Characterization of dengue virus 3'UTR RNA binding proteins in mosquitoes reveals that AeStaufen reduces subgenomic flaviviral RNA in saliva.

Dengue viruses (DENV) are expanding global pathogens that are transmitted through the bite of mosquitoes, mostly Aedes aegypti. As RNA viruses, DENV rely on RNA-binding proteins (RBPs) to complete their life cycle. Alternatively, RBPs can act as restriction factors that prevent DENV multiplication. While the importance of RBPs is well-supported in humans, there is a dearth of information about their influence on DENV transmission by mosquitoes. Such knowledge could be harnessed to design novel, effective interventions against DENV. Here, we successfully adapted RNA-affinity chromatography coupled with mass spectrometry-a technique initially developed in mammalian cells-to identify RBPs in Ae. aegypti cells. We identified fourteen RBPs interacting with DENV serotype 2 3'UTR, which is involved in the viral multiplication and produces subgenomic flaviviral RNA (sfRNA). We validated the RNA affinity results for two RBPs by confirming that AePur binds the 3'UTR, whereas AeStaufen interacts with both 3'UTR and sfRNA. Using in vivo functional evaluation, we determined that RBPs like AeRan, AeExoRNase, and AeRNase have pro-viral functions, whereas AeGTPase, AeAtu, and AePur have anti-viral functions in mosquitoes. Furthermore, we showed that human and mosquito Pur homologs have a shared affinity to DENV2 RNA, although the anti-viral effect is specific to the mosquito protein. Importantly, we revealed that AeStaufen mediates a reduction of gRNA and sfRNA copies in several mosquito tissues, including the salivary glands and that AeStaufen-mediated sfRNA reduction diminishes the concentration of transmission-enhancing sfRNA in saliva, thereby revealing AeStaufen's role in DENV transmission. By characterizing the first RBPs that associate with DENV2 3'UTR in mosquitoes, our study unravels new pro- and anti-viral targets for the design of novel therapeutic interventions as well as provides foundation for studying the role of RBPs in virus-vector interactions.

Cemeteries as sources of Aedes aegypti and other mosquito species in southeastern Puerto Rico.

OBJECTIVE: To investigate the presence and abundance of mosquito species in containers found in different types of cemeteries in Puerto Rico to assess their importance and make control recommendations. METHODS: We conducted surveys of containers with water in 16 cemeteries in southeastern Puerto Rico to detect the presence of larvae and pupae of Aedes aegypti and other mosquitoes; to identify the most common and productive containers and to study their variation in relation to the type of cemetery. RESULTS: The most common containers with water were flowerpots, followed in abundance by a variety of discarded containers and open tombs. We found a positive relationship between density of containers with water and rainfall. There was a rich community of mosquito species developing in containers of the inspected cemeteries: nine mosquito species belonging to four genera with Ae. aegypti and Ae. mediovittatus being the most frequent and abundant. We sampled 13 cement-type cemeteries, 2 mixed and only 1 lawn cemetery, consequently, we could not draw any conclusion regarding container productivity and cemetery type. CONCLUSIONS: Surveyed cemeteries were important sources of Ae. aegypti and other mosquitoes in flowerpots, discarded containers and open tombs. We recommend conducting further studies to establish how frequently inspections should occur; and mosquito control by emptying aquatic habitats and larviciding to reduce mosquito productivity and protect workers and visitors from mosquito bites and possible transmission of arboviruses.

Role of RNA-binding proteins during the late stages of Flavivirus replication cycle.

