Mirian Krystel De Siqueira

All Publications

• Adipose-tissue plasticity in health and disease. Cell Sakers, A., De Siqueira, M. K., Seale, P., Villanueva, C. J. 2022; 185 (3): 419-446

  Abstract

  Adipose tissue, colloquially known as "fat," is an extraordinarily flexible and heterogeneous organ. While historically viewed as a passive site for energy storage, we now appreciate that adipose tissue regulates many aspects of whole-body physiology, including food intake, maintenance of energy levels, insulin sensitivity, body temperature, and immune responses. A crucial property of adipose tissue is its high degree of plasticity. Physiologic stimuli induce dramatic alterations in adipose-tissue metabolism, structure, and phenotype to meet the needs of the organism. Limitations to this plasticity cause diminished or aberrant responses to physiologic cues and drive the progression of cardiometabolic disease along with other pathological consequences of obesity.

  View details for DOI 10.1016/j.cell.2021.12.016

  View details for PubMedID 35120662

  View details for PubMedCentralID PMC11152570

• Microbiota configuration determines nutritional immune optimization PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Han, S., Stacy, A., Corral, D., Link, V. M., Siqueira, M., Chi, L., Teijeiro, A., Yong, D. S., Perez-Chaparro, P., Bouladoux, N., Lim, A., Enamorado, M., Belkaid, Y., Collins, N. 2023; 120 (49): e2304905120

  Abstract

  Mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the development and quality of immune responses. However, the factors and mechanisms involved remain to be elucidated. Here, we propose that DR-induced optimization of immunological memory requires a complex cascade of events involving memory T cells, the intestinal microbiota, and myeloid cells. Our findings suggest that DR enhances the ability of memory T cells to recruit and activate myeloid cells in the context of a secondary infection. Concomitantly, DR promotes the expansion of commensal Bifidobacteria within the large intestine, which produce the short-chain fatty acid acetate. Acetate conditioning of the myeloid compartment during DR enhances the capacity of these cells to kill pathogens. Enhanced host protection during DR is compromised when Bifidobacteria expansion is prevented, indicating that microbiota configuration and function play an important role in determining immune responsiveness to this dietary intervention. Altogether, our study supports the idea that DR induces both memory T cells and the gut microbiota to produce distinct factors that converge on myeloid cells to promote optimal pathogen control. These findings suggest that nutritional cues can promote adaptation and co-operation between multiple immune cells and the gut microbiota, which synergize to optimize immunity and protect the collective metaorganism.

  View details for DOI 10.1073/pnas.2304905120

  View details for Web of Science ID 001145424400001

  View details for PubMedID 38011570

  View details for PubMedCentralID PMC10710091

• Infection-elicited microbiota promotes host adaptation to nutrient restriction. Proceedings of the National Academy of Sciences of the United States of America De Siqueira, M. K., Andrade-Oliveira, V., Stacy, A., Pedro Tôrres Guimarães, J., Wesley Alberca-Custodio, R., Castoldi, A., Marques Santos, J., Davoli-Ferreira, M., Menezes-Silva, L., Miguel Turato, W., Han, S. J., Glatman Zaretsky, A., Hand, T. W., Olsen Saraiva Câmara, N., Russo, M., Jancar, S., Morais da Fonseca, D., Belkaid, Y. 2023; 120 (4): e2214484120

  Abstract

  The microbiota performs multiple functions vital to host fitness, including defense against pathogens and adaptation to dietary changes. Yet, how environmental challenges shape microbiota resilience to nutrient fluctuation remains largely unexplored. Here, we show that transient gut infection can optimize host metabolism toward the usage of carbohydrates. Following acute infection and clearance of the pathogen, mice gained more weight as a result of white adipose tissue expansion. Concomitantly, previously infected mice exhibited enhanced carbohydrate (glucose) disposal and insulin sensitivity. This metabolic remodeling depended on alterations to the gut microbiota, with infection-elicited Betaproteobacteria being sufficient to enhance host carbohydrate metabolism. Further, infection-induced metabolic alteration protected mice against stunting in the context of limited nutrient availability. Together, these results propose that alterations to the microbiota imposed by acute infection may enhance host fitness and survival in the face of nutrient restriction, a phenomenon that may be adaptive in settings where both infection burden and food precarity are prevalent.

