Fiscal space for sustainable financing of health systems and universal health

[ABSTRACT]. The articles published in this series show that it is possible to create fiscal space for health in countries. This requires specific decisions since economic growth is not enough to generate the additional resources needed. The studies analyze the benefits of reviewing tax expenditures to identify exemptions, which are generally outdated and of low benefit for the countries; arguments in favor of increasing taxes on products harmful to health; and credits and donations, which do not result in a viable source of income for governments. Fiscal efforts must be accompanied by an improvement in efficiency, and the progressive creation of new revenues is key to improving equity. It is necessary to improve the collection of fiscal resources. It is necessary to develop a research and action agenda that includes the analysis of fiscal space within the processes of health system transformation and reform, including technical aspects not yet addressed and studies of the social efficiency of fiscal space for major development objectives such as the Sustainable Development Goals 2030. In the countries of the Region of the Americas it is essential to have efficient management to do more and better with more resources, even during adverse economic cycles. This should be evident at all levels, including solidarity for achieving better health outcomes, the strategic purchase of goods and services for health, and the strengthening of budget planning systems.

Espacio fiscal para el financiamiento sostenible de los sistemas de salud y la salud universal

[RESUMEN]. Los artículos publicados en esta serie muestran que es posible crear espacio fiscal para la salud en los países. Para esto se requieren decisiones específicas, ya que el crecimiento económico no es suficiente para generar los recursos adicionales necesarios. Los estudios analizan la conveniencia de revisar los gastos tributarios para identificar las exenciones —en general desactualizadas y de escasos beneficios para los países—; los argumentos para aumentar los impuestos sobre productos dañinos para la salud; y los créditos y donaciones, que no resultan una fuente de ingresos viable para los gobiernos. Los esfuerzos fiscales deben ser acompañados por una mejora de la eficiencia, y la creación progresiva de nuevos ingresos es clave para mejorar la equidad. Es necesario mejorar la recaudación de los recursos fiscales. Para esto se requiere desarrollar una agenda de investigación y acción que entienda el análisis del espacio fiscal inserto en los procesos de transformación y reforma de los sistemas de salud, que abarque los aspectos técnicos no abordados aún y estudios de la eficiencia social del espacio fiscal para los grandes objetivos de desarrollo como los Objetivos de Desarrollo Sostenible 2030. En los países de la Región de las Américas es imprescindible contar con una gestión eficiente para hacer más y mejor con más recursos, incluso durante los ciclos económicos adversos. Esta debe evidenciarse en todos los niveles, incluidas la solidaridad que logra mejores resultados en salud, los sistemas de asignación de recursos a los proveedores, la compra estratégica de bienes y servicios de salud y el fortalecimiento de los sistemas de planificación presupuestaria.

[ABSTRACT]. The articles published in this series show that it is possible to create fiscal space for health in the countries. This requires specific decisions since economic growth is not enough to generate the additional resources needed. The studies analyze the benefit of reviewing the tax expenditures to identify exemptions — generally outdated and of low benefit for the countries —; arguments to increase taxes on products harmful to health; and credits and donations, which do not result in a viable source of income for governments. Fiscal efforts must be accompanied by an improvement in efficiency, and the progressive creation of new revenues is key to improving equity. It is necessary to improve the collection of fiscal resources. To this end, it is necessary to develop a research and action agenda that understands the analysis of the fiscal space inserted in the processes of transformation and reform of health systems, including the technical aspects not yet addressed and studies of the social efficiency of the fiscal space for major development objectives such as the Sustainable Development Goals 2030. In the countries of the Region of the Americas it is essential to have efficient management to do more and better with more resources, even during adverse economic cycles. This should be evident at all levels, including solidarity for achieving better health outcomes, strategic purchase of health goods and services, and strengthening of budget planning systems.