The genus Flavivirus encompasses several worldwide-distributed arthropod-borne viruses including, dengue virus, Japanese encephalitis virus, West Nile virus, yellow fever virus, Zika virus, and tick-borne encephalitis virus. Infection with these viruses manifest with symptoms ranging from febrile illness to life- threatening hypotensive shock and encephalitis. Therefore, flaviviruses pose a great risk to public health. Currently, preventive measures are falling short to control epidemics and there are no antivirals against any Flavivirus.Flaviviruses carry a single stranded positive-sense RNA genome that plays multiple roles in infected cells: it is translated into viral proteins, used as template for genome replication, it is the precursor of the subgenomic flaviviral RNA and it is assembled into new virions. Furthermore, viral RNA genomes are also packaged into extracellular vesicles, e.g. exosomes, which represent an alternate mode of virus dissemination.Because RNA molecules are at the center of Flavivirus replication cycle, viral and host RNA-binding proteins (RBPs) are critical determinants of infection. Numerous studies have revealed the function of RBPs during Flavivirus infection, particularly at the level of RNA translation and replication. These proteins, however, are also critical participants at the late stages of the replication cycle. Here we revise the function of host RBPs and the viral proteins capsid, NS2A and NS3, during the packaging of viral RNA and the assembly of new virus particles. Furthermore, we go through the evidence pointing towards the importance of host RBPs in mediating cellular RNA export with the idea that the biogenesis of exosomes harboring Flavivirus RNA would follow an analogous pathway.

Initial Public Health Laboratory Response After Hurricane Maria - Puerto Rico, 2017.

Hurricane Maria made landfall in Puerto Rico on September 20, 2017, causing major damage to infrastructure and severely limiting access to potable water, electric power, transportation, and communications. Public services that were affected included operations of the Puerto Rico Department of Health (PRDOH), which provides critical laboratory testing and surveillance for diseases and other health hazards. PRDOH requested assistance from CDC for the restoration of laboratory infrastructure, surveillance capacity, and diagnostic testing for selected priority diseases, including influenza, rabies, leptospirosis, salmonellosis, and tuberculosis. PRDOH, CDC, and the Association of Public Health Laboratories (APHL) collaborated to conduct rapid needs assessments and, with assistance from the CDC Foundation, implement a temporary transport system for shipping samples from Puerto Rico to the continental United States for surveillance and diagnostic and confirmatory testing. This report describes the initial laboratory emergency response and engagement efforts among federal, state, and nongovernmental partners to reestablish public health laboratory services severely affected by Hurricane Maria. The implementation of a sample transport system allowed Puerto Rico to reinitiate priority infectious disease surveillance and laboratory testing for patient and public health interventions, while awaiting the rebuilding and reinstatement of PRDOH laboratory services.

Dengue tropism for macrophages and dendritic cells: the host cell effect.

Dengue virus infects immune cells, including monocytes, macrophages and dendritic cells (DC). We compared virus infectivity in macrophages and DC, and found that the virus origin determined the cell tropism of progeny virus. The highest efficiency of re-infection was seen for macrophage-derived dengue virus. Furthermore, in the presence of enhancing antibodies, macrophage-derived virus gave greater enhancement of infection compared with immature DC-derived virus. Taken together, our results highlight the importance of macrophages in dengue infection.

Complex interaction between dengue virus replication and expression of miRNA-133a.

BACKGROUND: Dengue virus (DENV) is the most common vector-borne viral infection worldwide with approximately 390 million cases and 25,000 reported deaths each year. MicroRNAs (miRNAs) are small non-coding RNA molecules responsible for the regulation of gene expression by repressing mRNA translation or inducing mRNA degradation. Although miRNAs possess antiviral activity against many mammalian-infecting viruses, their involvement in DENV replication is poorly understood. METHODS: Here, we explored the relationship between DENV and cellular microRNAs using bioinformatics tools. We overexpressed miRNA-133a in Vero cells to test its role in DENV replication and analyzed its expression using RT-qPCR. Furthermore, the expression of polypyrimidine tract binding protein (PTB), a protein involved in DENV replication, was analyzed by western blot. In addition, we profiled miRNA-133a expression in Vero cells challenged with DENV-2, using Taqman miRNA. RESULTS: Bioinformatic analysis revealed that the 3' untranslated region (3'UTR) of the DENV genome of all four DENV serotypes is targeted by several cellular miRNAs, including miRNA-133a. We found that overexpression of synthetic miRNA-133a suppressed DENV replication. Additionally, we observed that PTB transcription , a miRNA-133a target, is down-regulated during DENV infection. Based in our results we propose that 3'UTR of DENV down-regulates endogenous expression of miRNA-133a in Vero cells during the first hours of infection. CONCLUSIONS: miRNA-133a regulates DENV replication possibly through the modulation of a host factor such as PTB. Further investigations are needed to verify whether miRNA-133a has an anti-DENV effect in vivo.

