuropathy Screen. HIV-SN was defined as present if the patient had both symptoms and signs of peripheral neuropathy. If present, the distribution and intensity of symptoms were recorded. Of those exposed to stavudine, 57% (226/395) had HIV-SN. Pain was the most common symptom and was experienced by 74% (172/226). Of these, 76% (128/172) reported their pain as moderate to severe. As in previous studies, increasing age and height were independently associated with risk of HIV-SN. However nadir and current CD4 T-cell counts and sex were not associated with SN. Patients donated blood for DNA extraction and single nucleotide polymorphisms (SNPs) were selected from the literature and genotyped using Illumina Golden GateTM technology. 342 individuals were assessed for genetic associations with HIV-SN and a subset of 159 positive for HIV-SN were assessed for associations with painful HIV-SN. I completed four genetic analyses: SNPs and haplotypes from TNF and adjacent genes from the major histocompatability complex on chromosome six were assessed for association with HIV-SN. I found no association with TNF-1031, even though this had associated with risk of HIV-SN in Caucasian, Chinese and Malay cohorts. Novel associations were identified between HIV-SN protection and 5 other SNPs (BAT1 rs3130059, rs2523504; ATP6V1G2 rs2071594; NFKBIL1 rs2071592, rs2071591). Associations were also found with haplotypes: FV15-23 weakly associated with risk and FV30-31 associated with protection against HIV-SN in this cohort. Analysis of 8 SNPs not previously assessed produced two novel associations with LTA SNPs (rs1041981, rs909253), where the minor alleles conferred protection against HIV-SN. Analysis of linkage disequilibrium (LD) suggests that there is linkage disequilibrium within the TNF block, that it differs between ethnicities and that TNF-1031 is unlikely to be a causative SNP for risk of HIV-SN. SNPs from other cytokines and chemokines implicated in the pathogenesis of HIVSN and the associated pain were assessed in Chapter 5. The major allele of the antiinflammatory gene IL4 (rs2243250) associated with risk of HIV-SN. This allele has been associated with higher CD4 T-cell counts, so I have proposed a role for high IL- 4 in early stage HIV-SN. A 3-SNP haplotype of IL10 associated with protection against HIV-SN whilst another IL10 haplotype showed a trend for risk of painful HIVSN. These data and the involvement of TNF haplotype (Chapter 4) suggest an inflammatory etiology for HIV-SN. Polymorphisms of UCP2 (rs659366) and UCP3 (rs1800849) have previously associated with risk of diabetic neuropathy. These SNPs encode uncoupling proteins 2 and 3 which regulate reactive oxygen species and may affect development of neuropathy via the effects of oxidative stress and mitochondrial dysfunction. Alleles of these SNPs did not associate with HIV-SN in this cohort. Patterns of linkage disequilibrium may differ between the two ethnicities or UCP2 and UCP3 may associate with a mechanism particular to diabetic neuropathy. I also assessed a ‘pain protective haplotype’ and SNPs of GCH1 which have been associated with decreased pain intensity in radicular pain following lumbar discectomy. Associations of the 3-SNP ‘pain protective’ haplotype (rs10483639*C, rs3783641*A and rs8007267*T) and a 6-SNP haplotype containing this motif with protection against pain were significant but dependent on age, sex and CD4 T-cell count. Association of another 3-SNP haplotype (rs10483639*G, rs3783641*T and rs8007267*C) with increased risk of pain in HIV-SN was also not independent of age, sex and CD4 T-cell count. The weaker associations here compared to Caucasian cohorts may be a result of differing LD between ethnicities or demonstrate different pain mechanisms between HIV-SN and radicular pain following lumbar discectomy. My results highlight the prevalence of HIV-SN and frequency of pain in this Southern African cohort. The genetic studies identify a likely inflammatory component and identify genes worthy of further investigation both in HIV-SN and the associated pain.

