Aging mitochondria in the context of SARS-CoV-2: exploring interactions and implications.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented global challenges with a diverse clinical spectrum, including severe respiratory complications and systemic effects. This review explores the intricate relationship between mitochondrial dysfunction, aging, and obesity in COVID-19. Mitochondria are vital for cellular energy provision and resilience against age-related macromolecule damage accumulation. They manage energy allocation in cells, activating adaptive responses and stress signals such as redox imbalance and innate immunity activation. As organisms age, mitochondrial function diminishes. Aging and obesity, linked to mitochondrial dysfunction, compromise the antiviral response, affecting the release of interferons, and worsening COVID-19 severity. Furthermore, the development of post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID has been associated with altered energy metabolism, and chronic immune dysregulation derived from mitochondrial dysfunction. Understanding the interplay between mitochondria, aging, obesity, and viral infections provides insights into COVID-19 pathogenesis. Targeting mitochondrial health may offer potential therapeutic strategies to mitigate severe outcomes and address long-term consequences in infected individuals.

HIV Modulates Osteoblast Differentiation via Upregulation of RANKL and Vitronectin.

Bone loss is a prevalent characteristic among people with HIV (PWH). We focused on mesenchymal stem cells (MSCs) and osteoblasts, examining their susceptibility to different HIV strains (R5- and X4-tropic) and the subsequent effects on bone tissue homeostasis. Our findings suggest that MSCs and osteoblasts are susceptible to R5- and X4-tropic HIV but do not support productive HIV replication. HIV exposure during the osteoblast differentiation process revealed that the virus could not alter mineral and organic matrix deposition. However, the reduction in runt-related transcription factor 2 (RUNX2) transcription, the increase in the transcription of nuclear receptor activator ligand kappa B (RANKL), and the augmentation of vitronectin deposition strongly suggested that X4- and R5-HIV could affect bone homeostasis. This study highlights the HIV ability to alter MSCs' differentiation into osteoblasts, critical for maintaining bone and adipose tissue homeostasis and function.

SARS-CoV-2 Modulation of HIV Latency Reversal in a Myeloid Cell Line: Direct and Bystander Effects.

Coronavirus disease 2019 (COVID-19) might impact disease progression in people living with HIV (PLWH), including those on effective combination antiretroviral therapy (cART). These individuals often experience chronic conditions characterized by proviral latency or low-level viral replication in CD4+ memory T cells and tissue macrophages. Pro-inflammatory cytokines, such as TNF-α, IL-1ß, IL-6, and IFN-γ, can reactivate provirus expression in both primary cells and cell lines. These cytokines are often elevated in individuals infected with SARS-CoV-2, the virus causing COVID-19. However, it is still unknown whether SARS-CoV-2 can modulate HIV reactivation in infected cells. Here, we report that exposure of the chronically HIV-1-infected myeloid cell line U1 to two different SARS-CoV-2 viral isolates (ancestral and BA.5) reversed its latent state after 24 h. We also observed that SARS-CoV-2 exposure of human primary monocyte-derived macrophages (MDM) initially drove their polarization towards an M1 phenotype, which shifted towards M2 over time. This effect was associated with soluble factors released during the initial M1 polarization phase that reactivated HIV production in U1 cells, like MDM stimulated with the TLR agonist resiquimod. Our study suggests that SARS-CoV-2-induced systemic inflammation and interaction with macrophages could influence proviral HIV-1 latency in myeloid cells in PLWH.

Bystander Effects and Profibrotic Interactions in Hepatic Stellate Cells during HIV and HCV Coinfection.