Identification of Z-Tyr-Ala-CHN2, a Cathepsin L Inhibitor with Broad-Spectrum Cell-Specific Activity against Coronaviruses, including SARS-CoV-2.

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control by vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of severe COVID-19. We report the discovery of a small molecule, Z-Tyr-Ala-CHN2, which was identified in a cell-based antiviral screen. The molecule exerts sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and human coronavirus 229E. Time-of-addition studies reveal that Z-Tyr-Ala-CHN2 acts at the early phase of the infection cycle, which is in line with the observation that the molecule inhibits cathepsin L. This results in antiviral activity against SARS-CoV-2 in VeroE6, A549-hACE2, and HeLa-hACE2 cells, but not in Caco-2 cells or primary human nasal epithelial cells since the latter two cell types also permit entry via transmembrane protease serine subtype 2 (TMPRSS2). Given their cell-specific activity, cathepsin L inhibitors still need to prove their value in the clinic; nevertheless, the activity profile of Z-Tyr-Ala-CHN2 makes it an interesting tool compound for studying the biology of coronavirus entry and replication.

Y-Box Binding Protein 1 Interacts with Dengue Virus Nucleocapsid and Mediates Viral Assembly.

Infection with dengue virus (DENV) induces vast rearrangements of the endoplasmic reticulum, which allows the compartmentalization of viral RNA replication and particle assembly. Both processes occur in concert with viral and cellular proteins. Prior studies from our group suggest that the host RNA-binding protein (RBP) Y-box binding protein 1 (YBX1) is required for a late step in the DENV replication cycle. Here we report that YBX1 interacts with the viral nucleocapsid, distributes to DENV assembly sites and is required for efficient assembly of intracellular infectious virions and their secretion. Genetic ablation of YBX1 decreased the spatial proximity between capsid and envelope, increased the susceptibility of envelope to proteinase K mediated degradation, resulted in the formation of rough empty-looking particles, and decreased the secretion of viral particles. We propose a model wherein YBX1 enables the interaction between the viral nucleocapsid with the structural protein E, which is required for proper assembly of intracellular virus particles and their secretion. IMPORTANCE The global incidence of dengue virus (DENV) infections has steadily increased over the past decades representing an enormous challenge for public health. During infection, DENV viral RNA interacts with numerous host RNA binding proteins (RBPs) that aid viral replication and thus constitute potential molecular targets to curb infection. We recently reported that Y-box-binding protein 1 (YBX1) interacts with DENV RNA and is required at a late step of the replication cycle. Here we describe the molecular mechanism by which YBX1 mediates DENV infection. We show that YBX1 interacts with the viral nucleocapsid, distributes to DENV assembly sites and is required for efficient assembly of intracellular infectious virions. These results provide important insights into DENV assembly, revealing novel functions of host RBPs during viral infection and opening new avenues for antiviral intervention.

[Cells with immunoregulatory properties and their impact in the pathogenesis of sepsis]. / Células con propiedades inmunoreguladoras y su impacto en la patogénesis de la sepsis.

