Tatiana Rodrigues de Moura

Cyclic nucleotides cAMP and cGMP are potent suppressors of immune activation, yet how their intracellular levels are regulated within antigen-presenting myeloid cells remains undefined. Here we identify phosphodiesterase 1B (Pde1b) as a lineage-restricted regulator of cyclic nucleotide signaling in conventional type 1 dendritic cells (cDC1) and a subset of macrophages. Using genetic loss-of-function models and Listeria infection, we show that Pde1b is required for immune responses. Pde1b deficiency impairs bacterial clearance and reduces antigen-specific CD8+ and CD4 + T cell expansion, while myeloid transcriptional programs are skewed towards alternative and immunoregulatory states. These defects are largely attributable to DC dysfunction, as adoptive transfer of wild-type DC in Pde1b-deficient recipients partially rescues T cell priming. Macrophages exhibit parallel defects, including reduced frequency and impaired inflammatory and antimicrobial function. Mechanistically, Pde1b loss elevates cAMP and cGMP in cDC1 and macrophages, leading to increased PKA/PKG signaling and CREB-associated transcriptional reprogramming. Pharmacological inhibition of other phosphodiesterase families does not fully recapitulate Pde1b loss. Together, these findings identify Pde1b as a cell-type-specific regulator of cyclic nucleotide signaling essential for immune responses.

Highlights ■ SARS-CoV-2 infection leads to mild-to-moderate disease in children with cystic fibrosis. ■ No worsening of cystic fibrosis was observed months after infection. ABSTRACT Objective: This study aimed to evaluate the clinical manifestations of SARS-CoV-2 in children and adolescents with cystic fibrosis. Methods: This was a case-control analysis of clinical variables and pulmonary function test results in 43 children with cystic fibrosis, 17 (39.5%) of whom tested positive for SARS-CoV-2. Results: The infected children exhibited a higher frequency of

Background: Cutaneous Leishmaniasis (CL) is a neglected tropical disease endemic in Brazil. Morbidity and disabilities caused by CL lesions require an analysis of a Global Burden of Disease (GBD), which would help discern the impact on the Brazilian population. Herein, we assess the burden of CL and its spatial and temporal patterns in Brazil between 2001 and 2021. Methodology/Principal findings: We estimated rates per 100,000 population for years lived with disabilities (YLD), years of life lost prematurely (YLL) and disability-adjusted life years (DALY) for each year of the study, sex assigned at birth, age group, and for each municipality in Brazil. In addition, the relative changes in these metrics over time for each region and sex were determined, as well as temporal trends using segmented joinpoint regression models. Using spatiotemporal analysis tools, we created choropleth maps representing DALY, YLD and YLL for three distinct periods (P1 = 2001 to 2007; P2 = 2008 to 2014; P3 = 2015 to 2021). These maps were constructed to visualize the inferences from Bayesian spatial statistics and Moran’s autocorrelation using the Poisson model. The data were obtained from the DATASUS database. Although the global burden of CL has reduced over two decades, with the continual high impact among adults aged 20 to 39 years. In turn, YLL increased over time in 40-year-old populations, while among the elderly (>60 years old) this rate almost doubled from 2010 to 2021. Regarding the region of residence, we observed an average increase of 28% in YLL in Southeast, South and Central-West. Furthermore, the global burden of CL does not have a random spatial distribution, since there was a high-risk clustering of YLD in the north of the country. Interestingly, the YLL showed a vast geographic expansion through Brazilian territory. Conclusions: This study provides a comprehensive analysis of the burden of CL in Brazil, pointing out areas of highest disease burden, where control and surveillance efforts should be undertaken.