This study aims to explore the influence of coinfection with HCV and HIV on hepatic fibrosis. A coculture system was set up to actively replicate both viruses, incorporating CD4 T lymphocytes (Jurkat), hepatic stellate cells (LX-2), and hepatocytes (Huh7.5). LX-2 cells' susceptibility to HIV infection was assessed through measurements of HIV receptor expression, exposure to cell-free virus, and cell-to-cell contact with HIV-infected Jurkat cells. The study evaluated profibrotic parameters, including programed cell death, ROS imbalance, cytokines (IL-6, TGF-ß, and TNF-α), and extracellular matrix components (collagen, α-SMA, and MMP-9). The impact of HCV infection on LX-2/HIV-Jurkat was examined using soluble factors released from HCV-infected hepatocytes. Despite LX-2 cells being nonsusceptible to direct HIV infection, bystander effects were observed, leading to increased oxidative stress and dysregulated profibrotic cytokine release. Coculture with HIV-infected Jurkat cells intensified hepatic fibrosis, redox imbalance, expression of profibrotic cytokines, and extracellular matrix production. Conversely, HCV-infected Huh7.5 cells exhibited elevated profibrotic gene transcriptions but without measurable effects on the LX-2/HIV-Jurkat coculture. This study highlights how HIV-infected lymphocytes worsen hepatic fibrosis during HCV/HIV coinfection. They increase oxidative stress, profibrotic cytokine levels, and extracellular matrix production in hepatic stellate cells through direct contact and soluble factors. These insights offer valuable potential therapies for coinfected individuals.

Perilipin 2 inhibits replication of hepatitis B virus deoxyribonucleic acid by regulating autophagy under high-fat conditions.

Hepatitis B virus (HBV) infection poses a global health concern without a definitive cure; however, antiviral medications can effectively suppress viral replication. This study delves into the intricate interplay between lipid metabolism and HBV replication, implicating molecular mechanisms such as the stearoyl coenzyme A desaturase 1 autophagy pathway, SAC1-like phosphatidylinositol phosphatase, and galectin-9 mediated selective autophagy of viral core proteins in regulating HBV replication. Within lipid droplets, perilipin 2 (PLIN2) emerges as a pivotal guardian, with its overexpression protecting against autophagy and downregulation stimulating triglyceride catabolism through the autophagy pathway. This editorial discusses the correlation between hepatic steatosis and HBV replication, emphasizing the role of PLIN2 in this process. The study underscores the multifaceted roles of lipid metabolism, autophagy, and perilipins in HBV replication, shedding light on potential therapeutic avenues.

The abortive SARS-CoV-2 infection of osteoclast precursors promotes their differentiation into osteoclasts.

The Coronavirus Disease 2019 (COVID-19) pandemic has resulted in the loss of millions of lives, although a majority of those infected have managed to survive. Consequently, a set of outcomes, identified as long COVID, is now emerging. While the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the respiratory system, the impact of COVID-19 extends to various body parts, including the bone. This study aims to investigate the effects of acute SARS-CoV-2 infection on osteoclastogenesis, utilizing both ancestral and Omicron viral strains. Monocyte-derived macrophages, which serve as precursors to osteoclasts, were exposed to both viral variants. However, the infection proved abortive, even though ACE2 receptor expression increased postinfection, with no significant impact on cellular viability and redox balance. Both SARS-CoV-2 strains heightened osteoclast formation in a dose-dependent manner, as well as CD51/61 expression and bone resorptive ability. Notably, SARS-CoV-2 induced early pro-inflammatory M1 macrophage polarization, shifting toward an M2-like profile. Osteoclastogenesis-related genes (RANK, NFATc1, DC-STAMP, MMP9) were upregulated, and surprisingly, SARS-CoV-2 variants promoted RANKL-independent osteoclast formation. This thorough investigation illuminates the intricate interplay between SARS-CoV-2 and osteoclast precursors, suggesting potential implications for bone homeostasis and opening new avenues for therapeutic exploration in COVID-19.

HIV-Infected Hepatic Stellate Cells or HCV-Infected Hepatocytes Are Unable to Promote Latency Reversal among HIV-Infected Mononuclear Cells.

Due to a common mode of transmission through infected human blood, hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is relatively prevalent. In alignment with this, HCV co-infection is associated with an increased size of the HIV reservoir in highly active antiretroviral therapy (HAART)-treated individuals. Hence, it is crucial to comprehend the physiological mechanisms governing the latency and reactivation of HIV in reservoirs. Consequently, our study delves into the interplay between HCV/HIV co-infection in liver cells and its impact on the modulation of HIV latency. We utilized the latently infected monocytic cell line (U1) and the latently infected T-cell line (J-Lat) and found that mediators produced by the infection of hepatic stellate cells and hepatocytes with HIV and HCV, respectively, were incapable of inducing latency reversal under the studied conditions. This may favor the maintenance of the HIV reservoir size among latently infected mononuclear cells in the liver. Further investigations are essential to elucidate the role of the interaction between liver cells in regulating HIV latency and/or reactivation, providing a physiologically relevant model for comprehending reservoir microenvironments in vivo.