Degree of Doctor of Philosophy in Medicine by research only A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the Degree of Doctor of Philosophy in Medicine. Johannesburg, 2014 / Introduction Patients with HIV infection frequently encounter oral candidiasis, caused by Candida species. However, factors responsible for Candida colonisation and development of oral candidiasis in these patients are controversial. This study investigated the effect of social and clinical factors on oral Candida colonisation in HIV positive women. In addition, virulence of these organisms during clinical infection, the role of non-albicans Candida and reinfections with C. albicans were investigated.

Introduction: Migrant and mobile seasonal farm workers face multiple challenges in preventing sexual transmission of HIV. They also fall beyond direct reach of district health promotion services and national HIV prevention communication interventions. HIV prevalence rates in rural farming communities are significantly higher than provincial averages. An integrated health promotion intervention was initiated in 2005 on commercial farms in Hoedspruit, Limpopo province, through the International Organization for Migration. In terms of HIV prevention the Hlokomela project’s key innovation was to employ a local process of participatory communication, with and within the farm worker community, in order to create a local context enabling of health promotion and within which efforts to prevent HIV could be more effective. The research sought to explore the social processes and actions related to the on-going process of dialogue at the core of the participatory communication process. The objective was to describe and analyse the role of dialogue during regular purposive face to face interactions with farm worker change agents, in promoting health and addressing vulnerability to HIV. Method: The study population comprised Hlokomela coordinators, farm worker change agents (Nompilos and Gingirikani) and key farm stakeholders from the 59 partner farms. Research was conducted in Hoedspruit, at the Hlokomela Wellness Centre and on a partner farm. A grounded theory approach was used for sampling: participants were selected through purposive sampling for the initial study sample, and theoretical sampling for the balance. Data was gathered monthly, in three stages between August and November 2010, through: 10 semi-structured in-depth individual interviews; 5 focus group discussions, and observation of 2 monthly meetings and a special event organised by the change agents. Data was analysed using a grounded theory approach. Findings: Farm workers perceive and experience the process of on-going dialogue in face to face interactions as being intertwined with other aspects of the intervention, in particular identification and action to enable access to health services. Hlokomela Coordinators guide and support the process as a means to empower a corps of primary farm worker Change Agents (Nompilos). Nompilos, in turn, apply the system to benefit and empower a wider group of farm worker as second level change agents (Gingirikani). Through this system farm workers have found ways to negotiate HIV-related stigma and cultural taboos on speaking about sex, and to address interpersonal tensions and violence, often gender related, on farms. They have come to consider themselves leaders and role models. Individuals have been enabled to define for themselves appropriate HIV-protective behaviours, and new HIV protective social norms which enable protective behaviours, have gained local currency. These norms include placing value on the opportunity and ability to communicate, to learn from each other, to develop different views, and to attain or protect family, physical and spiritual wellness. Discussion: The process of engagement and regular dialogue, nested in processes related to the other elements of the projects, has positively altered the material, experiential and symbolic context on partner farms. It constitutes effective communication for social change, and has enabled health promotion, as described by the Ottawa Charter, to be realised. This demonstrates that an on-going, participatory process of local communication can create an enabling environment for health promotion. A community of communication practice has been developed in the farming community; this constitutes a reservoir of social capital and capacity to communicate and addresses the need for innovative communication in rural settings. A discursive space and public of discourse around wellness and HIV has been created, and new leaders and alternative narratives, which constitute self and collectively defined “AIDS competency” in a marginalised setting, are becoming visible, suggesting pathways for future interventions to enable equivalent responses in similar settings. Conclusion: An opportunity exists to make more effective use of the power of face to face communication in defined local settings, in order to enable disempowered individuals to claim their human and health rights, to protect themselves from HIV, and to help activate and realise synergies in health and development objectives such as the Millennium Development Goals.

Dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science in Medicine. Johannesburg, 2012 / Introduction: Most new HIV-1 infections world-wide are caused by subtype C viruses. The C3V4 region, including the alpha2-helix and V4 loop, has been identified as a major target for autologous neutralising antibodies in subtype C infections. Factors associated with the immunogenicity of this region, and the mechanisms of escape from anti-C3V4 responses have not been described, although charge changes in the alpha2-helix have been proposed to mediate neutralisation escape. Methods: Seventeen HIV-1 subtype C infected individuals were classified as C3V4 responders or nonresponders using chimeric viruses in env-pseudotyped neutralisation assays. Longitudinal sequences obtained from C3V4 responders were used to identify putative neutralisation escape mutations. The role of these mutations in mediating escape was investigated using site-directed mutagenesis. Results: The C3V4 region was confirmed as a major target in HIV-1 subtype C infections. The development of an anti-C3V4 response was associated with shorter V4 loops and fewer potential N-linked glycans (PNGs) in the C3V4 region. Anti-C3V4 responses were associated with higher autologous neutralising titres. Neutralisation escape from an anti-C3V4 response was rarely mediated by charge changes in the alpha2-helix and generally occurred through mutations in other structurally proximal regions of the envelope. This study confirmed the use of glycan shuffling as a predominant escape pathway. In three individuals multiple mechanisms of escape were identified and in two other cases escape mutations within the C3V4 and structurally proximal regions clustered at opposite termini of the alpha2-helix, inconsistent with the surface area of a single epitope. Conclusion: A more exposed and accessible C3V4 region was more likely to elicit an anti-C3V4 response. The highly immunogenic nature of this region may contribute to the higher overall neutralisation titres in subtype C infections. Distinct clusters of mutations may suggest the existence of two “sub-epitopes” within the C3V4 domain that warrant further investigation. These findings emphasise the adaptability and plasticity of the C3V4 region in the context of viral evasion of host defences.

No description available.

Digitaliseringen i skolan har lett till att det blivit allt vanligare med 1:1-satsningar, det vill säga införande av en dator per elev. Detta görs för att öka elevernas digitala kompetens, men också ofta med förhoppning om ökad motivation till skolarbete. I studien har 17 elever inom årskurs 4–6 intervjuats. Syftet har varit att undersöka hur eleverna upplever att användningen av datorn under matematiklektionerna påverkar deras motivation, samt vilka faktorer eleverna lyfter fram som för-och nackdelar vid användningen av datorn. Dessa faktorer har sedan analyserats utifrån motivationsteori för att se hur olika typer av motivation kan påverka lärande. Resultatet visar att användningen av datorn under matematiklektionerna kan bidra både till elevernas yttre- och inre motivation, men att motivation för datorn bör skiljas från motivation för matematikinnehållet. Resultatet visar även på en brist i lärarstöd och att datorn ofta inkluderas i undervisningen på ett sätt som inte främjar elevernas inre motivation och lärande i matematik. / The digitization in school has led to an increase in 1: 1 investment, also known as the introduction of one computer per pupil. This is to enhance students' digital competence, but also often with the hope of increased motivation for schoolwork. In the study, 17 students in grades 4–6 were interviewed. The purpose has been to investigate how the students feel that the use of the computer during lessons in mathematics affects their motivation, as well as what factors the students highlight as the pros and cons of using the computer. These factors have then been analysed against motivation theory to see how different types of motivation can affect learning. The result shows that the use of the computer during lessons in mathematics can contribute both to the students' extrinsic and intrinsic motivation, but that motivation for the computer should be separated from the motivation for the mathematical content. The result also shows a lack in teacher support, and that the computer is often included in a way that does not promote the students' intrinsic motivation and learning in mathematics.