Obesity alters the capacity of effective immune responses in infections. To further address this phenomenon in the context of COVID-19, this study investigated how the immunophenotype of leukocytes was altered in individuals with obesity in severe COVID-19. This cross-sectional study enrolled 27 ICU COVID-19 patients (67% women, 56.33 ± 19.55 years) that were assigned to obese (BMI ≥ 30 kg/m², n = 9) or non-obese (BMI < 30kg/m², n = 18) groups. Monocytes, NK, and both Low-Density (LD) and High-Density (HD) neutrophils were isolated from peripheral blood samples, and surface receptors’ frequency and expression patterns were analyzed by flow cytometry. Clinical status and biochemical data were additionally evaluated. The frequency of monocytes was negatively correlated with BMI, while NK cells and HD neutrophils were positively associated (p < 0.05). Patients with obesity showed a significant reduction of monocytes, and these cells expressed high levels of PD-L1 (p < 0.05). A higher frequency of NK cells and increased expression of TREM-1+ on HD neutrophils were detected in obese patients (p < 0.05). The expression of receptors related to antigen-presentation, phagocytosis, chemotaxis, inflammation and suppression were strongly correlated with clinical markers only in obese patients (p < 0.05). Collectively, these outcomes revealed that obesity differentially affected, and largely depressed, innate immune response in severe COVID-19.

Leprosy reaction (LR) and physical disability (PD) are the most significant clinical complications of leprosy. Herein, we assessed the circulating serum-sTREM-1 and TNF-α levels and their genetic polymorphisms in leprosy. Serum-sTREM-1 and TNF-α levels were measured in leprosy patients (LP) before treatment (n = 51) and from their household contacts (HHCs; n = 25). DNA samples were genotyped using TREM-1 rs2234246 and TNF-α rs1800629-SNP in 210 LPs and 168 endemic controls. The circulating sTREM-1 and TNF-α levels are higher in the multibacillary form. The ROC curve of the serum-sTREM-1 levels was able to differentiate LR from non-LR and PD from non-PD. Similarly, LPs with serum-sTREM-1 levels >210 pg/ml have 3-fold and 6-fold higher chances of presenting with LR and PD, respectively. Genotypes CC+CT of the TREM-1 were associated with leprosy. Taken together, our analyses indicated that sTREM-1 and TNF-α play an important role in the pathogenesis of leprosy and provide promising biomarkers to assist in the diagnosis of leprosy complications.

Exercise is an important tool against the deleterious effects of aging. Among the possibilities of exercise, bodyweight training (BWT) has been highlighted in the last years as a safe option to improve the health of older people. We compared the effects of 24 weeks of BWT and combined training (CT) on low-grade systematic inflammation and functional fitness in postmenopausal women. For this, 40 women were allocated and submitted to CT (n = 20, 64.43 ± 3.13 years, 29.56 ± 4.80 kg/m²) and BWT (n = 20, 65.10 ± 4.86 years, 28.76 ± 4.26 kg/m²). We measured inflammation by the interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) assessments. For functional fitness, we used tests similar to activities of daily living. At the end of the 16 weeks, data from 24 women were analyzed, CT (n = 14) and BT (n = 10). Both groups reduced TNF-α and IL-6 levels, without differences in IL-10. Regarding functional fitness, both groups demonstrated improvements in all tests after 24 weeks, except for rise from prone position and the 400-meter walk test for CT. In summary, CT and BWT are effective in reducing the plasma concentration of pro-inflammatory cytokines and improving functional fitness in postmenopausal women.

Background/Objectives: Obesity is a chronic inflammatory disease that may impair immunity against SARS-Cov-2 in severe disease states. This study investigated whether the innate immune compartment is associated with obesity in severe COVID-19.Methods: This cross-sectional study enrolled twenty-seven ICU COVID-19 patients that were assigned to obese (BMI≥30 kg/m², n=9) and non-obese (BMIResults: The frequency of monocytes was negatively correlated with BMI, while NK and neutrophils were positively associated (p HLA-DR expression on CD14+ monocytes was negatively associated with BMI (p=0.03) and total leukocytes (p=0.005). Patients with obesity also demonstrated a higher frequency of NK cells (p=0.01) and a hyperactivated phenotype (CD16+CD182+TREM-1+) in HD neutrophils (p=0.01). This phenotype was positively correlated with total leukocytes (p=0.01) and negatively correlated with the total numbers of HLA-DR+ monocytes in obese group (p=0.001). An increased expression of CD16 (p=0.01) and TREM-1+ (p=0.005) on mature HD neutrophils was detected in obese patients. In this group, CD16 was negatively correlated with IL-6 levels (p=0.03) and TREM-1+ positively correlated with PD-L1 on neutrophils (p=0.03). Furthermore, sTREM-1 levels correlated with PD-L1 of monocytes and LD neutrophils (p=0.02). Finally, aging may exacerbate cytotoxic and suppressive activity. Conclusion: Our data support that obesity differentially affected innate immune response in severe COVID-19 and highlight immune markers that should be further investigated as predictors for monitoring treatment in severe patients with comorbidities.