HIV and gp120-induced lipid droplets loss in hepatic stellate cells contribute to profibrotic profile.

Liver fibrosis is the excessive accumulation of extracellular matrix proteins, primarily collagen, in response to liver injury caused by chronic liver diseases. HIV infection accelerates the progression of liver fibrosis in patients co-infected with HCV or HBV compared to those who are only mono-infected. The early event in the progression of liver fibrosis involves the activation of hepatic stellate cells (HSCs), which entails the loss of lipid droplets (LD) to fuel the production of extracellular matrix components crucial for liver tissue healing. Thus, we are examining the mechanism by which HIV stimulates the progression of liver fibrosis. HIV-R5 tropic infection was unable to induce the expression of TGF-ß, collagen deposition, α-smooth muscle actin (α-SMA), and cellular proliferation. However, this infection induced the secretion of the profibrogenic cytokine IL-6 and the loss of LD. This process involved the participation of peroxisome proliferator-activated receptor (PPAR)-α and an increase in lysosomal acid lipase (LAL), along with the involvement of Microtubule-associated protein 1 A/1B-light chain 3 (LC3), strongly suggesting that LD loss could occur through acid lipolysis. These phenomena were mimicked by the gp120 protein from the R5 tropic strain of HIV. Preincubation of HSCs with the CCR5 receptor antagonist, TAK-779, blocked gp120 activity. Additionally, experiments performed with pseudotyped-HIV revealed that HIV replication could also contribute to LD loss. These results demonstrate that the cross-talk between HSCs and HIV involves a series of interactions that help explain some of the mechanisms involved in the exacerbation of liver damage observed in co-infected individuals.

Molecular mechanisms underlying SARS-CoV-2 hepatotropism and liver damage.

In coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) primarily targets the respiratory system, but evidence suggests extrapulmonary organ involvement, notably in the liver. Viral RNA has been detected in hepatic tissues, and in situ hybridization revealed virions in blood vessels and endothelial cells. Electron microscopy confirmed viral particles in hepatocytes, emphasizing the need for understanding hepatotropism and direct cytopathic effects in COVID-19-related liver injury. Various factors contribute to liver injury, including direct cytotoxicity, vascular changes, inflammatory responses, immune reactions from COVID-19 and vaccinations, and drug-induced liver injury. Although a typical hepatitis presentation is not widely documented, elevated liver biochemical markers are common in hospitalized COVID-19 patients, primarily showing a hepatocellular pattern of elevation. Long-term studies suggest progressive cholestasis may affect 20% of patients with chronic liver disease post-SARS-CoV-2 infection. The molecular mechanisms underlying SARS-CoV-2 infection in the liver and the resulting liver damage are complex. This "Editorial" highlights the expression of the Angiotensin-converting enzyme-2 receptor in liver cells, the role of inflammatory responses, the impact of hypoxia, the involvement of the liver's vascular system, the infection of bile duct epithelial cells, the activation of hepatic stellate cells, and the contribution of monocyte-derived macrophages. It also mentions that pre-existing liver conditions can worsen the outcomes of COVID-19. Understanding the interaction of SARS-CoV-2 with the liver is still evolving, and further research is required.

The interplay of aging, adipose tissue, and COVID-19: a potent alliance with implications for health.