Introdução: A disfunção erétil (DE) é definida como a incapacidade de alcançar ou manter a ereção do pênis para um desempenho sexual satisfatório, contribuindo significativamente para a baixa qualidade de vida e morbidade psicossocial masculina. A endotelina-1 (ET-1), um potente peptídeo vasoconstritor que promove contração lenta e sustentada em células de músculo liso vascular, possui grande importância na fisiopatologia da DE. Diversos estudos mostram que o aumento da expressão de mediadores inflamatórios está intimamente ligado ao desenvolvimento da DE. O inflamassoma é um complexo multiprotéico do sistema imune inato que atua através da ativação da caspase-1 e resulta na maturação de citocinas pró- inflamatórias, tais como interleucina- IL (IL-l?). O receptor NLRP3 faz parte do inflamassoma e sua ativação leva a clivagem de caspase-1 e consequente secreção de IL-1?. A ET-1, também possui papel importante na inflamação crônica vascular, mediando a liberação de citocinas pró-inflamatórias. No entanto, ainda é desconhecido se a ação pró- inflamatória da ET-1 em células de músculo liso é mediada pela ativação da via do inflamassoma. Hipótese: A ET-1 ativa o NLRP3 em células do músculo liso do corpo cavernoso (CMLCC), promovendo alterações na reatividade do corpo cavernoso (CC). Objetivo: Avaliar o papel da endotelina-1 na ativação do NLRP3 em CMLCC de camundongos. Métodos: CMLCC de camundongos C578BL/6 (WT) e NLRP3-/- foram cultivadas em meio de cultura DMEM acrescido de soro fetal bovino (SFB), 10%, foram pré- incubadas com endotelina-1 nas concentrações de 10-9, 10-8 e 10-7 M, em presença de LPS ou veículo. Avaliamos o efeito da deleção do NLRP3 sobre a reatividade do CC (contratilidade e relaxamento mediante estímulos por campo elétrico e/ou farmacológico). Após, avaliamos o efeito da ET-1 na ativação do NLRP3, nas alterações sobre a reatividade do CC de camundongos WT, e se estas persistiriam nos camundongos NLRP3-/- e caspase1/11-/- . Resultados: As células apresentaram-se fluorescentes para marcação para ?-actina e não para Von Willebrand, caracterizando assim que não houve contaminação com células endoteliais. A incubação com a ET-1 10-7 M por 24 h na presença de LPS ou veículo aumentou a atividade da caspase-1 em CMLCC de camundongos WT e este efeito não ocorreu nas CMLCC de camundongos NLRP3-/-. Não se observou diferença com relação à massa corporal ou massa dos órgãos entre os animais WT e NLRP3-/-. O CC de animais NLRP3-/- apresenta prejuízo para o relaxamento mediado por nitroprussiato de sódio (NPS) quando comparado com as tiras de CC de camundongos WT. A incubação com ET-1 10-7 M por 4 horas promove aumento na contração para fenilefrina (PE) e prejuízo no relaxamento induzido por nitroprussiato de sódio (NPS), e o mesmo efeito não é observado nas tiras de CC de camundongos NLRP3-/- e caspase1/11-/-. Conclusão: O NLRP3 contribui para o aumento na contração e prejuízo no relaxamento produzido pela ET-1 em CC de camundongos, possivelmente através da ativação da caspase-1 / Introduction: Erectile dysfunction (ED) is defined as the inability to achieve or maintain penile erection to perform sexual intercourse, it contributes significantly to the low quality of life and male psychosocial morbidity. Endothelin-1 (ET-1), a potent vasoconstrictor peptide that promotes slow and sustained contraction of vascular smooth muscle cells, has great importance in the pathophysiology of ED. Several studies show that increased expression of inflammatory mediators is closely linked to the development of ED. The inflammasome is a multiproteic complex of the innate immune system that acts through activation of caspase-1, which leads to maturation of pro-inflammatory cytokines such as interleukin-1 beta (IL-l?). The activation of NLRP3 receptor, part of the inflammasome, leads to caspase-1 cleavage and subsequent secretion of IL-1?. ET-1 also plays an important role in chronic vascular inflammation by mediating the release of pro-inflammatory cytokines. However, it is still unknown whether pro-inflammatory actions of ET-1 on smooth muscle cells is mediated by the activation of the inflammasome. Hypothesis: ET-1 activates NLRP3 in smooth muscle cells of the corpora cavernosa (SMCCC), promoting changes in corpus cavernosum (CC) reactivity. Objective: To evaluate the role of