  View details for DOI 10.1073/pnas.2214484120

  View details for PubMedID 36652484

  View details for PubMedCentralID PMC9942920

• When fat talks, the gut listens: IRONing out metabolism. Cell metabolism De Siqueira, M. K., Villanueva, C. J. 2021; 33 (8): 1505-1506

  Abstract

  In a new study, Zhang et al. (2021) show that reducing iron levels in adipose tissue improves metabolic function. This occurs through an interorgan communication system where signals from the adipocyte reduce intestinal lipid absorption.

  View details for DOI 10.1016/j.cmet.2021.07.012

  View details for PubMedID 34348093

• Allergen-Specific Immunotherapy With Liposome Containing CpG-ODN in Murine Model of Asthma Relies on MyD88 Signaling in Dendritic Cells. Frontiers in immunology Alberca-Custodio, R. W., Faustino, L. D., Gomes, E., Nunes, F. P., de Siqueira, M. K., Labrada, A., Almeida, R. R., Câmara, N. O., da Fonseca, D. M., Russo, M. 2020; 11: 692

  Abstract

  Changing the immune responses to allergens is the cornerstone of allergen immunotherapy. Allergen-specific immunotherapy that consists of repeated administration of increasing doses of allergen extract is potentially curative. The major inconveniences of allergen-specific immunotherapy include failure to modify immune responses, long-term treatment leading to non-compliance and the potential for developing life-threating anaphylaxis. Here we investigated the effect of a novel liposomal formulation carrying low dose of allergen combined with CpG-ODN, a synthetic TLR9 agonist, on established allergic lung inflammation. We found that challenge with allergen (OVA) encapsulated in cationic liposome induced significantly less severe cutaneous anaphylactic reaction. Notably, short-term treatment (three doses) with a liposomal formulation containing co-encapsulated allergen plus CpG-ODN, but not allergen or CpG-ODN alone, reversed an established allergic lung inflammation and provided long-term protection. This liposomal formulation was also effective against allergens derived from Blomia tropicalis mite extract. The attenuation of allergic inflammation was not associated with increased numbers of Foxp3-positive or IL-10-producing regulatory T cells or with increased levels of IFN-gamma in the lungs. Instead, the anti-allergic effect of the liposomal formulation was dependent of the innate immune signal transduction generated in CD11c-positive putative dendritic cells expressing MyD88 molecule. Therefore, we highlight the pivotal role of dendritic cells in mediating the attenuation of established allergic lung inflammation following immunotherapy with a liposomal formulation containing allergen plus CpG-ODN.

  View details for DOI 10.3389/fimmu.2020.00692

  View details for PubMedID 32391011

  View details for PubMedCentralID PMC7191058

• A new Aura virus isolate in Brazil shows segment duplication in the variable region of the nsP3 gene. Parasites & vectors Mosimann, A. L., de Siqueira, M. K., Ceole, L. F., Nunes Duarte Dos Santos, C. 2018; 11 (1): 321

  Abstract

  A new isolate of Aura virus serendipitously discovered as a cell culture contaminant is reported in this manuscript. Aura virus belongs to the family Togaviridae and is classified in the genus Alphavirus. There are only two reports of Aura virus isolation from mosquitoes in the scientific literature, and the existence of a vertebrate host is still unknown. The discovery of this new isolate was based on transmission electron microscopy and nucleic acid amplification through a non-specific RT-PCR amplification protocol followed by sequencing.Genetic analysis has shown that the new virus shares a high degree of identity with the previously described isolate (GenBank: AF126284.1). A major difference was observed in the nsP3 gene in which a 234-nucleotide duplication has been identified. Furthermore, a pronounced difference was observed in cell cultures compared to the data available for the previously described isolate. Cell permissiveness and phenotypic characteristics in C6/36, Vero and BHK-21 cells were found to differ from previous reports. This may be due to the genetic differences that have been observed.The genetic and biological characteristics of the new Aura virus isolate are suggestive of viral adaptation to the cell substrate. The development of a cDNA clone will lend a perspective and better understanding of these results as well as open avenues for its use as a biotechnological tool, as seen for other alphaviruses.

  View details for DOI 10.1186/s13071-018-2907-4

  View details for PubMedID 29843810

  View details for PubMedCentralID PMC5975265