Barroso MV, Graça-Reis A, Cattani-Cavalieri I, Gitirana LB, Valenca SS, Lanzetti M. Mate tea reduces high fat diet-induced liver and metabolic disorders in mice. Biomed Pharmacother. 2019 Jan;109:1547-1555.
DOI: 10.1016/j.biopha.2018.11.007
///
High-fat diet (HFD)-induced obesity is a worldwide health problem and can cause lipid accumulation in the liver. We evaluated the hepatoprotective effect of mate tea treatment in mice submitted to an HFD. C57BL/6 mice were fed an HFD for 13 weeks with and without mate tea. A separate group of mice was treated with fenofibrate as a positive control (a regular drug for lipid disorders). Histological analyses, glucose tolerance tests (GTT), and quantification of mediators related to lipid peroxidation, oxidative stress and blood biomarkers for lipid profile were performed. The weight of animals and major organs related to hepatic steatosis was determined, and proinflammatory cytokines and the participation of the Nrf2 pathway and adiponectin were evaluated. Mate tea prevented the accumulation of lipid droplets in hepatocytes as well as weight gain in animals submitted to the HFD. Mate tea treatment also prevented increases in the liver weight, heart weight and amount of visceral and subcutaneous white adipose tissue. Mate tea was able to prevent the deregulation of glucose uptake, as evaluated by GTT, and improved the indicators of oxidative stress, such as nitrite levels, catalase activity, and oxidative damage, as evaluated by protein carbonylation and the MDA levels. Mate tea had an anti-inflammatory effect, preventing the increase of IL-1β and KC and upregulating the expression of Nrf2. Mate tea prevented insulin increase and HDL cholesterol decrease but did not affect total cholesterol or triglycerides levels. Treatment also prevented adiponectin increase. Mate tea may be a good resource to reduce hepatic steatosis in the future since it has anti-diabetic, anti-inflammatory and antioxidant effects, which prevent the accumulation of fat in the liver.
Figueiredo CM, Neris RLDS, Gavino-Leopoldino D, da Silva MOL, Almeida JS, Dos-Santos JS, Figueiredo CP, Bellio M, Bozza MT, Assunção-Miranda I. Mayaro Virus Replication Restriction and Induction of Muscular Inflammation in Mice Are Dependent on Age, Type-I Interferon Response, and Adaptive Immunity. Front Microbiol. 2019 Oct 1;10:2246.
///
Mayaro virus (MAYV) is an emergent arbovirus first described in forest regions of the American continent, with recent and increasing notification of urban area circulation. Similar to Chikungunya (CHIKV) and other arthritogenic Alphavirus, MAYV-induced disease shows a high prevalence of persistent arthralgia, and myalgia. Despite this, knowledge regarding pathogenesis and characteristics of host immune response of MAYV infections are still limited. Here, using different ages of wild-type (WT), adult Type I Interferon receptor deficient (IFNAR–/–), and adult recombination activation gene-1 deficient (RAG–/–) mice, we have investigated the dependence of age, innate and adaptive immunity for the control of MAYV replication, tissue damage, and inflammation in mice. We have found that MAYV induces clinical signal and replicates in young WT mice, which gain the ability to restrict MAYV replication with aging. In addition, we observed that mice age and type I interferon response are related to restriction of MAYV infection and muscular inflammation in mice. Moreover, MAYV continues to replicate persistently in RAG–/– mice, being detected at blood and tissues 40 days post infection, indicating that adaptive immunity is essential to MAYV clearance. Despite chronic replication, infected adult RAG–/– mice did not develop an apparent signal of muscle damage in early and late infection. On the other hand, MAYV infection in young WT and adult IFNAR-/- mice triggers an increase in the expression of pro-inflammatory mediators, such as TNF, IL-6, KC, IL-1β, MCP-1, and RANTES, in muscle tissue, and decreases TGF-β expression, that were not significantly modulated in adult WT and RAG–/– mice. Taken together, our data demonstrated that age, innate and adaptive immunity are important to restrict MAYV replication and that adaptive immunity is also involved in MAYV-induced tissue damage. These results contribute to the comprehension of MAYV pathogenesis, and describe translational mice models for further studies of MAYV infection, vaccine tests, and therapeutic strategies against this virus.
Mustafá YM, Meuren LM, Coelho SVA, de Arruda LB. Pathways Exploited by Flaviviruses to Counteract the Blood-Brain Barrier and Invade the Central Nervous System. Front Microbiol. 2019 Mar 28;10:525.
