Biology subjects

Andrade, B. B.

Publications and source records attributed to Andrade, B. B..

8 recordsLinked to original sources

bioRxiv2026

Early tuberculosis treatment remodels blood mRNA and small RNA, and a baseline host signature is associated with early culture conversion

Tuberculosis (TB) treatment monitoring relies on sputum-based microbiological assays, which are slow and provide limited insight into the host response. Blood-based biomarkers could offer rapid and minimally invasive treatment monitoring. We performed an integrative multi-omics analysis of paired whole-blood samples collected at baseline and four weeks after treatment initiation across three South African cohorts. A meta-analysis combined RNA sequencing data from GSE89403 (86 pairs) and a prospective cohort (11 pairs), with directional concordance assessed in an independent microarray cohort, GSE31348 (27 pairs). In the prospective cohort, small RNA sequencing profiled microRNAs (miRNAs) and tRNA-derived fragments (tRFs). In GSE89403 (n = 76), a k-top scoring pairs signature (EARLY5) was developed using leave-one-out cross-validation to predict week-4 sputum culture conversion from baseline samples. The meta-analysis identified 63 concordantly regulated genes. These changes reflected attenuation of neutrophil, inflammatory and complement programs, and deconvolution showed decreased neutrophils with increased T-cell and NK-cell populations. Seven miRNAs and eight nuclear-encoded tRFs changed during treatment, including erythroid-associated miR-144, with computationally identified candidate interactions involving complement genes. EARLY5 identified participants who converted by week 4 with a cross-validated AUC of 0.76 and remained associated with conversion after adjustment for baseline bacterial burden in logistic regression and performed comparably to existing TB signatures. Early TB treatment induces coordinated remodeling of blood mRNA and small RNA profiles. Baseline host transcriptional profiles were associated with early culture conversion after accounting for bacterial burden, supporting further evaluation in independent cohorts.

immunology↗

bioRxiv2024

The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication

SARS-CoV-2 infection leads to vastly divergent clinical outcomes ranging from asymptomatic infection to fatal disease. Co-morbidities, sex, age, host genetics and vaccine status are known to affect disease severity. Yet, how the inflammatory milieu of the lung at the time of SARS-CoV-2 exposure impacts the control of viral replication remains poorly understood. We demonstrate here that immune events in the mouse lung closely preceding SARS-CoV-2 infection significantly impact viral control and we identify key innate immune pathways required to limit viral replication. A diverse set of pulmonary inflammatory stimuli, including resolved antecedent respiratory infections with S. aureus or influenza, ongoing pulmonary M. tuberculosis infection, ovalbumin/alum-induced asthma or airway administration of defined TLR ligands and recombinant cytokines, all establish an antiviral state in the lung that restricts SARS-CoV-2 replication upon infection. In addition to antiviral type I interferons, the broadly inducible inflammatory cytokines TNF and IL-1 precondition the lung for enhanced viral control. Collectively, our work shows that SARS-CoV-2 may benefit from an immunologically quiescent lung microenvironment and suggests that heterogeneity in pulmonary inflammation that precedes or accompanies SARS-CoV-2 exposure may be a significant factor contributing to the population-wide variability in COVID-19 disease outcomes.

immunology↗

bioRxiv2021

CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection

The HIV-mediated decline in circulating CD4 T cells correlates with increased the risk of active tuberculosis (TB)1-4. However, HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals also have an increased incidence of TB prior to loss of CD4 T cells in blood3,5, raising the possibility that HIV co-infection leads to disruption of CD4 T cell responses at the site of lung infection before they are observed systemically. Here we used a rhesus macaque model of SIV/Mtb co-infection to study the early effects of acute SIV infection on CD4 T cells in pulmonary Mtb granulomas. Two weeks after SIV co-infection CD4 T cells were dramatically depleted from granulomas, before significant bacterial outgrowth, disease reactivation as measured by PET-CT imaging, or CD4 T cell loss in blood, airways, and lymph nodes. Mtb-specific CD4 T cells, CCR5-expressing, in granulomas were preferentially depleted by SIV infection. Moreover, CD4 T cells were preferentially depleted from the granuloma core and lymphocyte cuff relative to B cell-rich regions, and live imaging of granuloma explants showed that SIV co-infection reduced T cell motility. Thus, Mtb-specific CD4 T cells in pulmonary granulomas may be decimated before many patients even experience the first symptoms of acute HIV infection.

immunology↗

bioRxiv2021

Eosinophils are an integral component of the pulmonary granulocyte response in Tuberculosis and promote host resistance in mice

Host resistance to Mycobacterium tuberculosis infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis are incompletely understood. Here we uncover an unexpected association between eosinophils and Mtb infection. In humans, eosinophils are decreased in the blood but enriched in resected human tuberculosis lung lesions and autopsy granulomas. Influx of eosinophils is also evident in infected zebrafish, mice, and nonhuman primate granulomas, where they are functionally activated and degranulate. Importantly, employing complementary genetic models of eosinophil deficiency, we demonstrate that, in mice, eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings uncover an unexpected recruitment of eosinophils to the infected lung tissue and a protective role for these cells in the control of Mtb infection in mice.