Sepsis, defined as a systemic inflammatory response syndrome caused by an infection, is a significant cause of mortality worldwide. It is currently accepted that death associated to sepsis is due to an immune hyperactivation state involving the development of a broad proinflammatory response along with alterations in the coagulation system. It is now clear that besides the inflammatory events, the clinical course of sepsis is characterized by the development of an anti-inflammatory response that could lead to death in its attempt to balance the initial response. The purpose of this review is to summarize current mechanisms that explain the pathogenesis of sepsis, underlying the role that cells with immunoregulatory properties play during the course of this complex syndrome. A better understanding of these processes will contribute in the search of more successful therapeutic strategies.

Tomatidine, a natural steroidal alkaloid shows antiviral activity towards chikungunya virus in vitro.

In recent decades, chikungunya virus (CHIKV) has re-emerged, leading to outbreaks of chikungunya fever in Africa, Asia and Central and South America. The disease is characterized by a rapid onset febrile illness with (poly)arthralgia, myalgia, rashes, headaches and nausea. In 30 to 40% of the cases, CHIKV infection causes persistent (poly)arthralgia, lasting for months or even years after initial infection. Despite the drastic re-emergence and clinical impact there is no vaccine nor antiviral compound available to prevent or control CHIKV infection. Here, we evaluated the antiviral potential of tomatidine towards CHIKV infection. We demonstrate that tomatidine potently inhibits virus particle production of multiple CHIKV strains. Time-of -addition experiments in Huh7 cells revealed that tomatidine acts at a post-entry step of the virus replication cycle. Furthermore, a marked decrease in the number of CHIKV-infected cells was seen, suggesting that tomatidine predominantly acts early in infection yet after virus attachment and cell entry. Antiviral activity was still detected at 24 hours post-infection, indicating that tomatidine controls multiple rounds of CHIKV replication. Solasodine and sarsasapogenin, two structural derivatives of tomatidine, also showed strong albeit less potent antiviral activity towards CHIKV. In conclusion, this study identifies tomatidine as a novel compound to combat CHIKV infection in vitro.

Tomatidine, a novel antiviral compound towards dengue virus.

Dengue is the most common arboviral disease worldwide with 96 million symptomatic cases annually. Despite its major impact on global human health and huge economic burden there is no antiviral drug available to treat the disease. The first tetravalent dengue virus vaccine was licensed in 2015 for individuals aged 9 to 45, however, most cases are reported in infants and young children. This, together with the limited efficacy of the vaccine to dengue virus (DENV) serotype 2, stresses the need to continue the search for compounds with antiviral activity to DENV. In this report, we describe tomatidine as a novel compound with potent antiviral properties towards all DENV serotypes and the related Zika virus. The strongest effect was observed for DENV-2 with an EC50 and EC90 value of 0.82 and 1.61 µM, respectively, following infection of Huh7 cells at multiplicity of infection of 1. The selectivity index is 97.7. Time-of-drug-addition experiments revealed that tomatidine inhibits virus particle production when added pre, during and up to 12 h post-infection. Subsequent experiments show that tomatidine predominantly acts at a step after virus-cell binding and membrane fusion but prior to the secretion of progeny virions. Tomatidine was found to control the expression of the cellular protein activating transcription factor 4 (ATF4), yet, this protein is not solely responsible for the observed antiviral effect. Here, we propose tomatidine as a candidate for the treatment of dengue given its potent antiviral activity.

Lessons from the reestablishment of Public Health Laboratory activities in Puerto Rico after Hurricane Maria.

Public Health Laboratories (PHLs) in Puerto Rico did not escape the devastation caused by Hurricane Maria. We implemented a quality management system (QMS) approach to systematically reestablish laboratory testing, after evaluating structural and functional damage. PHLs were inoperable immediately after the storm. Our QMS-based approach began in October 2017, ended in May 2018, and resulted in the reestablishment of 92% of baseline laboratory testing capacity. Here, we share lessons learned from the historic recovery of the largest United States' jurisdiction to lose its PHL capacity, and provide broadly applicable tools for other jurisdictions to enhance preparedness for public health emergencies.