[RESUMO]. Os artigos publicados nesta série mostram que é possível criar espaço fiscal para a saúde nos países. Isso requer decisões específicas, já que o crescimento econômico não é suficiente para gerar os recursos adicionais necessários. Os estudos analisam o benefício de rever as despesas fiscais para identificar isenções—geralmente desatualizadas e de baixo benefício para os países—; argumentos para aumentar os impostos sobre os produtos prejudiciais à saúde; e créditos e doações, que não resultam em uma fonte viável de renda para os governos. Os esforços fiscais devem ser acompanhados por uma melhoria na eficiência, e a criação progressiva de novas receitas é fundamental para melhorar a equidade. É necessário melhorar a arrecadação de recursos fiscais. Para tanto, é necessário desenvolver uma agenda de pesquisa e ação que compreenda a análise do espaço fiscal inserido nos processos de transformação e reforma dos sistemas de saúde, incluindo os aspectos técnicos ainda não abordados e estudos sobre a eficiência social do espaço fiscal para grandes objetivos de desenvolvimento, como os Objetivos de Desenvolvimento Sustentável 2030. Nos países da Região das Américas é essencial ter uma gestão eficiente para fazer mais e melhor com mais recursos, mesmo durante ciclos econômicos adversos. Isso deve ser evidente em todos os níveis, incluindo a solidariedade para alcançar melhores resultados de saúde, a compra estratégica de bens e serviços de saúde e o fortalecimento dos sistemas de planejamento orçamentário.

[Fiscal space for sustainable financing of health systems and universal healthEspaço fiscal para o financiamento sustentável dos sistemas de saúde e saúde universal]. / Espacio fiscal para el financiamiento sostenible de los sistemas de salud y la salud universal.

The articles published in this series show that it is possible to create fiscal space for health in the countries. This requires specific decisions since economic growth is not enough to generate the additional resources needed. The studies analyze the benefit of reviewing the tax expenditures to identify exemptions - generally outdated and of low benefit for the countries -; arguments to increase taxes on products harmful to health; and credits and donations, which do not result in a viable source of income for governments. Fiscal efforts must be accompanied by an improvement in efficiency, and the progressive creation of new revenues is key to improving equity. It is necessary to improve the collection of fiscal resources.To this end, it is necessary to develop a research and action agenda that understands the analysis of the fiscal space inserted in the processes of transformation and reform of health systems, including the technical aspects not yet addressed and studies of the social efficiency of the fiscal space for major development objectives such as the Sustainable Development Goals 2030. In the countries of the Region of the Americas it is essential to have efficient management to do more and better with more resources, even during adverse economic cycles. This should be evident at all levels, including solidarity for achieving better health outcomes, strategic purchase of health goods and services, and strengthening of budget planning systems.

Os artigos publicados nesta série mostram que é possível criar espaço fiscal para a saúde nos países. Isso requer decisões específicas, já que o crescimento econômico não é suficiente para gerar os recursos adicionais necessários. Os estudos analisam o benefício de rever as despesas fiscais para identificar isenções­geralmente desatualizadas e de baixo benefício para os países­; argumentos para aumentar os impostos sobre os produtos prejudiciais à saúde; e créditos e doações, que não resultam em uma fonte viável de renda para os governos. Os esforços fiscais devem ser acompanhados por uma melhoria na eficiência, e a criação progressiva de novas receitas é fundamental para melhorar a equidade. É necessário melhorar a arrecadação de recursos fiscais.Para tanto, é necessário desenvolver uma agenda de pesquisa e ação que compreenda a análise do espaço fiscal inserido nos processos de transformação e reforma dos sistemas de saúde, incluindo os aspectos técnicos ainda não abordados e estudos sobre a eficiência social do espaço fiscal para grandes objetivos de desenvolvimento, como os Objetivos de Desenvolvimento Sustentável 2030. Nos países da Região das Américas é essencial ter uma gestão eficiente para fazer mais e melhor com mais recursos, mesmo durante ciclos econômicos adversos. Isso deve ser evidente em todos os níveis, incluindo a solidariedade para alcançar melhores resultados de saúde, a compra estratégica de bens e serviços de saúde e o fortalecimento dos sistemas de planejamento orçamentário.

Espacio fiscal para el financiamiento sostenible de los sistemas de salud y la salud universal / Fiscal space for sustainable financing of health systems and universal health / Espaço fiscal para o financiamento sustentável dos sistemas de saúde e saúde universal

RESUMEN Los artículos publicados en esta serie muestran que es posible crear espacio fiscal para la salud en los países. Para esto se requieren decisiones específicas, ya que el crecimiento económico no es suficiente para generar los recursos adicionales necesarios. Los estudios analizan la conveniencia de revisar los gastos tributarios para identificar las exenciones —en general desactualizadas y de escasos beneficios para los países—; los argumentos para aumentar los impuestos sobre productos dañinos para la salud; y los créditos y donaciones, que no resultan una fuente de ingresos viable para los gobiernos. Los esfuerzos fiscales deben ser acompañados por una mejora de la eficiencia, y la creación progresiva de nuevos ingresos es clave para mejorar la equidad. Es necesario mejorar la recaudación de los recursos fiscales. Para esto se requiere desarrollar una agenda de investigación y acción que entienda el análisis del espacio fiscal inserto en los procesos de transformación y reforma de los sistemas de salud, que abarque los aspectos técnicos no abordados aún y estudios de la eficiencia social del espacio fiscal para los grandes objetivos de desarrollo como los Objetivos de Desarrollo Sostenible 2030. En los países de la Región de las Américas es imprescindible contar con una gestión eficiente para hacer más y mejor con más recursos, incluso durante los ciclos económicos adversos. Esta debe evidenciarse en todos los niveles, incluidas la solidaridad que logra mejores resultados en salud, los sistemas de asignación de recursos a los proveedores, la compra estratégica de bienes y servicios de salud y el fortalecimiento de los sistemas de planificación presupuestaria.