endothelin-1 in the activation of the NLRP3 in SMCCC of mice. Methods: SMCCC of C57BL/6 (WT) and NLRP3-/- mice were grown in DMEM culture medium supplemented with bovine fetal serum (FBS) 10%, pre-incubated with endothelin-1 at concentrations of 10-9, 10- 8 and 10-7M, in the presence of LPS or vehicle. We evaluated the effect of the NLRP3 deletion on the reactivity of the CC (contractility and relaxation by electric field and/or pharmacological stimulation). After that, we evaluated the ET-1 effect on activation NLRP3, changes on the reactivity of the CC of WT, and if these alterations would persist NLRP3-/- and caspase1/11-/- mice. Results: The cells presented fluorescent labeling to ?-actin, but not for Von Willebrand factor, characterizing absence of endothelial cells contamination. The incubation with 10-7 M ET-1 for 24 h in the presence of LPS or vehicle increased caspase-1 activity in SMCCC from WT, but not from NLRP3-/- mice. No difference was observed in body mass or weight of the organs between WT and NLRP3-/- animals. The CC from NLRP3-/- animals displayed impaired relaxation mediated by sodium nitroprusside (SNP) when compared to WT CC. The incubation with ET-1 10-7 M for 4 hours promoted an increase in the contraction to phenylephrine (PE) and reduced relaxation induced by sodium nitroprusside (SNP). The same effect was not observed in CC strips from NLRP3-/- and caspase1/11-/- mice. Conclusion: NLRP3 contributes to the increase in contraction and impaired relaxation produced by ET-1 in mice CC, possibly by activation of caspase-1

A galectina-1 (Gal1) é uma lectina, altamente conservada, que reconhece ?- galactosídeos, e está envolvida na regulação da tolerância da imunidade celular e na homeostase. Dados da literatura mostram que esta lectina endógena é amplamente expressa em locais de inflamação e na tumorigênese, participando diretamente dos processos de adesão celular, crescimento tumoral, metástase e angiogênese, ressaltando a relevância de sua detecção em amostras biológicas, e sugerindo que a inibição dirigida da Gal1 pode resultar em benefícios no tratamento de distúrbios inflamatórios e em novas estratégias terapêuticas antitumorais. Entretanto, ainda são escassos os dados sobre inibidores de Gal1 com real impacto terapêutico no bloqueio da atividade biológica dessa lectina. Os aptâmeros são oligonucleotídeos de cadeia simples (DNA ou RNA), que podem se ligar a uma vasta diversidade de alvos, tais como íons, peptídeos, proteínas, moléculas orgânicas e inorgânicas, com alta afinidade e especificidade. Os aptâmeros são selecionados a partir de bibliotecas com sequências randômicas de oligonucleotídeos fita simples (ssDNA) constituídos por uma região central variável, flanqueada por duas regiões de interação com primers para amplificação das sequências via PCR. Esse processo de seleção é denominado de Evolução Sistemática de Ligantes por Enriquecimento Exponencial (SELEX). Neste trabalho foram selecionados e caracterizados aptâmeros de DNA que se ligam a Gal1 humana recombinante e inibem sua atividade lectínica. O processo de seleção dos aptâmeros foi feito através de uma variação da metodologia SELEX, desenvolvida neste trabalho e aqui denominada de \"single vial selection\" (SVS), na qual todas as etapas de seleção dos aptâmeros ocorreram em um único recipiente, de forma rápida e eficiente, evitando etapas cromatográficas, que geralmente são utilizadas no SELEX. Análises com a técnica de termoflúor (TSA) e espectroscopia de fluorescência intrínseca do triptofano permitiram confirmar que os aptâmeros, de fato, se ligam a Gal1, mas em um sítio afastado do CRD. Ensaios de hemaglutinação mostraram que os aptâmeros selecionados conseguiram inibir a ligação da Gal1 com as glicanas da superfície celular, bloqueando a atividade lectínica da proteína. Assim, esse conjunto de resultados mostram que foi possível o desenvolvimento de uma nova classe de inibidores da Gal1 baseada em aptâmeros de DNA, a partir de uma nova metodologia de SELEX, e que não atuam através dos mecanismos clássicos de bloqueio da atividade lectínica via CRD, abrindo nossas possibilidades no desenvolvimento de estratégias diagnósticas e terapêuticas envolvendo esta proteína. / Galectin-1 (Gal1) is a highly conserved lectin that recognizes ?