Obesity has emerged as a significant public health challenge. With the ongoing increase in life expectancy, the prevalence of obesity is steadily growing, particularly among older age demographics. The extension of life expectancy frequently results in additional years of vulnerability to chronic health issues associated with obesity in the elderly.The concept of SARS-CoV-2 directly infecting adipose tissue stems from the fact that both adipocytes and stromal vascular fraction cells express ACE2, the primary receptor facilitating SARS-CoV-2 entry. It is noteworthy that adipose tissue demonstrates ACE2 expression levels similar to those found in the lungs within the same individual. Additionally, ACE2 expression in the adipose tissue of obese individuals surpasses that in non-obese counterparts. Viral attachment to ACE2 has the potential to disturb the equilibrium of renin-angiotensin system homeostasis, leading to an exacerbated inflammatory response.Consequently, adipose tissue has been investigated as a potential site for active SARS-CoV-2 infection, suggesting its plausible role in virus persistence and contribution to both acute and long-term consequences associated with COVID-19.This review is dedicated to presenting current evidence concerning the presence of SARS-CoV-2 in the adipose tissue of elderly individuals infected with the virus. Both obesity and aging are circumstances that contribute to severe health challenges, heightening the risk of disease and mortality. We will particularly focus on examining the mechanisms implicated in the long-term consequences, with the intention of providing insights into potential strategies for mitigating the aftermath of the disease.

Editorial: Metabolomics in chronic hepatitis C: Decoding fibrosis grading and underlying pathways.

In the management of the growing population of hepatitis C virus-infected patients, a significant clinical challenge exists in determining the most effective methods for assessing liver impairment. The prognosis and treatment of chronic hepatitis C depend, in part, on the evaluation of histological activity, specifically cell necrosis and inflammation, and the extent of liver fibrosis. These parameters are traditionally obtained through a liver biopsy. However, liver biopsy presents both invasiveness and potential sampling errors, primarily due to inadequate biopsy size. To circumvent these issues, several non-invasive markers have been proposed as alternatives for diagnosing liver damage. Different imaging techniques and blood parameters as single markers or combined with clinical information are included. This Editorial discusses the identification of a set of six distinctive lipid metabolites in every fibrosis grade that appear to show a pronounced propensity to create clusters among patients who share the same fibrosis grade, thereby demonstrating enhanced efficacy in distinguishing between the different grades.

Massively HIV-1-infected macrophages exhibit a severely hampered ability to differentiate into osteoclasts.

Introduction: Osteoclasts play a crucial role in bone resorption, and impairment of their differentiation can have significant implications for bone density, especially in individuals with HIV who may be at risk of altered bone health. The present study aimed to investigate the effects of HIV infection on osteoclast differentiation using primary human monocyte-derived macrophages as precursors. The study focused on assessing the impact of HIV infection on cellular adhesion, cathepsin K expression, resorptive activity, cytokine production, expression of co-receptors, and transcriptional regulation of key factors involved in osteoclastogenesis. Methods: Primary human monocyte-derived macrophages were utilized as precursors for osteoclast differentiation. These precursors were infected with HIV, and the effects of different inoculum sizes and kinetics of viral replication were analyzed. Subsequently, osteoclastogenesis was evaluated by measuring cellular adhesion, cathepsin K expression, and resorptive activity. Furthermore, cytokine production was assessed by monitoring the production of IL-1ß, RANK-L, and osteoclasts. The expression levels of co-receptors CCR5, CD9, and CD81 were measured before and after infection with HIV. The transcriptional levels of key factors for osteoclastogenesis (RANK, NFATc1, and DC-STAMP) were examined following HIV infection. Results: Rapid, massive, and productive HIV infection severely impaired osteoclast differentiation, leading to compromised cellular adhesion, cathepsin K expression, and resorptive activity. HIV infection resulted in an earlier production of IL-1ß concurrent with RANK-L, thereby suppressing osteoclast production. Infection with a high inoculum of HIV increased the expression of the co-receptor CCR5, as well as the tetraspanins CD9 and CD81, which correlated with deficient osteoclastogenesis. Massive HIV infection of osteoclast precursors affected the transcriptional levels of key factors involved in osteoclastogenesis, including RANK, NFATc1, and DC-STAMP. Conclusions: The effects of HIV infection on osteoclast precursors were found to be dependent on the size of the inoculum and the kinetics of viral replication. These findings underscore the importance of understanding the underlying mechanisms to develop novel strategies for the prevention and treatment of bone disorders in individuals with HIV.

Viable SARS-CoV-2 Omicron sub-variants isolated from autopsy tissues.

