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The pathogenesis of SARS-CoV-2 remains to be completely understood, and detailed SARS-CoV-2 cellular cytopathic effects requires definition. We performed a comparative ultrastructural study of SARS-CoV-1 and SARS-CoV-2 infection in Vero E6 cells and in lungs from deceased COVID-19 patients. SARS-CoV-2 induces rapid death associated with profound ultrastructural changes in Vero cells. Type II pneumocytes in lung tissue showed prominent altered features with numerous vacuoles and swollen mitochondria with presence of abundant lipid droplets. The accumulation of lipids was the most striking finding we observed in SARS-CoV-2 infected cells, both in vitro and in the lungs of patients, suggesting that lipids can be involved in SARS-CoV-2 pathogenesis. Considering that in most cases, COVID-19 patients show alteration of blood cholesterol and lipoprotein homeostasis, our findings highlight a peculiar important topic that can suggest new approaches for pharmacological treatment to contrast the pathogenicity of SARS-CoV-2.

The identification of the large protein Ambra-1, which regulates autophagy and plays a crucial role in embryogenesis is described. The absence of Ambra-1 function during development results in severe neural tube defects associated with autophagy impairment, accumulation of ubiquitinated proteins, unbalanced cell proliferation and excessive apoptotic cell death. Autophagy is a self-degradative process involved both in basal turnover of cellular components and in response to nutrient starvation or organelle damage in a wide range of eukaryotes 1 , 2 , 3 . During autophagy, portions of the cytoplasm are sequestered by double-membraned vesicles called autophagosomes, and are degraded after fusion with lysosomes for subsequent recycling 4 . In vertebrates, this process acts as a pro-survival or pro-death mechanism in different physiological and pathological conditions, such as neurodegeneration and cancer 2 , 5 , 6 , 7 ; however, the roles of autophagy during embryonic development are still largely uncharacterized 3 . Beclin1 (Becn1; coiled-coil, myosin-like BCL2-interacting protein) is a principal regulator in autophagosome formation, and its deficiency results in early embryonic lethality 8 , 9 . Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy, as revealed by its overexpression and by RNA interference experiments in vitro . Notably, Ambra1 functional deficiency in mouse embryos leads to severe neural tube defects associated with autophagy impairment, accumulation of ubiquitinated proteins, unbalanced cell proliferation and excessive apoptotic cell death. In addition to identifying a new and essential element regulating the autophagy programme, our results provide in vivo evidence supporting the existence of a complex interplay between autophagy, cell growth and cell death required for neural development in mammals.

Background A considerable number of SARS-CoV-2 infected individuals could be asymptomatic and don’t need medical treatment. The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic cases, medium-intensity forms with mild to moderate symptoms, to severe ones with bilateral pneumonia and respiratory distress. In cases with severe presentation of SARS-CoV-2 infection, the induction of hypercoagulability is one of the pathophysiological mechanism that can contribute to death. Case presentation Here, we reported autoptic evidences of thrombotic pulmonary arterial fatal lesions in an asymptomatic COVID-19 patient, after swab negativization. Whole body complete post-mortem examination was performed, showing the presence of a large thrombus occluding the main pulmonary artery that was the cause of death. Histopathological analysis showed heterogeneous pattern of pathological changes in the lung tissue with numerous vascular thrombi, inflammatory cardiomyopathy and other histopathological modifications in kidneys, spleen and liver. Conclusions This study provides evidences that also asymptomatic patients may be at risk to develop thrombotic complications. An appropriate diagnostic screening for thrombotic complications and the early treatment recommendations of antithrombotic drugs could represent an important topic even in asymptomatic individuals.

Human immunodeficiency virus (HIV) infection continues to be a major global health challenge, affecting 38.4 million according to the Joint United Nations Program on HIV/AIDS (UNAIDS) at the end of 2021 with 1.5 million new infections. New HIV infections increased during the 2 years after the COVID-19 pandemic. Understanding the intricate cellular processes underlying HIV pathogenesis is crucial for developing effective therapeutic strategies. Among these processes, autophagy and programmed cell death modalities, including apoptosis, necroptosis, pyroptosis, and ferroptosis, play pivotal roles in the host–virus interaction dynamics. Autophagy, a highly conserved cellular mechanism, acts as a double-edged sword in HIV infection, influencing viral replication, immune response modulation, and the fate of infected cells. Conversely, apoptosis, a programmed cell death mechanism, is a critical defense mechanism against viral spread and contributes to the depletion of CD4+ T cells, a hallmark of HIV/AIDS progression. This review aims to dissect the complex interplay between autophagy and these programmed cell death modalities in HIV-induced pathogenesis. It highlights the molecular mechanisms involved, their roles in viral persistence and immune dysfunction, and the challenges posed by the viral reservoir and drug resistance, which continue to impede effective management of HIV pathology. Targeting these pathways holds promise for novel therapeutic strategies to mitigate immune depletion and chronic inflammation, ultimately improving outcomes for individuals living with HIV.

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.