-galactosides, involved in the regulation of cellular immunity tolerance and homeostasis. Data from the literature show that this endogenous lectin is widely expressed in sites of inflammation and tumorigenesis, directly participating in cell adhesion processes, tumor growth, metastasis and angiogenesis, highlighting the relevance of its detection in biological samples, and suggesting that its direct inhibition may result in benefits in the treatment of inflammatory disorders and in novel antitumor therapeutic strategies. However, data on Gal1 inhibitors with real therapeutic impact in blocking the biological activity of this lectin are still scarce. Aptamers are single-stranded oligonucleotides (DNA or RNA), which can bind to a wide variety of targets, such as ions, peptides, proteins, organic and inorganic molecules, with high affinity and specificity. The aptamers are selected from pools of random single-stranded oligonucleotide (ssDNA) sequences consisting of a variable central region, flanked by two sites of primers interaction for PCR amplification. This selection process is called Systematic Evolution of Ligands by EXponential enrichment (SELEX). In this work, DNA aptamers that bind to recombinant human Gal1 and inhibit their lectin activity have been selected and characterized. The aptamers selection process was done through a variation of SELEX methodology, developed in this work and here called \"single vial selection\" (SVS), in which all stages of aptamers selection occurred in a single container, quickly and efficient, avoiding chromatographic steps, which are usually used in SELEX. Analyzes by Thermofluor (TSA) method and intrinsic tryptophan fluorescence spectroscopy have confirmed that aptamers actually bind to Gal1, but at a site away from the CRD. Hemagglutination assay showed that selected aptamers succeeded in inhibiting the Gal1 binding to cell surface glycans, blocking the protein lectin activity. Thus, this set of results showed that it was possible to develop a new class of Gal1 inhibitors based on DNA aptamers and on a new SELEX methodology, that does not act through the classic blocking mechanisms of lectin activity via CRD, opening new possibilities for the development of diagnostic and therapeutic strategies involving this protein.

Le récepteur TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) joue un rôle crucial dans la mise en place du sepsis en amplifiant la réponse immunitaire de l'hôte. TLT-1 (TREM-Like Transcript-1) appartient à la famille des récepteurs TREMs, est exprimé exclusivement sur les plaquettes activées et est connu pour faciliter l'agrégation plaquettaire en liant le fibrinogène. Ces travaux montrent qu'une forme soluble de TLT-1 est impliquée dans la régulation de l'inflammation au cours du sepsis en modulant l'activation leucocytaire et le dialogue plaquette-neutrophile. Un peptide de 17 acides aminés issu de sa portion extracellulaire est porteur de cette activité par compétition avec le ligand de TREM-1. Alors que l'administration tant précoce que tardive de LR17 au cours du sepsis expérimental murin augmentait la survie, les animaux KO TLT-1 étaient hautement susceptibles à l'infection. Nous avons identifié ici un récepteur soluble libéré au cours de l'activation plaquettaire comme un potentiel régulateur de la réaction inflammatoire au cours du sepsis, ouvrant ainsi de nouvelles perspectives thérapeutiques / The Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) plays a crucial role during the onset of sepsis by amplifying the host immune response. The TREM-Like Transcript-1 (TLT-1) belongs to the TREM family, is selectively expressed on activated platelets, and is known to facilitate platelet aggregation through binding to fibrinogen. Here we show that a soluble form of TLT-1 is implicated in the regulation of inflammation during sepsis by dampening leukocytes activation and modulating platelet-neutrophil crosstalk. A 17-aa sequence of the TLT-1 extracellular domain (LR17) is responsible for this activity through competition with the TREM-1 ligand. While early or late LR17 treatment of septic mice improves survival, treml-1-/- animals are highly susceptible to polymicrobial infection. The present findings identify platelet derived sTLT-1 as a potent endogenous regulator of sepsis associated inflammation and open new therapeutic perspectives