ApoA1 Neutralizes Proinflammatory Effects of Dengue Virus NS1 Protein and Modulates Viral Immune Evasion.

Dengue is a mosquito-borne infectious disease that is highly endemic in tropical and subtropical countries. Symptomatic patients can rapidly progress to severe conditions of hemorrhage, plasma extravasation, and hypovolemic shock, which leads to death. The blood tests of patients with severe dengue typically reveal low levels of high-density lipoprotein (HDL), which is responsible for reverse cholesterol transport (RCT) and regulation of the lipid composition in peripheral tissues. It is well known that dengue virus (DENV) depends on membrane cholesterol rafts to infect and to replicate in mammalian cells. Here, we describe the interaction of DENV nonstructural protein 1 (NS1) with apolipoprotein A1 (ApoA1), which is the major protein component of HDL. NS1 is secreted by infected cells and can be found circulating in the serum of patients with the onset of symptoms. NS1 concentrations in plasma are related to dengue severity, which is attributed to immune evasion and an acute inflammatory response. Our data show that the DENV NS1 protein induces an increase of lipid rafts in noninfected cell membranes and enhances further DENV infection. We also show that ApoA1-mediated lipid raft depletion inhibits DENV attachment to the cell surface. In addition, ApoA1 is able to neutralize NS1-induced cell activation and to prevent NS1-mediated enhancement of DENV infection. Furthermore, we demonstrate that the ApoA1 mimetic peptide 4F is also capable of mediating lipid raft depletion to control DENV infection. Taken together, our results suggest the potential of RCT-based therapies for dengue treatment. These results should motivate studies to assess the importance of RCT in DENV infection in vivo. IMPORTANCE DENV is one of the most relevant mosquito-transmitted viruses worldwide, infecting more than 390 million people every year and leading to more than 20 thousand deaths. Although a DENV vaccine has already been approved, its potential side effects have hampered its use in large-scale immunizations. Therefore, new treatment options are urgently needed to prevent disease worsening or to improve current clinical management of severe cases. In this study, we describe a new interaction of the NS1 protein, one of the major viral components, with a key component of HDL, ApoA1. This interaction seems to alter membrane susceptibility to virus infection and modulates the mechanisms triggered by DENV to evade the immune response. We also propose the use of a mimetic peptide named 4F, which was originally developed for atherosclerosis, as a potential therapy for relieving DENV symptoms.

Subacute and low dose of tributyltin exposure leads to brown adipose abnormalities in male rats.

Tributyltin (TBT) is an obesogenic endocrine disrupting chemical (EDC) linked with several metabolic complications. Brown adipose tissue (BAT) is the principal site for thermogenesis, making it a potential target for obesity management and metabolic disease. However, few studies have evaluated TBT effect on BAT function. In this investigation, we assessed whether subacute (15 days) and low dose of TBT exposure (100 ng/kg/day) results in abnormal BAT morphophysiology in adult male rats. Body temperature, BAT morphology, inflammation, oxidative stress, collagen deposition and BAT metabolic gene expression markers were assessed in room temperature (Room, ∼24 ºC) and after cold tolerance test (Cold, ∼4 ºC) conditions. A reduction in body temperature was observed in both Room and Cold conditions in TBT rats, suggesting abnormal BAT thermogenic function. Changes in BAT morphology were observed in TBT rats, with an increase in BAT lipid accumulation, an increase in BAT unilocular adipocyte number and a decrease in BAT multilocular adipocyte number in Room condition. All these parameters were opposite in Cold condition TBT rats, leading to a borderline increase in BAT UCP1 protein expression. An increase in BAT mast cell number was observed in TBT rats in Room condition. An increase in ED1 protein expression (macrophage marker) was observed in TBT rats in Cold condition. Oxidative stress and collagen deposition increased in both Room and Cold conditions in TBT rats. TBT exposure caused a borderline increase in BAT COL1A1 protein expression in Cold condition. Further, strong negative correlations were observed between body temperature and BAT lipid accumulation, and BAT lipid accumulation and multilocular adipocyte number. Thus, these data suggest that TBT exposure impaired BAT morphophysiology through impacts on lipid accumulation, inflammation, fibrosis and oxidative stress in male rats.

Overview on Chikungunya Virus Infection: From Epidemiology to State-of-the-Art Experimental Models.

Chikungunya virus (CHIKV) is currently one of the most relevant arboviruses to public health. It is a member of the Togaviridae family and alphavirus genus and causes an arthritogenic disease known as chikungunya fever (CHIKF). It is characterized by a multifaceted disease, which is distinguished from other arbovirus infections by the intense and debilitating arthralgia that can last for months or years in some individuals. Despite the great social and economic burden caused by CHIKV infection, there is no vaccine or specific antiviral drugs currently available. Recent outbreaks have shown a change in the severity profile of the disease in which atypical and severe manifestation lead to hundreds of deaths, reinforcing the necessity to understand the replication and pathogenesis processes. CHIKF is a complex disease resultant from the infection of a plethora of cell types. Although there are several in vivo models for studying CHIKV infection, none of them reproduces integrally the disease signature observed in humans, which is a challenge for vaccine and drug development. Therefore, understanding the potentials and limitations of the state-of-the-art experimental models is imperative to advance in the field. In this context, the present review outlines the present knowledge on CHIKV epidemiology, replication, pathogenesis, and immunity and also brings a critical perspective on the current in vitro and in vivo state-of-the-art experimental models of CHIKF.