Introduction: Pulmonary and extrapulmonary manifestations have been described after infection with SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). The virus is known to persist in multiple organs due to its tropism for several tissues. However, previous reports were unable to provide definitive information about whether the virus is viable and transmissible. It has been hypothesized that the persisting reservoirs of SARS-CoV-2 in tissues could be one of the multiple potentially overlapping causes of long COVID. Methods: In the present study, we investigated autopsy materials obtained from 21 cadaveric donors with documented first infection or reinfection at the time of death. The cases studied included recipients of different formulations of COVID-19 vaccines. The aim was to find the presence of SARS-CoV-2 in the lungs, heart, liver, kidneys, and intestines. We used two technical approaches: the detection and quantification of viral genomic RNA using RT-qPCR, and virus infectivity using permissive in vitro Vero E6 culture. Results: All tissues analyzed showed the presence of SARS-CoV-2 genomic RNA but at dissimilar levels ranging from 1.01 × 102 copies/mL to 1.14 × 108 copies/mL, even among those cases who had been COVID-19 vaccinated. Importantly, different amounts of replication-competent virus were detected in the culture media from the studied tissues. The highest viral load were measured in the lung (≈1.4 × 106 copies/mL) and heart (≈1.9 × 106 copies/mL) samples. Additionally, based on partial Spike gene sequences, SARS-CoV-2 characterization revealed the presence of multiple Omicron sub-variants exhibiting a high level of nucleotide and amino acid identity among them. Discussion: These findings highlight that SARS-CoV-2 can spread to multiple tissue locations such as the lungs, heart, liver, kidneys, and intestines, both after primary infection and after reinfections with the Omicron variant, contributing to extending knowledge about the pathogenesis of acute infection and understanding the sequelae of clinical manifestations that are observed during post-acute COVID-19.

Changing molecular epidemiology of Hepatitis A virus in Santiago, Chile from 2010 to 2021.

OBJECTIVES: Hepatitis A (HAV) virus causes asymptomatic to life-treating fulminant hepatitis. During infection, patients show large viral excretion in their stools. Resistance of HAV to environmental conditions, allows us to recover viral nucleotide sequences from wastewater and trace its evolutionary history. METHODS: We characterize twelve years of HAV circulation in wastewater from Santiago, Chile, and conducted phylogenetic analyses to decipher the dynamics of circulating lineages. RESULTS: We observed the exclusive circulation of the HAV IA genotype. The molecular epidemiologic analyses showed a steady circulation of a dominant lineage with low genetic diversity (d = 0,007) between 2010 and 2017. An outbreak of Hepatitis A associated with men who have sex with men, in 2017 was associated with the irruption of a new lineage. Remarkably, a dramatic change in the dynamic of HAV circulation was observed in the period post-outbreak; between 2017 and 2021 when 4 different lineages were transiently detected. Exhaustive phylogenetic analyses indicate that these lineages were introduced and possibly derived from isolates from other Latin American countries. CONCLUSION: The HAV circulation in recent years in Chile is rapidly changing and suggests that this phenomenon could be a consequence of massive population migrations in Latin America caused by political instability and natural disasters.

B. abortus Infection Promotes an Imbalance in the Adipocyte-Osteoblast Crosstalk Favoring Bone Resorption.

Osteoarticular injury is the most common presentation of active brucellosis in humans. Osteoblasts and adipocytes originate from mesenchymal stem cells (MSC). Since those osteoblasts are bone-forming cells, the predilection of MSC to differentiate into adipocytes or osteoblasts is a potential factor involved in bone loss. In addition, osteoblasts and adipocytes can be converted into each other according to the surrounding microenvironment. Here, we study the incumbency of B. abortus infection in the crosstalk between adipocytes and osteoblasts during differentiation from its precursors. Our results indicate that soluble mediators present in culture supernatants from B. abotus-infected adipocytes inhibit osteoblast mineral matrix deposition in a mechanism dependent on the presence of IL-6 with the concomitant reduction of Runt-related transcription factor 2 (RUNX-2) transcription, but without altering organic matrix deposition and inducing nuclear receptor activator ligand kß (RANKL) expression. Secondly, B. abortus-infected osteoblasts stimulate adipocyte differentiation with the induction of peroxisome proliferator-activated receptor γ (PPAR-γ) and CCAAT enhancer binding protein ß (C/EBP-ß). We conclude that adipocyte-osteoblast crosstalk during B. abortus infection could modulate mutual differentiation from its precursor cells, contributing to bone resorption.