MicroRNA profiling of human primary macrophages exposed to dengue virus identifies miRNA-3614-5p as antiviral and regulator of ADAR1 expression.

BACKGROUND: Due to the high burden of dengue disease worldwide, a better understanding of the interactions between dengue virus (DENV) and its human host cells is of the utmost importance. Although microRNAs modulate the outcome of several viral infections, their contribution to DENV replication is poorly understood. METHODS AND PRINCIPAL FINDINGS: We investigated the microRNA expression profile of primary human macrophages challenged with DENV and deciphered the contribution of microRNAs to infection. To this end, human primary macrophages were challenged with GFP-expressing DENV and sorted to differentiate between truly infected cells (DENV-positive) and DENV-exposed but non-infected cells (DENV-negative cells). The miRNAome was determined by small RNA-Seq analysis and the effect of differentially expressed microRNAs on DENV yield was examined. Five microRNAs were differentially expressed in human macrophages challenged with DENV. Of these, miR-3614-5p was found upregulated in DENV-negative cells and its overexpression reduced DENV infectivity. The cellular targets of miR-3614-5p were identified by liquid chromatography/mass spectrometry and western blot. Adenosine deaminase acting on RNA 1 (ADAR1) was identified as one of the targets of miR-3614-5p and was shown to promote DENV infectivity at early time points post-infection. CONCLUSION/SIGNIFICANCE: Overall, miRNAs appear to play a limited role in DENV replication in primary human macrophages. The miRNAs that were found upregulated in DENV-infected cells did not control the production of infectious virus particles. On the other hand, miR-3614-5p, which was upregulated in DENV-negative macrophages, reduced DENV infectivity and regulated ADAR1 expression, a protein that facilitates viral replication.

Antibody-Dependent Enhancement of Dengue Virus Infection in Primary Human Macrophages; Balancing Higher Fusion against Antiviral Responses.

The dogma is that the human immune system protects us against pathogens. Yet, several viruses, like dengue virus, antagonize the hosts' antibodies to enhance their viral load and disease severity; a phenomenon called antibody-dependent enhancement of infection. This study offers novel insights in the molecular mechanism of antibody-mediated enhancement (ADE) of dengue virus infection in primary human macrophages. No differences were observed in the number of bound and internalized DENV particles following infection in the absence and presence of enhancing concentrations of antibodies. Yet, we did find an increase in membrane fusion activity during ADE of DENV infection. The higher fusion activity is coupled to a low antiviral response early in infection and subsequently a higher infection efficiency. Apparently, subtle enhancements early in the viral life cycle cascades into strong effects on infection, virus production and immune response. Importantly, and in contrast to other studies, the antibody-opsonized virus particles do not trigger immune suppression and remain sensitive to interferon. Additionally, this study gives insight in how human macrophages interact and respond to viral infections and the tight regulation thereof under various conditions of infection.

Dietary apigenin reduces LPS-induced expression of miR-155 restoring immune balance during inflammation.

SCOPE: High incidence of inflammatory diseases afflicts the increasing aging-population infringing a great health burden. Dietary flavonoids, including the flavone apigenin, are emerging as important anti-inflammatory nutraceuticals due to their health benefits, lack of adverse effects and reduced costs. MicroRNAs (miRs) play a central role in inflammation by regulating gene expression, yet how dietary ingredients affect miRs is poorly understood. The aim of this study was to identify miRs involved in the anti-inflammatory activity of apigenin and apigenin-rich diets and determine their immune regulatory mechanisms in macrophages and in vivo. METHODS AND RESULTS: A high-throughput quantitative reverse transcriptase PCR screen of 312 miRs in macrophages revealed that apigenin reduced LPS-induced miR-155 expression. Analyses of miR-155 precursor and primary transcript indicated that apigenin regulated miR-155 transcriptionally. Apigenin-reduced expression of miR-155 led to the increase of anti-inflammatory regulators forkhead box O3a and smooth-muscle-actin and MAD-related protein 2 in LPS-treated macrophages. In vivo, apigenin or a celery-based apigenin-rich diet reduced LPS-induced expression of miR-155 and decreased tumor necrosis factor α in lungs from LPS-treated mice. CONCLUSION: These results demonstrate that apigenin and apigenin-rich diets exert effective anti-inflammatory activity in vivo by reducing LPS-induced expression of miR-155, thereby restoring immune balance.