ABSTRACT The articles published in this series show that it is possible to create fiscal space for health in the countries. This requires specific decisions since economic growth is not enough to generate the additional resources needed. The studies analyze the benefit of reviewing the tax expenditures to identify exemptions — generally outdated and of low benefit for the countries —; arguments to increase taxes on products harmful to health; and credits and donations, which do not result in a viable source of income for governments. Fiscal efforts must be accompanied by an improvement in efficiency, and the progressive creation of new revenues is key to improving equity. It is necessary to improve the collection of fiscal resources. To this end, it is necessary to develop a research and action agenda that understands the analysis of the fiscal space inserted in the processes of transformation and reform of health systems, including the technical aspects not yet addressed and studies of the social efficiency of the fiscal space for major development objectives such as the Sustainable Development Goals 2030. In the countries of the Region of the Americas it is essential to have efficient management to do more and better with more resources, even during adverse economic cycles. This should be evident at all levels, including solidarity for achieving better health outcomes, strategic purchase of health goods and services, and strengthening of budget planning systems.

RESUMO Os artigos publicados nesta série mostram que é possível criar espaço fiscal para a saúde nos países. Isso requer decisões específicas, já que o crescimento econômico não é suficiente para gerar os recursos adicionais necessários. Os estudos analisam o benefício de rever as despesas fiscais para identificar isenções—geralmente desatualizadas e de baixo benefício para os países—; argumentos para aumentar os impostos sobre os produtos prejudiciais à saúde; e créditos e doações, que não resultam em uma fonte viável de renda para os governos. Os esforços fiscais devem ser acompanhados por uma melhoria na eficiência, e a criação progressiva de novas receitas é fundamental para melhorar a equidade. É necessário melhorar a arrecadação de recursos fiscais. Para tanto, é necessário desenvolver uma agenda de pesquisa e ação que compreenda a análise do espaço fiscal inserido nos processos de transformação e reforma dos sistemas de saúde, incluindo os aspectos técnicos ainda não abordados e estudos sobre a eficiência social do espaço fiscal para grandes objetivos de desenvolvimento, como os Objetivos de Desenvolvimento Sustentável 2030. Nos países da Região das Américas é essencial ter uma gestão eficiente para fazer mais e melhor com mais recursos, mesmo durante ciclos econômicos adversos. Isso deve ser evidente em todos os níveis, incluindo a solidariedade para alcançar melhores resultados de saúde, a compra estratégica de bens e serviços de saúde e o fortalecimento dos sistemas de planejamento orçamentário.

Getting it right when budgets are tight: Using optimal expansion pathways to prioritize responses to concentrated and mixed HIV epidemics.

BACKGROUND: Prioritizing investments across health interventions is complicated by the nonlinear relationship between intervention coverage and epidemiological outcomes. It can be difficult for countries to know which interventions to prioritize for greatest epidemiological impact, particularly when budgets are uncertain. METHODS: We examined four case studies of HIV epidemics in diverse settings, each with different characteristics. These case studies were based on public data available for Belarus, Peru, Togo, and Myanmar. The Optima HIV model and software package was used to estimate the optimal distribution of resources across interventions associated with a range of budget envelopes. We constructed "investment staircases", a useful tool for understanding investment priorities. These were used to estimate the best attainable cost-effectiveness of the response at each investment level. FINDINGS: We find that when budgets are very limited, the optimal HIV response consists of a smaller number of 'core' interventions. As budgets increase, those core interventions should first be scaled up, and then new interventions introduced. We estimate that the cost-effectiveness of HIV programming decreases as investment levels increase, but that the overall cost-effectiveness remains below GDP per capita. SIGNIFICANCE: It is important for HIV programming to respond effectively to the overall level of funding availability. The analytic tools presented here can help to guide program planners understand the most cost-effective HIV responses and plan for an uncertain future.

