Salmonella and Caspase-1: A complex Interplay of Detection and Evasion

Salmonellae are intracellular pathogens that replicate within epithelial cells and macrophages, and are a significant public health threat in both developed and developing countries. The innate immune system detects microbes through pattern recognition receptors, which are compartmentalized on the subcellular level to detect either extracellular (e.g., TLRs) or cytosolic (e.g., NLRs) perturbations. Salmonella infection is detected by the NLRC4 and NLRP3 inflammasomes, which activate Caspase-1, resulting in reduced bacterial burdens during infection. NLRC4 responds to the SPI1 type III secretion system via detection of inadvertently translocated flagellin and rod protein. The signals for NLRP3 detection during Salmonella infection remain undefined. Salmonella have evolved evasion strategies to attenuate Caspase-1 responses. We review recent findings describing the interplay between detection and evasion of S. typhimurium infection by the inflammasome. We discuss how the interplay between detection and evasion affects Caspase-1 effector functions mediated by IL-1β secretion, IL-18 secretion, and pyroptosis

Salmonella and Caspase-1: A complex Interplay of Detection and Evasion

Salmonellae are intracellular pathogens that replicate within epithelial cells and macrophages, and are a significant public health threat in both developed and developing countries. The innate immune system detects microbes through pattern recognition receptors, which are compartmentalized on the subcellular level to detect either extracellular (e.g., TLRs) or cytosolic (e.g., NLRs) perturbations. Salmonella infection is detected by the NLRC4 and NLRP3 inflammasomes, which activate Caspase-1, resulting in reduced bacterial burdens during infection. NLRC4 responds to the SPI1 type III secretion system via detection of inadvertently translocated flagellin and rod protein. The signals for NLRP3 detection during Salmonella infection remain undefined. Salmonella have evolved evasion strategies to attenuate Caspase-1 responses. We review recent findings describing the interplay between detection and evasion of S. typhimurium infection by the inflammasome. We discuss how the interplay between detection and evasion affects Caspase-1 effector functions mediated by IL-1β secretion, IL-18 secretion, and pyroptosis

Caspase-1-induced pyroptotic cell death

Programmed cell death is a necessary part of development and tissue homeostasis enabling the removal of unwanted cells. In the setting of infectious disease, cells that have been commandeered by microbial pathogens become detrimental to the host. When macrophages and dendritic cells are compromised in this way, they can be lysed by pyroptosis, a cell death mechanism that is distinct from apoptosis and oncosis/necrosis. Pyroptosis is triggered by Caspase-1 after its activation by various inflammasomes and results in lysis of the affected cell. Both pyroptosis and apoptosis are programmed cell death mechanisms but are dependent on different caspases, unlike oncosis. Similar to oncosis and unlike apoptosis, pyroptosis results in cellular lysis and release of the cytosolic contents to the extracellular space. This event is predicted to be inherently inflammatory and coincides with interleukin-1β (IL-1β) and IL-18 secretion. We discuss the role of distinct inflammasomes, including NLRC4, NLRP3, and AIM2, as well as the role of the ASC focus in Caspase-1 signaling. We further review the importance of pyroptosis in vivo as a potent mechanism to clear intracellular pathogens

Differences in the Prevalence of Non-Communicable Disease between Slum Dwellers and the General Population in a Large Urban Area in Brazil.

Residents of urban slums are at greater risk for disease than their non-slum dwelling urban counterparts. We sought to contrast the prevalences of selected non-communicable diseases (NCDs) between Brazilian adults living in a slum and the general population of the same city, by comparing the age and sex-standardized prevalences of selected NCDs from a 2010 survey in Pau da Lima, Salvador Brazil, with a 2010 national population-based telephone survey. NCD prevalences in both populations were similar for hypertension (23.6% (95% CI 20.9⁻26.4) and 22.9% (21.2⁻24.6), respectively) and for dyslipidemia (22.7% (19.8⁻25.5) and 21.5% (19.7⁻23.4)). Slum residents had higher prevalences of diabetes mellitus (10.1% (7.9⁻12.3)) and of overweight/obesity (46.5% (43.1⁻49.9)), compared to 5.2% (4.2⁻6.1) and 40.6% (38.5⁻42.8) of the general population in Salvador. Fourteen percent (14.5% (12.1⁻17.0)) of slum residents smoked cigarettes compared to 8.3% (7.1⁻9.5) of the general population in Salvador. The national telephone survey underestimated the prevalence of diabetes mellitus, overweight/obesity, and smoking in the slum population, likely in part due to differential sampling inside and outside of slums. Further research and targeted policies are needed to mitigate these inequalities, which could have significant economic and social impacts on slum residents and their communities

Clinical and epidemiological characteristics associated with unfavorable tuberculosis treatment outcomes in TB-HIV co-infected patients in Brazil : a hierarchical polytomous analysis