Arthropod-borne flaviviruses and RNA interference: seeking new approaches for antiviral therapy.

Flaviviruses are the most prevalent arthropod-borne viruses worldwide, and nearly half of the 70 Flavivirus members identified are human pathogens. Despite the huge clinical impact of flaviviruses, there is no specific human antiviral therapy available to treat infection with any of the flaviviruses. Therefore, there is a continued search for novel therapies, and this review describes the current knowledge on the usage of RNA interference (RNAi) in combating flavivirus infections. RNAi is a process of sequence-specific gene silencing triggered by double-stranded RNA. Antiviral RNAi strategies against arthropod-borne flaviviruses have been reported and although several hurdles must be overcome to employ this technology in clinical applications, they potentially represent a new therapeutic tool.

Flavone deglycosylation increases their anti-inflammatory activity and absorption.

SCOPE: Flavones have reported anti-inflammatory activities, but the ability of flavone-rich foods to reduce inflammation is unclear. Here, we report the effect of flavone glycosylation in the regulation of inflammatory mediators in vitro and the absorption of dietary flavones in vivo. METHODS AND RESULTS: The anti-inflammatory activities of celery extracts, some rich in flavone aglycones and others rich in flavone glycosides, were tested on the inflammatory mediators tumor necrosis factor α (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in lipopolysaccharide-stimulated macrophages. Pure flavone aglycones and aglycone-rich extracts effectively reduced TNF-α production and inhibited the transcriptional activity of NF-κB, while glycoside-rich extracts showed no significant effects. Deglycosylation of flavones increased cellular uptake and cytoplasmic localization as shown by high-performance liquid chromatography (HPLC) and microscopy using the flavonoid fluorescent dye diphenylboric acid 2-aminoethyl ester (DPBA). Celery diets with different glycoside or aglycone contents were formulated and absorption was evaluated in mice fed with 5 or 10% celery diets. Relative absorption in vivo was significantly higher in mice fed with aglycone-rich diets as determined by HPLC-MS/MS (where MS/MS is tandem mass spectrometry). CONCLUSION: These results demonstrate that deglycosylation increases absorption of dietary flavones in vivo and modulates inflammation by reducing TNF-α and NF-κB, suggesting the potential use of functional foods rich in flavones for the treatment and prevention of inflammatory diseases.

Increased frequency of NK and gamma delta 1 T cells in a cohort of patients with sepsis * / Incremento en la frecuencia de células NK y células T gamma delta 1 en una cohorte de pacientes con sepsis

Introduction: The mechanisms involved in the immunopathogenesis of sepsis are not well established. The clinical and therapeutic relevance of several soluble mediators has been described and the contribution of cellular components with immunoregulatory roles has begun to be elucidated. Objective: To describe changes in the frequency and production of IFN- γ and IL-10 occurring in NK cells and γδ T lymphocytes in a cohort of patients with different manifestations of septic syndrome. Materials and methods: This was a prospective cohort study. Patients with sepsis (n=26), and severe sepsis (n=83) from adult emergency rooms and intensive care units, as well as healthy volunteers (n=8), were included. For all participants, the frequency and phenotype of NK cells and γδ T lymphocytes and the percentage of IFN- γ and IL-10 positive NK and γδ T cells were evaluated by flow cytometry. The NK cells were phenotyped based on the expression of CD56 and CD16 and the γδ T cells on the expression of d 1 and d 2 chains. Results: Patients with sepsis and severe sepsis exhibited an increase in the frequency of NK cells with changes in the proportion of the CD56 bright /CD16¯, CD56 bright /CD16 dim and CD56 dim CD16¯ subpopulations; these cells showed a proinflammatory cytokine profile. A decrease in the V d 2 subset of γδ T lymphocyte s was also observed. Conclusions: Our results indicate a role for NK and γδ T cells during sepsis, however, their exact contribution in the pathogenesis of sepsis syndrome requires further studies.