[Hospital performance in a segmented and unequal health system: Chile 2001-2010]. / Desempeño hospitalario en un sistema de salud segmentado y desigual: Chile 2001-2010.

OBJECTIVE:: To analyze the differences in health outcomes by hospital characteristics, focusing on ownership: public, private not-for-profit (PNFP) and private for-profit (PFP). MATERIALS AND METHODS:: We used a discharged patient dataset of Chilean hospitals for the period 2001-2010 with a total of 16 205 314 discharges in 20 public, six PNFP and 15 PFP hospitals.We selected a subsample of two medical conditions: myocardial infarction and stroke.We used probit regression analyses with mortality rates as dependent variable, ownership status as the key explanatory variable, and control variables which included patients' health status and socioeconomic level, and hospital characteristics. RESULTS:: Private hospitals showed lower risk of death relative to public hospitals: 1.3% in PNFP, 0.7% in PFP and 3.5% in public hospitals. CONCLUSIONS:: The analysis shows the inequities that exist between public hospitals and the private sector.

Desempeño hospitalario en un sistema de salud segmentado y desigual: Chile 2001-2010 / Hospital performance in a segmented and unequal health system: Chile 2001-2010

Resumen: Objetivo: Analizar las diferencias en los resultados en salud según condiciones observadas de los hospitales, en particular su tipo de propiedad: hospitales públicos, privados sin fines de lucro (PSL) y privados con fines de lucro (PCL). Material y métodos: Se utilizó información de egresos hospitalarios en Chile entre 2001 y 2010 con un total de 16 205 314 altas de 20 hospitales públicos, 6 de PSL y 15 de PCL. Se seleccionó una muestra de pacientes con infarto al miocardio (IAM) y accidente cerebrovascular (ACV). Se estimó una regresión probit utilizando como variable dependiente la mortalidad intrahospitalaria y controlando por variables como estado de salud, nivel socioeconómico y características del hospital. Resultados: Los hospitales privados tienen menor riesgo de mortalidad intrahospitalaria: 1.3% en PSL y 0.7% en PCL, mientras que en los hospitales públicos el riesgo llega a 3.5%. Conclusiones: Este análisis muestra las inequidades que el sector público tiene respecto de los demás sectores.

Abstract: Objective: To analyze the differences in health outcomes by hospital characteristics, focusing on ownership: public, private not-for-profit (PNFP) and private for-profit (PFP). Materials and methods: We used a discharged patient dataset of Chilean hospitals for the period 2001-2010 with a total of 16 205 314 discharges in 20 public, six PNFP and 15 PFP hospitals.We selected a subsample of two medical conditions: myocardial infarction and stroke.We used probit regression analyses with mortality rates as dependent variable, ownership status as the key explanatory variable, and control variables which included patients' health status and socioeconomic level, and hospital characteristics. Results: Private hospitals showed lower risk of death relative to public hospitals: 1.3% in PNFP, 0.7% in PFP and 3.5% in public hospitals. Conclusions: The analysis shows the inequities that exist between public hospitals and the private sector.

Dissociation of innate immune responses in microglia infected with Listeria monocytogenes.

Microglia, the innate immune cells of the brain, plays a central role in cerebral listeriosis. Here, we present evidence that microglia control Listeria infection differently than macrophages. Infection of primary microglial cultures and murine cell lines with Listeria resulted in a dual function of the two gene expression programmes involved in early and late immune responses in macrophages. Whereas the bacterial gene hly seems responsible for both transcriptional programmes in macrophages, Listeria induces in microglia only the tumor necrosis factor (TNF)-regulated transcriptional programme. Listeria also represses in microglia the late immune response gathered in two clusters, microbial degradation, and interferon (IFN)-inducible genes. The bacterial gene actA was required in microglia to induce TNF-regulated responses and to repress the late response. Isolation of microglial phagosomes revealed a phagosomal environment unable to destroy Listeria. Microglial phagosomes were also defective in several signaling and trafficking components reported as relevant for Listeria innate immune responses. This transcriptional strategy in microglia induced high levels of TNF-α and monocyte chemotactic protein-1 and low production of other neurotoxic compounds such as nitric oxide, hydrogen peroxide, and Type I IFNs. These cytokines and toxic microglial products are also released by primary microglia, and this cytokine and chemokine cocktail display a low potential to trigger neuronal apoptosis. This overall bacterial strategy strongly suggests that microglia limit Listeria inflammation pattern exclusively through TNF-mediated responses to preserve brain integrity.