Background Autophagy is the primary catabolic process responsible for degrading intracellular components and potentially harmful cytosolic entities by delivering them to lysosomes. Notably, this mechanism is crucial for controlling intracellular pathogens, with significant implications for both innate and adaptive immunity. In the context of HIV-1 infection, emerging evidence suggests that autophagy contributes to immune responses against the virus. Various compounds can modulate autophagy, among which vitamin D₃ is particularly effective due to its ability to prevent inflammation and slow HIV-1 disease progression. Indeed, vitamin D₃ contributes to regulating both innate and adaptive immunity, thereby modulating antiviral and antibacterial inflammatory responses. Importantly, vitamin D₃ deficiency is highly prevalent among people with HIV (PWH) and has been associated with an increased risk of severe disease progression. Results In this study, we investigated the relationship between serum vitamin D₃ levels and the expression of autophagy markers in peripheral blood mononuclear cells from different categories of PWH: PWH under antiretroviral therapy (ART) with either normal vitamin D₃ levels or hypovitaminosis, and treatment-naïve PWH with either normal vitamin D₃ levels or hypovitaminosis. Our results show that low vitamin D₃ blood levels is associated with lower expression of the main factors involved in the autophagy mechanism, particularly in treatment-naïve PWH. Conclusions Our findings suggest that normal blood level of vitamin D₃ may play a crucial role in promoting autophagy in PWH. The observed differences in autophagy-related protein expression between ART-treated and untreated individuals underscore the intricate relationship between vitamin D₃ levels, ART exposure, and autophagic regulation. This is a preliminary exploration of the effects of vitamin D₃ on autophagy in PWH. Further studies are needed to deepen and explore the interplay between vitamin D₃ and autophagy in greater depth. A better understanding of these mechanisms could help to develop novel therapeutic strategies aimed at mitigating immune depletion and chronic inflammation, ultimately improving clinical outcomes for individuals living with HIV.

Cystic fibrosis (CF) is a rare autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common mutation is F508del-CFTR (ΔF) which leads the encoded ion channel towards misfolding and premature degradation. The disease is characterized by chronic bronchopulmonary obstruction, inflammation and airways colonization by bacteria, which are the major cause of morbidity and mortality. The STING pathway is the main signaling route activated in the presence of both self and pathogen DNA, leading to Type I Interferon (IFN I) production and the innate immune response. In this study, we show for the first time the relationship existing in CF between resistant and recurrent opportunistic infections by Pseudomonas aeruginosa and the innate immunity impairment. We demonstrate through ex vivo and in vivo experiments that the pathway is inadequately activated in ΔF condition and the use of direct STING agonists, as 2′,3′-cyclic GMP-AMP (2’, 3’ cGAMP), is able to restore the immune response against bacterial colonization. Indeed, upon treatment with the STING pathway agonists, we found a reduction of colony forming units (CFUs) consequent to IFN-β enhanced production in Pseudomonas aeruginosa infected bone marrow derived macrophages and lung tissues from mice affected by Cystic Fibrosis. Importantly, we also verified that the impairment detected in the primary PBMCs obtained from ΔF patients can be corrected by 2’, 3’ cGAMP. Our work indicates that the cGAS/STING pathway integrity is crucial in the Cystic Fibrosis response against pathogens and that the restoration of the pathway by 2’, 3’ cGAMP could be exploited as a possible new target for the symptomatic treatment of the disease.

Understanding the viral–host cell interface during HIV-1 infection is a prerequisite for the development of innovative antiviral therapies. Here we show that the suppressor of G2 allele of skp1 (SUGT1) is a permissive factor for human immunodeficiency virus (HIV)-1 infection. Expression of SUGT1 increases in infected cells on human brain sections and in permissive host cells. We found that SUGT1 determines the permissiveness to infection of lymphocytes and macrophages by modulating the nuclear import of the viral genome. More importantly, SUGT1 stabilizes the microtubule plus-ends (+MTs) of host cells (through the modulation of microtubule acetylation and the formation of end-binding protein 1 (EB1) comets). This effect on microtubules favors HIV-1 retrograde trafficking and replication. SUGT1 depletion impairs the replication of HIV-1 patient primary isolates and mutant virus that is resistant to raltegravir antiretroviral agent. Altogether our results identify SUGT1 as a cellular factor involved in the post-entry steps of HIV-1 infection that may be targeted for new therapeutic approaches.

[This corrects the article DOI: 10.3389/fcimb.2025.1612198.].

Polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSC) are elevated in COVID-19 patients, playing a crucial role in suppressing the SARS-CoV-2 specific T-cell response and serving as an early marker for disease progression. In this study, we investigated the involvement of PMN-MDSC from COVID-19 patients in the formation of extracellular traps (ET). Fifty RT-PCR-confirmed severe COVID-19 patients admitted to the ICU and ten healthy donors were enrolled. PBMC were isolated from peripheral blood by density gradient centrifugation, and PMN-MDSC frequency was evaluated by flow cytometry. PMN-MDSC were isolated by immunomagnetic separation. ET extrusion was analyzed by immunofluorescence imaging. Apoptosis of pulmonary microvascular endothelial cells cultured with PMN-MDSC was measured by flow cytometry. We found that platelet-rich plasma (PRP) from COVID-19 patients, unlike that from healthy donors, induced ET formation by PMN-MDSC. Furthermore, the PRP-induced ET was found to be independent of Toll-like receptor 4 (TLR4) signaling. Interestingly, the SARS-CoV-2 Spike protein itself can trigger ET formation via a TLR4-dependent pathway. Additionally, PMN-MDSC induced endothelial cell apoptosis through an ET-independent mechanism. These findings highlight a previously unrecognized contribution of PMN-MDSCs to the thrombotic complications in severe COVID-19 cases, underscoring their detrimental impact on disease progression.