Introducción: Los mecanimos involucrados en la inmunopatogénesis de las sepsis no han sido claramente establecidos. La importancia clínica y terapéutica de diferentes mediadores solubles ha sido descrita y la contribución de componentes celulares con propiedades inmunorreguladoras ha empezado a dilucidarse. Objetivo: Describir los cambios en la frecuencia y en la producción de IFN- γ e IL-10 que se observa en células NK y linfocitos T γδ en una cohorte de pacientes con diferentes manifestaciones del síndrome séptico. Materiales y métodos: Estudio de cohorte prospectiva, donde pacientes con sepsis (n = 26) y sepsis grave (n = 83) provenientes de las salas de emergencias y unidades de cuidado intensivo, y controles sanos (n = 8) fueron incluidos. Tanto la frecuencia y fenotipo de las células NK y T γδ como el porcentaje de células IFN- γ+ e IL-10+ fueron evaluados mediante citometría de flujo. Las células NK fueron fenotipificadas con base en la expresión de las moléculas CD56 y CD 16 y los T γδ con base en la expresión de las cadenas δ1 y δ2. Resultados: En los pacientes con sepsis y sepsis grave se observó un incremento en la frecuencia de las células NK con cambios en las proporciones de las subpoblaciones CD56 bright /CD 16 ¯, CD56 bright /CD16 dim y CD56 dim CD16¯; en estas células se observó un perfil de citocinas proinflamarias. Se observó una reducción en el porcentaje de células Vδ2. Conclusiones: Los resultados sugieren un papel de las células NK y linfocitos T γδ durante la sepsis; sin embargo, su contribución en la patogénesis de este síndrome requiere estudios adicionales.

Células con propiedades inmunoreguladoras y su impacto en la patogénesis de la sepsis / Cells with immunoregulatory properties and their impact in the pathogenesis of sepsis

Sepsis, defined as a systemic inflammatory response syndrome caused by an infection, is a significant cause of mortality worldwide. It is currently accepted that death associated to sepsis is due to an immune hyperactivation state involving the development of a broad proinflammatory response along with alterations in the coagulation system. It is now clear that besides the inflammatory events, the clinical course of sepsis is characterized by the development of an anti-inflammatory response that could lead to death in its attempt to balance the initial response. The purpose of this review is to summarize current mechanisms that explain the pathogenesis of sepsis, underlying the role that cells with immunoregulatory properties play during the course of this complex syndrome. A better understanding of these processes will contribute in the search of more successful therapeutic strategies.

El síndrome de respuesta sistémica consecuencia de una infección, denominado sepsis, constituye una causa significativa de muerte en el mundo. Históricamente se ha aceptado que la muerte por sepsis se debe a un estado de hiperactivación inmunológica, que implica el desarrollo de una vasta respuesta pro-inflamatoria acompañada de alteraciones en el sistema de coagulación. Ahora es claro que además de los sucesos inflamatorios, el curso clínico de la sepsis se caracteriza por el desarrollo de una respuesta anti-inflamatoria que busca contrarrestar la respuesta inicial, y es ésta finalmente en gran parte responsable de la muerte de los pacientes. El propósito de esta revisión es resumir los mecanismos actuales que explican la patogénesis de la sepsis, y específicamente el papel que desempeñan las subpoblaciones celulares con propiedades inmuno-reguladoras durante el curso de la enfermedad. El mejor entendimiento de estos procesos contribuirá a la búsqueda de estrategias terapéuticas más exitosas.