The comparative cost-effectiveness of an equity-focused approach to child survival, health, and nutrition: a modelling approach.

Progress on child mortality and undernutrition has seen widening inequities and a concentration of child deaths and undernutrition in the most deprived communities, threatening the achievement of the Millennium Development Goals. Conversely, a series of recent process and technological innovations have provided effective and efficient options to reach the most deprived populations. These trends raise the possibility that the perceived trade-off between equity and efficiency no longer applies for child health--that prioritising services for the poorest and most marginalised is now more effective and cost effective than mainstream approaches. We tested this hypothesis with a mathematical-modelling approach by comparing the cost-effectiveness in terms of child deaths and stunting events averted between two approaches (from 2011-15 in 14 countries and one province): an equity-focused approach that prioritises the most deprived communities, and a mainstream approach that is representative of current strategies. We combined some existing models, notably the Marginal Budgeting for Bottlenecks Toolkit and the Lives Saved Tool, to do our analysis. We showed that, with the same level of investment, disproportionately higher effects are possible by prioritising the poorest and most marginalised populations, for averting both child mortality and stunting. Our results suggest that an equity-focused approach could result in sharper decreases in child mortality and stunting and higher cost-effectiveness than mainstream approaches, while reducing inequities in effective intervention coverage, health outcomes, and out-of-pocket spending between the most and least deprived groups and geographic areas within countries. Our findings should be interpreted with caution due to uncertainties around some of the model parameters and baseline data. Further research is needed to address some of these gaps in the evidence base. Strategies for improving child nutrition and survival, however, should account for an increasing prioritisation of the most deprived communities and the increased use of community-based interventions.

LIMP-2 links late phagosomal trafficking with the onset of the innate immune response to Listeria monocytogenes: a role in macrophage activation.

The innate immune response to Listeria monocytogenes depends on phagosomal bacterial degradation by macrophages. Here, we describe the role of LIMP-2, a lysosomal type III transmembrane glycoprotein and scavenger-like protein, in Listeria phagocytosis. LIMP-2-deficient mice display a macrophage-related defect in Listeria innate immunity. They produce less acute phase pro-inflammatory cytokines/chemokines, MCP-1, TNF-α, and IL-6 but normal levels of IL-12, IL-10, and IFN-γ and a 25-fold increase in susceptibility to Listeria infection. This macrophage defect results in a low listericidal potential, poor response to TNF-α activation signals, impaired phago-lysosome transformation into antigen-processing compartments, and uncontrolled LM cytosolic growth that fails to induce normal levels of acute phase pro-inflammatory cytokines. LIMP-2 transfection of CHO cells confirmed that LIMP-2 participates in the degradation of Listeria within phagosomes, controls the late endosomal/lysosomal fusion machinery, and is linked to the activation of Rab5a. Therefore, the role of LIMP-2 appears to be connected to the TNF-α-dependent and early activation of Listeria macrophages through internal signals linking the regulation of late trafficking events with the onset of the innate Listeria immune response.

Interleukin-1RN gene polymorphisms in elderly patients with rheumatic inflammatory chronic conditions: Association of IL-1RN*2/2 genotype with polymyalgia rheumatica.

The objective of this study was to investigate whether there is an association between IL1RN polymorphism and disease susceptibility for three age-related inflammatory conditions: polymyalgia rheumatica (PMR), giant cell arteritis (GCA), and elderly-onset rheumatoid arthritis (EORA). A tandem-repeat polymorphism within IL1RN intron 2 was analyzed in 139 PMR, 69 GCA, and 156 RA patients (75 with EORA) as well as in 437 healthy subjects, together with the in vitro production of IL-1beta. Our results showed that the IL1RN*2/2 genotype was more frequent in PMR patients compared with controls (p = 0.032, odds ratio = 1.785, 95% confidence interval = 1.047-3.044) and GCA patients (p = 0.008, odds ratio = 4.661, 95% confidence interval = 1.352-16.065). We found no difference in the distribution of genotypes between PMR and EORA or between EORA and controls. However, the frequency of the IL-1RN*2/2 genotype had a tendency to be higher in patients with EORA compared with young onset RA. The presence of IL1RN*1 or IL1RN*2 allele was not associated with severity of the disease in PMR and GCA patients and did not influence the production of IL-1beta. In conclusion, the IL1RN*2 polymorphism in a homozygous state was associated with an increased susceptibility to PMR and may give some clues for a differential therapy with GCA.