Malaria is a major health issue with more than 200 million cases occurring annually. Moreover, in Malaria endemic area are frequently observed Malaria-enteroparasite co-infections associated with the modulation of inflammatory response. In this aspect, biomarkers play an important role in the disease prognosis. This study aimed to evaluate inflammatory mediators in malaria during coinfection with enteroparasites. A subset of serum samples already collected was analyzed and divided into four groups: Malaria (n = 34), Co-infected (n = 116), Enteroparasite (n = 120) and Control (n = 95). The serum levels of sTREM-1 and IL-6 were measured by ELISA. TNF-α, and IL-10 levels were previously carried out by flow cytometry. Higher serum levels of sTREM-1 and IL-6 were showed in malaria patients compared to healthy controls. In co-infected malarial patients sTREM-1 serum levels were similar to control group. Interestingly, co-infected malaria patients showed IL-6 serum levels decreased compared to individuals only infected with P. vivax. However, in Malaria patients and co-infected there was a positive correlation between the IL-6 and IL-10 levels (P < 0.0001). This is the first report of sTREM-1 levels in P. vivax infected. Moreover, the results revealing a divergent effect of co-infection with the increased balance between pro-and anti-inflammatory cytokines and reduced IL-6 levels but increases the anemia occurrence. The results also highlight the potential use of IL-6 as a biomarker for P. vivax and enteroparasites coinfection.

Visceral leishmaniasis (VL) is a systemic chronic and potentially fatal disease for humans. Mechanisms related to the dysregulation of the inflammatory response may be involved in both the pathogenesis and prognosis of VL. Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) is a receptor constitutively expressed on neutrophils and monocyte subsets. The protein serves to regulate and amplify inflammatory responses. This study aimed to evaluate the expression profile of TREM-1 on the surface of neutrophils from patients with VL at varying time points during leishmanicidal treatment. For this purpose, neutrophils were isolated from the peripheral blood of patients with VL at different stages of treatment, which include 0, 7, and 30 days after treatment. Surface TREM-1 expression was assessed by immunophenotyping neutrophil populations. In addition, the association of TREM-1 expression on the surface of neutrophils with clinical and laboratory parameters and serum levels of inflammatory mediators was also evaluated. Results demonstrate a lower surface expression of TREM-1 in VL patients in the absence of treatment. However, increased levels of TREM-1 expression were observed 7 and 30 days after the start of treatment, with levels similar to those of healthy controls. TREM-1 expression was directly correlated with lymphocyte and erythrocyte count and indirectly correlated with spleen and liver size. Furthermore, elevated levels of TREM-1 expression were also correlated with lower serum levels of interleukin (IL)-22. Taken together, these results suggest that infection by Leishmania infantum leads to depressed TREM-1 expression on the neutrophil surface and may contribute to the inflammatory imbalance that characterizes active VL disease.

The Northeast region of Brazil (NRB) includes the states with the highest prevalence of visceral leishmaniasis (VL), as well as those with significant increases in HIV cases. This study aims to analyze the spatiotemporal patterns of VL-HIV coinfection and its association with the social determinants of health (SDH) in the NRB. Time trend analysis and Bayesian spatial statistical inferences, Moran’s autocorrelation, and retrospective space–time scanning were performed. Spatial regression modelling was used to build an explanatory model for the occurrence of VL-HIV coinfection within NRB. A total of 1550 cases of VL-HIV coinfection were confirmed. We observed a higher prevalence among males (1232; 83%), individuals aged from 20 to 59 years (850; 54.8%), non-white skin color (1,422; 91.7%), and with low education (550; 35.48%). NRB showed an increasing and significant trend in the detection rate of coinfection (APC, 5.3; 95% CI, 1.4 to 9.4). The states of Maranhão and Piauí comprised the high-risk cluster. The SDH that most correlated with the occurrence of coinfection were poor housing, low income, and low education. VL-HIV is dispersed in the NRB but chiefly affects states with greater social vulnerability. Taken together, these findings reinforce the necessity to implement surveillance strategies that will contribute to the reduction of cases in these populations.