Poliomyelitis is a current challenge: long-term sequelae and circulating vaccine-derived poliovirus.

For more than 20 years, the World Health Organization Western Pacific Region (WPR) has been polio-free. However, two current challenges are still polio-related. First, around half of poliomyelitis elderly survivors suffer late poliomyelitis sequelae with a substantial impact on daily activities and quality of life, experiencing varying degrees of residual weakness as they age. The post-polio syndrome as well as accelerated aging may be involved. Second, after the worldwide Sabin oral poliovirus (OPV) vaccination, the recent reappearance of strains of vaccine-derived poliovirus (VDPV) circulating in the environment is worrisome and able to persistent person-to-person transmission. Such VDPV strains exhibit atypical genetic characteristics and reversed neurovirulence that can cause paralysis similarly to wild poliovirus, posing a significant obstacle to the elimination of polio. Immunization is essential for preventing paralysis in those who are exposed to the poliovirus. Stress the necessity of maintaining high vaccination rates because declining immunity increases the likelihood of reemergence. If mankind wants to eradicate polio in the near future, measures to raise immunization rates and living conditions in poorer nations are needed, along with strict observation. New oral polio vaccine candidates offer a promissory tool for this goal.

HIV-induced bystander cell death in astrocytes requires cell-to-cell viral transmission.

Human immunodeficiency virus (HIV) neuroinvasion occurs early after infection through the trafficking of virus-infected immune cells into the central nervous system (CNS) and viral dissemination into the brain. There, it can infect resident brain cells including astrocytes, the most abundant cell type that is crucial to brain homeostasis. In this report, we examined the HIV-related mechanism able to induce bystander cell death in astrocytes mediated by cell-to-cell contact with productively infected (PI) ones. We first demonstrate that HIV-induced bystander cell death involves mitochondrial dysfunction that promotes exacerbated reactive oxygen species production. Such a phenomenon is a contagious cell death that requires contact with HIV-PI astrocytes that trigger caspase-dependent (apoptosis and pyroptosis) and caspase-independent cell death pathways. The HIV accessory proteins Nef, Vpu, and Vpr counteract astrocyte death among PI cells but, in contrast, participate to promote contagious bystander cell death by inducing mitochondrial reactive oxygen species production. Our findings indicate that astrocytes PI by HIV became capable to counteract infection-derived death signals, surviving, and spreading the bystander cell death into neighboring uninfected cells by a cell-to-cell contact-dependent mechanism. Considering that astrocytes have been proposed as a long-term HIV reservoir in the CNS, ascertaining the mechanism of survival and contagious bystander death will afford clear targets in the current goal to achieve a functional cure.

Henipaviruses: an expanding global public health concern?

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic zoonotic viruses of the genus Henipavirus, family Paramyxoviridae that cause severe disease outbreaks in humans and also can infect and cause lethal disease across a broad range of mammalian species. Another related Henipavirus has been very recently identified in China in febrile patients with pneumonia, the Langya virus (LayV) of probable animal origin in shrews. NiV and HeV were first identified as the causative agents of severe respiratory and encephalitic disease in the 1990s across Australia and Southern Asia with mortality rates reaching up to 90%. They are responsible for rare and sporadic outbreaks with no approved treatment modalities. NiV and HeV have wide cellular tropism that contributes to their high pathogenicity. From their natural hosts bats, different scenarios propitiate their spillover to pigs, horses, and humans. Henipavirus-associated respiratory disease arises from vasculitis and respiratory epithelial cell infection while the neuropathogenesis of Henipavirus infection is still not completely understood but appears to arise from dual mechanisms of vascular disease and direct parenchymal brain infection. This brief review offers an overview of direct and indirect mechanisms of HeV and NiV pathogenicity and their interaction with the human immune system, as well as the main viral strategies to subvert such responses.