///
Human infection by different flaviviruses may cause severe neurologic syndromes, through pathogenic mechanisms that are still largely unknown. Japanese encephalitis virus (JEV), West Nile virus (WNV), Zika virus (ZIKV), yellow fever virus (YFV), dengue virus (DENV), and tick-borne encephalitis virus (TBEV) are believed to reach the central nervous system by a hematogenous route, upon crossing the blood-brain barrier. Although the disruption of BBB during flavivirus infection has been largely evidenced in experimental models, the relevance of BBB breakdown for virus entering the brain was not completely elucidated. In vitro models of BBB had demonstrated that these viruses replicated in brain microvascular endothelial cells (BMECs), which induced downregulation of tight junction proteins and increased the permeability of the barrier. Other reports demonstrated that infection of BMECs allowed the basolateral release of infectious particles, without a remarkable cytopathic effect, what might be sufficient for virus invasion. Virus replication and activation of other cells associated to the BBB, mostly astrocytes and microglia, were also reported to affect the endothelial barrier permeability. This event might occur simultaneously or after BMECs infection, being a secondary effect leading to BBB disruption. Importantly, activation of BMECs, astrocytes, and microglia by flaviviruses was associated to the expression and secretion of inflammatory mediators, which are believed to recruit leukocytes to the CNS. The leukocyte infiltrate could further mediate viral invasion through a Trojan horse mechanism and might contribute to BBB breakdown and to neurological alterations. This review discussed the previous studies regarding in vitro and in vivo models of JEV, WNV, ZIKV, YFV, DENV, and TBEV infection and addressed the pathways for BBB overcome and invasion of the CNS described for each virus infection, aiming to increment the knowledge and stimulate further discussion about the role of BBB in the neuropathogenesis of flavivirus infection.
Vaccari M, Fourati S, Brown DR, Silva de Castro I, Bissa M, Schifanella L, Doster MN, Foulds KE, Roederer M, Koup RA, Sui Y, Berzofsky JA, Sekaly RP, Franchini G. Myeloid Cell Crosstalk Regulates the Efficacy of the DNA/ALVAC/gp120 HIV Vaccine Candidate. Front Immunol. 2019 May 14;10:1072.
///
Vaccination with DNA-SIV + ALVAC-SIV + gp120 alum results in inflammasome activation, high levels of IL-1β production, emergency myelopoiesis, and the egress of CXCR4+ CD14+ pre-monocytes from bone marrow. Previously we have shown that this vaccine-induced innate monocyte memory is associated with decreased risk of SIVmac251 acquisition. Because IL-1β also promotes the propagation of monocyte-derived suppressor (M-MDSC)-like cells, here we extended our analysis to this negative regulator subset, characterizing its levels and functions in macaques. Interestingly, we found that DNA prime engages M-MDSC-like cells and their levels are positively associated with the frequency of CD14+ classical monocytes, and negatively with the levels of CD16+ monocytes, correlates of decreased and increased risk of SIV acquisition, respectively. Accordingly, M-MDSC frequency, arginase activity, and NO were all associated with decrease of CD8 T cells responses and worse vaccination outcome. DNA vaccination thus induces innate immunity by engaging three subsets of myeloid cells, M-MDSCs, CD14+ innate monocyte memory, and CD16+ monocytes all playing different role in protection. The full characterization of the immunological space created by myeloid cell crosstalk will likely provide clues to improve the efficacy of HIV vaccine candidates.
Cavalcanti De Albuquerque R, Granato A, Silva Castro I, Carvalho Torres R, Santos Souza F, Lima MA, Celestino Bezerra Leite AC, de Melo Espíndola O, Echevarria-Lima J. Phenotypic and functional changes in gamma delta T lymphocytes from HTLV-1 carriers. J Leukoc Biol. 2019 Sep;106(3):607-618.
///
Human T-cell lymphotropic virus type-1 (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is a chronic inflammatory disease that leads to gradual loss of motor movement as a result of the death of spinal cord cells through immune mediated mechanisms. The risk to develop HAM/TSP disease positively correlates with the magnitude of HTLV-1 proviral load. Gamma-delta T lymphocytes have been recognized as important players in a variety of infectious diseases. Therefore, we have investigated interactions between HTLV-1 infection and γδ T lymphocytes during HAM/TSP. Similar frequencies of total γδ T lymphocytes and their Vγ9δ2+ and Vγ9δ2neg subpopulations were observed in HAM/TSP patients. However, T lymphocytes obtained from HTLV-1 carriers displayed significantly higher rates of spontaneous proliferation and NKp30 expression when compared to cells from uninfected donors. In addition, an important decrease in the frequency of granzyme B+ γδ T lymphocytes (approximately 50%) was observed in HAM/TSP patients. Higher proportion of IFN-γ+ γδ T lymphocytes was found in HTLV-1-infected patients, which positively correlated with the HTLV-1 proviral load in peripheral blood mononuclear cells. Collectively, our data indicates that HTLV-1 infection leads to phenotypic and functional changes in the population of γδ T lymphocyte population, suggesting that HTLV-1 infection modulates functions associated to these cells, which might be involved in controlling the infection or in the development of HTLV-1-associated diseases.