immunology↗

bioRxiv2020

Association between neurofibromatosis type 1 and cerebrovascular diseases in children: a systematic review

BackgroundNeurofibromatosis type 1 (NF-1) is an autosomal dominant disease that affects one in every 3000 individuals. This disease can present a wide range of clinical manifestations, ranging from skin abnormalities to severe vascular changes. Although little recognized, cerebrovascular diseases (CVD), often present since childhood and diagnosed late, may have clinical manifestations ranging from headache and cognitive deficits to aneurysm rupture causing death. Thus, the CVD play an important role in the clinical manifestations, the severity of the condition and the prognosis of patients with NF-1. This systematic review aims to summarize the body of evidence linking NF-1 and CVD the in children. MethodsTwo independent reviewers performed a systematic review on the PubMed and EMBASE search platforms, using the following key terms: "neurofibromatosis type 1", "recklinghausen disease", "children", "adolescents", "stroke", "moyamoya disease", "vascular diseases", "cerebrovascular disorders", "aneurysm" and "congenital abnormalities". Studies focused on assessing the development of CVD in children with NF-1 were included. ResultsSeven studies met the inclusion criteria. Twelve different clinical manifestations have been associated with cerebrovascular changes in children with NF-1; 44,5% of diagnosed patients were asymptomatic. ConclusionThe available evidence suggests that cerebrovascular diseases are related with the progression of NF-1, even in the absence of a clear clinical manifestation. In addition, better prognosis was observed when imaging tests were performed to screen for cerebrovascular changes. This generated early interventions and consequently more favorable outcomes.

neuroscience↗

bioRxiv2020

PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques

Boosting immune cell function by targeting the co-inhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with PD-1 mAb developed worse disease and higher granuloma bacterial loads compared to isotype control treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in PD-1 treated macaques were not increased in number or function in granulomas, upregulated high levels of CTLA-4 and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of PD-1 treated animals, multiple pro-inflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Lastly, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota prior to infection in individual macaques. Therefore, PD-1-mediated co-inhibition is required for control of Mtb infection in macaques, perhaps due to its role in dampening detrimental inflammation as well as allowing for normal CD4 T cell responses.

immunology↗

bioRxiv2020

Aging increases the systemic molecular degree of inflammatory perturbation in patients with tuberculosis

Tuberculosis (TB) in a chronic infection that can affect individuals of all ages. The description of determinants of immunopathogenesis in TB is a field of tremendous interest due to the perspective of finding a reliable host-directed therapy to reduce disease burden. The association between specific biomarker profiles related to inflammation and the diverse clinical disease presentations in TB has been extensively studied in adults. However, relatively scarce data on profiling the inflammatory responses in pediatric TB are available. Here, we employed the molecular degree of perturbation (MDP) score adapted to plasma biomarkers in two distinct databanks from studies that examined either adults or children presenting with pulmonary or extrapulmonary disease. We used multidimensional statistical analyses to characterize the impact of age on the overall changes in the systemic inflammation profiles in subpopulation of TB patients. Our findings indicated that TB results in significant increases in MDP values, with the highest values being detected in adult patients. Furthermore, there were unique differences in the biomarker perturbation patterns and the overall degree of inflammation according to disease site and age. Importantly, the molecular degree of perturbation was not influenced by sex. Our results revealed that aging is an important determinant of the differences in quality and magnitude of systemic inflammatory perturbation in distinct clinical forms of TB.

immunology↗

bioRxiv2019

Systems biology analysis of publicly available transcriptomic data reveals a critical link between AKR1B10 gene expression, smoking and occurrence of lung cancer

BackgroundCigarette smoking is associated with increased risk of developing respiratory diseases and various types of cancer. Early identification of such unfavorable outcomes in patients who smoke is critical for optimizing personalized medical care.\n\nMethodsHere, we perform a comprehensive analysis using Systems Biology tools of publicly available data from a total of six transcriptomic studies, which examined different specimens of lung tissue and/or cells of smokers and nonsmokers to identify potential markers associated with lung cancer.\n\nResultsExpression level of twenty-two genes was capable of classifying smokers from non-smokers. A machine learning algorithm revealed that AKR1B10 was the most informative gene among the 22 DEGs accounting for the classification of the clinical groups. AKR1B10 expression was higher in smokers compared to non-smokers in datasets examining small and large airway epithelia, but not in the data from a study of sorted alveolar macrophages. We next tested whether AKR1B10 expression could be useful in identification of cancer tissue in patients who were not exposed to smoking. AKR1B10 expression was substantially higher in lung cancer specimens compared to matched healthy tissue obtained from nonsmoking individuals (accuracy: 80%, p<0.0001). Finally, we searched the expression of 11 single nucleotide polymorphisms (SNPs) of AKR1B10 worldwide. We found that the SNP rs782881 was the most frequent mutant allele in the majority of continents. Africa was the continent which exhibited higher frequency of SNPs associated with lower AKR1B10 expression and displayed lower lung cancer incidence and deaths attributable to tobacco.\n\nConclusionThe systematic analysis of transcriptomic studies performed here revealed a potential critical link between AKR1B10 expression, smoking and occurrence of lung cancer.

genomics↗