Biology subjects

Muro, A.

Publications and source records attributed to Muro, A..

3 recordsLinked to original sources

bioRxiv2024

Angiotensin Converting Enzyme (ACE) expression in microglia reduces amyloid β deposition and neurodegeneration by increasing SYK signaling and endolysosomal trafficking.

Genome-wide association studies (GWAS) have identified many gene polymorphisms associated with an increased risk of developing Late Onset Alzheimers Disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing microglia innate immune responses and lipid metabolism. Angiotensin Converting Enzyme (ACE), a GWAS LOAD risk-associated gene best known for its role in regulating systemic blood pressure, also enhances innate immunity and lipid processing in peripheral myeloid cells, but a role for ACE in modulating the function of myeloid-derived microglia remains unexplored. Using novel mice engineered to express ACE in microglia and CNS associated macrophages (CAMs), we find that ACE expression in microglia reduces A{beta} plaque load, preserves vulnerable neurons and excitatory synapses, and greatly reduces learning and memory abnormalities in the 5xFAD amyloid mouse model of Alzheimers Disease (AD). ACE-expressing microglia show enhanced A{beta} phagocytosis and endolysosomal trafficking, increased clustering around amyloid plaques, and increased SYK tyrosine kinase activation downstream of the major A{beta} receptors, TREM2 and CLEC7A. Single microglia sequencing and digital spatial profiling identifies downstream SYK signaling modules that are expressed by ACE expression in microglia that mediate endolysosomal biogenesis and trafficking, mTOR and PI3K/AKT signaling, and increased oxidative phosphorylation, while gene silencing or pharmacologic inhibition of SYK activity in ACE-expressing microglia abrogates the potentiated A{beta} engulfment and endolysosomal trafficking. These findings establish a role for ACE in enhancing microglial immune function and they identify a potential use for ACE-expressing microglia as a cell-based therapy to augment endogenous microglial responses to A{beta} in AD.

neuroscience↗

bioRxiv2022

Identification of genomic regions implicated in susceptibility to Schistosoma mansoni infection in a murine genetic model (backcross)

High levels of infection and severe liver fibrosis in schistosomiasis appear only in a few cases of infected people with high susceptibility. Tissue damage is caused by the inflammatory response to eggs trapped in the liver. The genetic background influences susceptibility to schistosome infection. To assess the genetic basis of susceptibility to schistosomiasis and identify the chromosomic regions involved, we used a backcross strategy to generate a mouse cohort with high variation in schistosomiasis susceptibility. Thus, we crossed the resistant C57BL/6 mouse strain with the susceptible CBA one; and later; the F1 females (C57 x CBA) were backcrossed with CBA males generating the F1BX cohort. The spectrum of phenotypes in the F1BX mice showed gradation from mild to severe disease, lacking a fully resistant group. We differentiated four levels of infection intensity using cluster and principal component analyses and K-means based on parasitological, pathological and immunological trait measurements. Mice were massively genotyped with 961 informative SNPs. We identify 19 new quantitative trait loci (QTL) associated with phenotype indicators of parasite burden, liver lesion, white blood cell populations, and antibody responses evaluated in the backcross cohort. Two QTLs on chromosomes 15 and 18 were simultaneously linked to the number of granulomas, grade of liver lesion and IgM levels. The human syntenic regions are located in chromosomes 8 and 18. None of the significant QTL identified coincided with previously reported mice association or were syntenic with human chromosomes. Author summaryHigh number of cases of infection and high levels of infection and liver fibrosis in schistosomiasis appear only in a few cases of people with high susceptibility, because the genetic background influences this susceptibility. To assess this, we used a backcross strategy crossing a resistant strain of mouse C57BL/6 with another susceptible CBA, and later F1 females were backcrossed with males susceptible, generating the F1BX cohort, which showed gradation from mild to severe disease. We differentiated four levels of infection according to cluster, principal component analysis and K-means, and based on parasitological, pathological and immunological measurements. Mice were massively genotyped and 19 quantitative trait loci (QTL) were identified, associated with phenotype indicators evaluated in backcross cohort. Two QTLs on chromosomes 15 and 18 were simultaneously linked to the number of granulomas, grade of liver lesion and IgM levels. None of the significant QTL identified coincided with previously reported mice association or were syntenic with human chromosomes.

pathology↗

bioRxiv2019

Peptides derived of kunitz-type serine protease inhibitor as potential vaccine against experimental schistosomiasis

Schistosomiasis is a significant public health problem in sub-Saharan Africa, China, South-East Asia and regions of South and central America affecting about 189 million people. Kunitz-type serine protease inhibitors have been identified as important players in the interaction of other flatworm parasites with their mammalian hosts. Here, we evaluate the protective efficacy of chemically synthesized of T- and B-cell peptide epitopes derived from a kunitz protein from Schistosoma mansoni. Putative kunitz-type protease inhibitor proteins were identified in the S. mansoni genome and their expression analyzed by RNA-seq. Gene expression analyses showed that the kunitz protein Smp_147730 (Syn. Smp_311670) was dramatically and significantly up-regulated in schistosomula and adult worms when compared to the invading cercariae. T- and B-cell epitopes were predicted using bioinformatics tools, chemically synthesized and formulated in the Adjuvant Adaptation (ADAD) vaccination system. BALB/c mice were vaccinated and challenged with S. mansoni cercariae. Kunitz peptides were highly protective in vaccinated BALB/c mice showing significant reductions in recovery of adult females (89-91%), and in the numbers of eggs trapped in the livers (77-81%) and guts (57-77%) of mice. Moreover, liver lesions were significantly reduced in vaccinated mice (64-65%) compared to infected control mice. The vaccination regime was well tolerated with both peptides. We propose the use of these peptides, alone or in combination, as reliable candidates for vaccination against schistosomiasis.

immunology↗