Biology subjects

Oliveira-Brito, P. K. M.

Publications and source records attributed to Oliveira-Brito, P. K. M..

3 recordsLinked to original sources

bioRxiv2024

A novel Mannan-specific chimeric antigen receptor M-CAR redirects T cells to interact with Candida spp. hyphae and Rhizopus oryzae spores

Invasive fungal infections (IFIs) are responsible for elevated rates of morbidity and mortality, causing around of 1.5 million deaths annually worldwide. One of the main causative agents of IFIs is Candida albicans, and non-albicans Candida species have emerged as a spreading global public health concernment. Furthermore, COVID-19 has contributed to a boost in the incidence of IFIs, such as mucormycosis, in which Rhizopus oryzae is the most prevalent causative agent. The effector host immune response against IFIs depends on the activity of T cells, which are susceptible to the regulatory effects triggered by fungal virulence factors. The fungal cell wall plays a crucial role as a virulence factor, and its remodeling compromises the development of a specific T-cell response. The redirection of Jurkat T cells to target Candida spp. by recognizing targets expressed on the fungal cell wall can be facilitated using chimeric antigen receptor (CAR) technology. This study generated an M-CAR that contains an scFv with specificity to -1,6 mannose backbone of fungal mannan, and the expression of M-CAR on the surface of modified Jurkat cells triggered a strong activation against Candida albicans (hyphae form), Candida tropicalis (hyphae form), Candida parapsilosis (pseudohyphal form), and Candida glabrata (yeast form). Moreover, M-CAR Jurkat cells recognized Rhizopus oryzae spores, which induced high expression of cell activation markers. Thus, a novel Mannan-specific CAR enabled strong signal transduction in modified Jurkat cells in the presence of Candida spp. or R. oryzae.

bioengineering↗

bioRxiv2024

Enhanced antifungal activity of NK-92 cells against Candida albicans mediated by a mannan-specific chimeric antigen receptor

Chimeric antigen receptors (CARs) offer promising prospects for innovative cell-based therapies against invasive fungal infections such as invasive candidiasis. Here, we have developed four CARs targeting Candida albicans with distinct single-chain variable fragments (scFvs): scFv3-CAR, scFv5-CAR, scFv12-CAR, and scFv{kappa}3-1-CAR. In T cells, scFv5-CAR induced IL-2 expression in response to C. albicans hyphae, while scFv3-CAR and scFv12-CAR did not mediate cell activation against C. albicans. Notably, scFv{kappa}3-1-CAR mediated the strongest cell activation against C. albicans yeast, hyphae, and other clinically relevant Candida species. scFv{kappa}3-1-CAR-NK-92 cells exhibited elevated IFN-{gamma} and CD107a expression, reducing C. albicans viability. NOD scid gamma (NSG) mice treated with scFv{kappa}3-1-CAR-NK-92 cells had reduced C. albicans burden in the kidney 24 hours postinfection. We showed that scFv{kappa}3-1-CAR targets C. albicans mannan but no other glycans in glycan microarray screening analyses. These findings reveal the scFv{kappa}3-1-CAR potential as a therapeutic strategy for treating Candida spp. by modifying peripheral blood mononuclear cells. ImportanceRecent studies on novel immunotherapies, including chimeric antigen receptor (CAR)-T cells, have shown promising results in preclinical models against invasive fungal infections (IFIs). However, the application of CAR technology in natural killer (NK) cells for treating IFIs remains unexplored. NK cells play a key role in early fungal clearance due to their antifungal activity mediated by granzymes, perforins, and the secretion of proinflammatory cytokines. This study is the first to demonstrate the feasibility and efficacy of CAR-modified NK cells targeting Candida spp. We provided proof-of-concept data showing that CAR-expressing NK cells exhibit enhanced activation and antifungal effects against clinically relevant Candida species by targeting mannan in the fungal cell wall. These findings are significant as they open new avenues for developing CAR-NK-based therapies to treat invasive candidiasis - a severe infection with limited treatment options and high mortality rates, particularly in immunocompromised patients.

bioengineering↗

bioRxiv2019

Galectin-3 inhibits Paracoccidioides brasiliensis growth and impacts paracoccidioidomycosis through multiple mechanisms

The thermodimorphic pathogenic fungi Paracoccidioides brasiliensis and Paracoccioidioides lutzii are the etiologic causes of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America. Galectin-3 (Gal-3), an animal {beta}-galactoside-binding protein, modulates important roles during microbial infections, such as triggering a Th2-polarized immune response in PCM. Herein, we demonstrate that Gal-3 also plays other important roles in P. brasiliensis infection. We verified Gal-3 levels are upregulated in human and mice infections and establish that Gal-3 inhibits P. brasiliensis growth by inhibiting budding. Furthermore, Gal-3 affects disruption and internalization of extracellular vesicles (EV) from P. brasiliensis by macrophages. Our results suggest important roles for Gal-3 in P. brasiliensis infection, indicating that increased Gal-3 production during P. brasiliensis infection may account for affecting the fungal growth and EV stability, promoting a benefic course of experimental PCM. IMPORTANCEParacoccidiodomycosis (PCM) is the most prevalent systemic mycosis in Latin America. Although the immune mechanisms to control PCM are still not fully understood, several events of the host innate and adaptive immunity are crucial to determine the progress of the infection. Mammalian {beta}-galactoside-binding protein Galectin-3 (Gal-3) plays significant roles during microbial infections, and has been studied for its immunomodulatory roles but it can also have direct antimicrobial effects. We asked whether this protein plays a role in P. brasiliensis. We report herein that Gal-3 indeed has direct effects on fungal pathogen, inhibiting fungal growth and reducing extracellular vesicles stability. Our results suggest a direct role for Gal-3 in P. brasiliensis infection, with beneficial effects for the mammalian host.

microbiology↗