Background: TB patients co-infected with HIV have worse treatment outcomes than non-coinfected patients. How clinical characteristics of TB and socioeconomic characteristics influence these outcomes is poorly understood. Here, we use polytomous regression analysis to identify clinical and epidemiological characteristics associated with unfavorable treatment outcomes among TB-HIV co-infected patients in Brazil. Methods: TB-HIV cases reported in the Brazilian information system (SINAN) between January 1, 2001 and December 31, 2011 were identified and categorized by TB treatment outcome (cure, default, death, and development of MDR TB). We modeled treatment outcome as a function of clinical characteristics of TB and patient socioeconomic characteristics by polytomous regression analysis. For each treatment outcome, we used cure as the reference outcome. Results: between 2001 and 2011, 990,017 cases of TB were reported in SINAN, of which 93,147 (9.4%) were HIV co-infected. Patients aged 15–19 (OR = 2.86; 95% CI: 2.09–3.91) and 20–39 years old (OR = 2.30; 95% CI: 1.81–2.92) were more likely to default on TB treatment than those aged 0–14 years old. In contrast, patients aged ≥60 years were more likely to die from TB (OR = 2.22; 95% CI: 1.43–3.44) or other causes (OR = 2.86; 95% CI: 2.14–3.83). Black patients were more likely to default on TB treatment (OR = 1.33; 95% CI: 1.22–1.44) and die from TB (OR = 1.50; 95% CI: 1.29–1.74). Finally, alcoholism was associated with all unfavorable outcomes: default (OR = 1.94; 95% CI: 1.73–2.17), death due to TB (OR = 1.46; 95% CI: 1.25–1.71), death due to other causes (OR = 1.38; 95% CI: 1.21–1.57) and MDR-TB (OR = 2.29; 95% CI: 1.46–3.58). Conclusions: socio-economic vulnerability has a significant effect on treatment outcomes among TB-HIV co-infected patients in Brazil. Enhancing social support, incorporation of alcohol abuse screening and counseling into current TB surveillance programs and targeting interventions to specific age groups are interventions that could improve treatment outcomes

Prevalencia de infección latente de la tuberculosis y factores de riesgo entre profesionales de salud en la atención primaria en Brasil