Interleukin-12 plasma levels in drug-naïve patients with a first episode of psychosis: effects of antipsychotic drugs.

An overactivation of the Th1 activity in schizophrenia had been described. Interleukin-12 (IL-12), a proinflammatory cytokine, plays a key role in the regulation of the Th1 response. The aims of this study were to investigate the effect of first and second generation antipsychotic drugs on IL-12 production during the acute phase of the illness and its association with clinical features. Participants comprised 56 drug-naïve first episode psychotic patients and 28 healthy volunteers. Patients were initially randomly assigned to risperidone (n=16), olanzapine (n=20) or haloperidol (n=20); subject were maintained on the same medication throughout the study. Clinical assessments were conducted at baseline and at 6 weeks. IL-12 plasma levels were assessed at baseline and after 6 weeks of antipsychotic treatment. IL-12 haplotypes were also analysed. Patients showed higher IL-12 plasma levels at baseline compared with controls, and had a significant increase in IL-12 plasma level after 6 weeks of antipsychotic treatment. No significant differences in IL-12 level increase were found among the three antipsychotic treatments. IL-12 plasma levels at week 6 were not significantly associated with the severity of psychopathology at week 6. Thus, patients with a first episode of psychosis have inflammatory-like immunological function during early phases of the illness that it is independent of the antipsychotic treatment used.

Characterization of a Listeria monocytogenes protein interfering with Rab5a.

Listeria monocytogenes (LM) phagocytic strategy implies recruitment and inhibition of Rab5a. Here, we identify a Listeria protein that binds to Rab5a and is responsible for Rab5a recruitment to phagosomes and impairment of the GDP/GTP exchange activity. This protein was identified as a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Listeria (p40 protein, Lmo 2459). The p40 protein was found within the phagosomal membrane. Analysis of the sequence of LM p40 protein revealed two enzymatic domains: the nicotinamide adenine dinucleotide (NAD)-binding domain at the N-terminal and the C-terminal glycolytic domain. The putative ADP-ribosylating ability of this Listeria protein located in the N-terminal domain was examined and showed some similarities to the activity and Rab5a inhibition exerted by Pseudomonas aeruginosa ExoS onto endosome-endosome fusion. Listeria p40 caused Rab5a-specific ADP ribosylation and blocked Rab5a-exchange factor (Vps9) and GDI interaction and function, explaining the inhibition observed in Rab5a-mediated phagosome-endosome fusion. Meanwhile, ExoS impaired Rab5-early endosomal antigen 1 (EEA1) interaction and showed a wider Rab specificity. Listeria GAPDH might be the first intracellular gram-positive enzyme targeted to Rab proteins with ADP-ribosylating ability and a putative novel virulence factor.

Role of Trypanosoma cruzi autoreactive T cells in the generation of cardiac pathology.

Chagas disease, caused by Trypanosoma cruzi, affects several million people in Central and South America. About 30% of chronic patients develop cardiomyopathy probably caused by parasite persistence and/or autoimmunity. While several cross-reactive antibodies generated during mammal T. cruzi infection have been described, very few cross-reactive T cells have been identified. We performed adoptive transfer experiments of T cells isolated from chronically infected mice. The results showed the generation of cardiac pathology in the absence of parasites. We also transferred cross-reactive SAPA-specific T cells and observed unspecific alterations in heart repolarization, cardiac inflammatory infiltration, and tissue damage.

Cutting edge: a novel nonoxidative phagosomal mechanism exerted by cathepsin-D controls Listeria monocytogenes intracellular growth.

Deciphering how Listeria monocytogenes exploits the host cell machinery to invade mammalian cells is a key issue in understanding the pathogenesis of this food-borne pathogen, which can cause diseases ranging from gastroenteritis to meningitis and abortion. In this study, we show that the lysosomal aspartyl-protease cathepsin-D (Ctsd) is of considerable importance for nonoxidative listericidal defense mechanisms. We observed enhanced susceptibility to L. monocytogenes infection of fibroblasts and bone-marrow macrophages and increased intraphagosomal viability of bacteria in fibroblasts isolated from Ctsd-deficient mice compared with wild type. These findings are further supported by prolonged survival of L. monocytogenes in Ctsd-deficient mice after infection. Transient transfection of Ctsd in wild-type cells was sufficient to revert these wild-type phagosomes back to microbicidal compartments. Based on infection experiments with mutant bacteria, in vitro degradation, and immunoprecipitation experiments, we suggest that a major target of cathepsin D is the main virulence factor listeriolysin O.