Os profissionais de saúde apresentam risco aumentado de infecção latente da tuberculose (ILTB) em função da exposição ocupacional ao Mycobacterium tuberculosis. O estudo teve como objetivo estimar a prevalência da ILTB e fatores de risco entre profissionais de saúde na atenção primária em cinco cidades brasileiras. Realizamos um estudo transversal entre 2011 e 2013 entre profissionais de saúde na atenção primária, usando um questionário estruturado, e avaliamos a ILTB com o teste Quantiferon-TB Gold In-Tube. A magnitude das associações foi avaliada com o uso de modelos de regressão logística hierárquica. Entre 708 profissionais de saúde, a prevalência de ILTB era 27% (n = 196; IC95%: 24%-31%). Os seguintes fatores mostraram associação positiva com ILTB entre profissionais de saúde na atenção primária: idade > 50 anos (OR = 2,94; IC95%: 1,44-5,99), ausência de cicatriz de BCG (OR = 2,10; IC95%: 1,28-3,43), ex-tabagista (OR = 1,80; IC95%: 1,04-3,11), profissão enfermeiro (OR = 2,97; IC95%: 1,13-7,83), profissão técnico de enfermagem (OR = 3,10; IC95%: 1,26-7,60), profissão agente comunitário de saúde (OR = 2,60; IC95%: 1,06-6,40) e uso irregular de máscaras N95 (OR = 2,51; IC95%: 1,11-5,98). Enquanto isso, os profissionais de saúde que não trabalham em serviços de saúde que dispõem de programa de controle da TB tem menor probabilidade de apresentar ILTB (OR = 0,66; IC95%: 0,45-0,97). O estudo demonstrou risco ocupacional substancial de ILTB entre profissionais de saúde na atenção primária no Brasil. O programa brasileiro de controle da tuberculose, assim como os programas locais, devem focar esses profissionais de saúde, de risco elevado, através de atividades educativas, assim como, equipamento de proteção individual melhor para prevenir a aquisição de novos casos de infecção pela tuberculose.Health care workers (HCW) are at increased risk of latent tuberculosis infection (LTBI) from occupational exposure to Mycobacterium tuberculosis. The objective was to determine the prevalence of and risk factors for LTBI among primary HCW in five Brazilian cities. We conducted a cross-sectional study, from 2011 to 2013, among primary HCW, using a structured questionnaire and an evaluated for LTBI using the Quantiferon-TB Gold in-tube test. The magnitude of the associations was assessed using hierarchical logistic regression models. Among 708 HCW, the LTBI prevalence was 27% (n = 196; 95%CI: 24%-31%). We found that the following factors were positively associated with LTBI in primary HCW: age > 50 years (OR = 2.94; 95%CI: 1.44-5.99), absence of a BCG scar (OR = 2.10; 95%CI: 1.28-3.43), self-reported ex-smoker status (OR = 1.80; 95%CI: 1.04-3.11), being a nurse (OR = 2.97; 95%CI: 1.13-7.83), being a nurse technician (OR = 3.10; 95%CI: 1.26-7.60), being a community health agent (OR = 2.60; 95%CI: 1.06-6.40), and irregular use of N95 masks (OR = 2.51; 95%CI: 1.11-5.98). In contrast, HCWs who do not work in health care facilities with a TB control program were less likely to have LTBI (OR = 0.66; 95%CI: 0.45-0.97). This study demonstrated a substantial occupational risk of LTBI among primary HCW in Brazil. The Brazilian TB control program, as well as local programs, need to target these high-risk HCW with education, as well as with better personal protective equipment to prevent acquisition of new TB infection.Los profesionales de salud presentan un riesgo aumentado de infección latente de la tuberculosis (ILTB), en función de la exposición ocupacional al Mycobacterium tuberculosis. El objetivo del estudio fue estimar la prevalencia de la ILTB y sus factores de riesgo entre profesionales de salud en la atención primaria en cinco ciudades brasileñas. Realizamos un estudio transversal entre 2011 y 2013 entre profesionales de salud en la atención primaria, usando un cuestionario estructurado, y evaluamos la ILTB con el test Quantiferon-TB Gold In-Tube. La magnitud de las asociaciones fue evaluada con el uso de modelos de regresión logística jerárquica. Entre 708 profesionales de salud, la prevalencia de ILTB era 27% (n = 196; IC95%: 24%-31%). Los siguientes factores mostraron una asociación positiva con ILTB entre profesionales de salud en la atención primaria: edad > 50 años (OR = 2,94; IC95%: 1,44-5,99), ausencia de cicatriz de BCG (OR = 2,10; IC95%: 1,28-3,43), ex-fumador (OR = 1,80; IC95%: 1,04-3,11), profesión enfermero (OR = 2,97; IC95%: 1,13-7,83), profesión técnico de enfermería (OR = 3,10; IC95%: 1,26-7,60), profesión agente comunitario de salud (OR = 2,60; IC95%: 1,06-6,40) y uso irregular de máscaras N95 (OR = 2,51; IC95%: 1,11-5,98). Por otra parte, los profesionales de salud que no trabajan en servicios de salud que disponen de programa de control de la TB tienen una menor probabilidad de presentar ILTB (OR = 0,66; IC95%: 0,45-0,97). El estudio demostró riesgo ocupacional substancial de ILTB entre profesionales de salud en la atención primaria en Brasil. El programa brasileño de control de la tuberculosis, así como los programas locales, deben centrarse en esos profesionales de salud, de riesgo elevado, a través de actividades educativas, así como un mejor equipamiento de protección individual para prevenir el surgimiento de nuevos casos de infección por tuberculosis

Understanding the barriers to successful adoption and use of a mobile health information system in a community health center in São Paulo, Brazil: a cohort study

BACKGROUND: Mobile technology to support community health has surged in popularity, yet few studies have systematically examined usability of mobile platforms for this setting. METHODS: We conducted a mixed-methods study of 14 community healthcare workers at a public healthcare clinic in São Paulo, Brazil. We held focus groups with community healthcare workers to elicit their ideas about a mobile health application and used this input to build a prototype app. A pre-use test survey was administered to all participants, who subsequently use-tested the app on three different devices (iPhone, iPad mini, iPad Air). Usability was assessed by objectively scored data entry errors and through a post-use focus group held to gather open-ended feedback on end-user satisfaction. RESULTS: All of the participants were women, ranging from 18–64 years old. A large percentage (85.7%) of participants had at least a high school education. Internet (92.8%), computer (85.7%) and cell phone (71.4%) use rates were high. Data entry error rates were also high, particularly in free text fields, ranging from 92.3 to 100%. Error rates were comparable across device type. In a post-use focus group, participants reported that they found the app easy to use and felt that its design was consistent with their vision. The participants raised several concerns, including that they did not find filling out the forms in the app to be a useful task. They also were concerned about an app potentially creating more work for them and personal security issues related to carrying a mobile device in low-income areas. CONCLUSION: In a cohort of formally educated community healthcare workers with high levels of personal computer and cell phone use, we identified no technological barriers to adapting their existing work to a mobile device based system. Transferring current data entry work into a mobile platform, however, uncovered underlying dissatisfaction with some data entry tasks. This dissatisfaction may be a more significant barrier than the data entry errors our testing revealed. Our results highlight the fact that without a deep understanding of local process to optimize usability, technology-based solutions in health may fail. Developing such an understanding must be a central component in the design of any mHealth solution in global health