Rare Fundus Lesions in Patients after SARS-Cov-2 Infection: A Multicenter and Multimodal Imaging Study (preprint)

Purpose To define the characteristics of fundus manifestations in patients after SARS-Cov-2 infection with multimodal imaging techniques.Methods This is a retrospective multicenter and multimodal imaging study including 90 patients. All patients with a visual complaint occurring immediately after SARS-Cov-2 infection were referred to six clinics between December 2022 and February 2023. Demographic information and the temporal relationship between SARS-Cov-2 infection and visual symptoms were documented. The characteristics of the fundus lesions were evaluated using multimodal imaging.Results Ninety patients from six hospitals were enrolled in this study, including 24 males (26.67%) and 66 (73.33%) females. Seventy-eight patients (86.66%) (146 eyes) were diagnosed with AMN. The AMN patients were primarily young women (67.95%). Sixty-eight patients (87.18%) had AMN in both eyes. Thirty-eight eyes (24.36%) included Purtscher or Purtscher-like lesions. optical coherence tomography and infrared retinal photographs can show AMN lesions well. Eleven cases were diagnosed with simple Purtscher or Purtscher-like retinopathy (2 cases, 2.22%), VKH or VKH-like uveitis (3 cases, 3.33%), MEWDS (2 cases, 2.22%), and ROCM (5 cases, 5.56%).Conclusions After SARS-Cov-2 infection, diversified fundus lesions were evident in patients with visual complaints. In this report, AMN was the dominant manifestation, followed by Purtscher or Purtscher-like retinopathy, MEWDS, VKH-like uveitis, and ROCM.

Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response.

Very long-chain fatty acids (VLCFA) are critical for human cytomegalovirus replication and accumulate upon infection. Here, we used Epstein-Barr virus (EBV) infection of human B cells to elucidate how herpesviruses target VLCFA metabolism. Gene expression profiling revealed that, despite a general induction of peroxisome-related genes, EBV early infection decreased expression of the peroxisomal VLCFA transporters ABCD1 and ABCD2, thus impairing VLCFA degradation. The mechanism underlying ABCD1 and ABCD2 repression involved RNA interference by the EBV-induced microRNAs miR-9-5p and miR-155, respectively, causing significantly increased VLCFA levels. Treatment with 25-hydroxycholesterol, an antiviral innate immune modulator produced by macrophages, restored ABCD1 expression and reduced VLCFA accumulation in EBV-infected B-lymphocytes, and, upon lytic reactivation, reduced virus production in control but not ABCD1-deficient cells. Finally, also other herpesviruses and coronaviruses target ABCD1 expression. Because viral infection might trigger neuroinflammation in X-linked adrenoleukodystrophy (X-ALD, inherited ABCD1 deficiency), we explored a possible link between EBV infection and cerebral X-ALD. However, neither immunohistochemistry of post-mortem brains nor analysis of EBV seropositivity in 35 X-ALD children supported involvement of EBV in the onset of neuroinflammation. Collectively, our findings indicate a previously unrecognized, pivotal role of ABCD1 in viral infection and host defence, prompting consideration of other viral triggers in cerebral X-ALD.

NLRP3 Inflammasome: Mechanism of Action, Role, and Therapeutics in Liver Diseases (preprint)

Liver inflammation is a universal characteristic of chronic liver diseases. NLRP3 is an intracellular sensor that recognizes various endogenous danger signals and environmental irritants, contributing to the formation and activation of the NLRP3 inflammasome. NLRP3 inflammasome is closely related to the progression of various liver diseases and is strongly associated with replicating COVID-19, which is still spreading globally. The assembly and activation of NLRP3 inflammasome in the liver diseases aggravate inflammation and subsequent fibrosis, and this effect is abolished by genetic or pharmacologic deletion of NLRP3 inflammasome. Here, we summarized the latest advances in the critical regulatory role of NLRP3 inflammasome in a variety of liver diseases, including COVID-19 induced liver diseases, NAFLD, ALD, and ischemia-reperfusion (I/R) injury. Additionally, we also discuss small-molecule inhibitors identifying the NLRP3 inflammasome signaling are novel therapeutic targets in treating liver diseases. Our review provides novel insights into the underlying mechanisms of NLRP3 inflammasome in liver diseases and may offer a potential therapeutic strategy for treating liver diseases by targeting NLRP3 inflammasome.

Acute Macular Neuroretinopathy as a Manifestation of Coronavirus Disease 2019: a Case Report (preprint)

This is a new case of simultaneous occurrences of AMN and COVID-19 in a previously healthy woman. The importance of the current report lies in increasing the awareness of all physicians about the probable association of COVID-19 with retinal vascular injury and ischemia.

A vimentin-targeting oral compound with host-directed antiviral and anti-inflammatory actions addresses multiple features of COVID-19 and related diseases (preprint)

Damage in COVID-19 results from both the SARS-CoV-2 virus and its triggered overreactive host immune responses. Therapeutic agents that focus solely on reducing viral load or hyperinflammation fail to provide satisfying outcomes in all cases. Although viral and cellular factors have been extensively profiled to identify potential anti-COVID targets, new drugs with significant efficacy remain to be developed. Here, we report the potent preclinical efficacy of ALD-R491, a vimentin-targeting small molecule compound, in treating COVID-19 through its host-directed antiviral and anti-inflammatory actions. We found that by altering the physical properties of vimentin filaments, ALD-491 affected general cellular processes as well as specific cellular functions relevant to SARS-CoV-2 infection. Specifically, ALD-R491 reduced endocytosis, endosomal trafficking, and exosomal release, thus impeding the entry and egress of the virus; increased the microcidal capacity of macrophages, thus facilitating the pathogen clearance; and enhanced the activity of regulatory T cells, therefore suppressing the overreactive immune responses. In cultured cells, ALD-R491 potently inhibited the SARS-CoV-2 spike protein and human ACE2-mediated pseudoviral infection. In aged mice with ongoing, productive SARS-CoV-2 infection, ALD-R491 reduced disease symptoms as well as lung damage. In rats, ALD-R491 also reduced bleomycin-induced lung injury and fibrosis. Our results indicate a unique mechanism and significant therapeutic potential for ALD-R491 against COVID-19. We anticipate that ALD-R491, an oral, fast-acting, and non-toxic agent targeting the cellular protein with multipart actions, will be convenient, safe, and broadly effective, regardless of viral mutations, for patients with early- or late-stage disease, post-COVID complications and other related diseases. IMPORTANCEWith the Delta variant currently fueling a resurgence of new infections in the fully-vaccinated population, developing an effective therapeutic drug is especially critical and urgent in fighting COVID-19. In contrast to the many efforts to repurpose existing drugs or address only one aspect of COVID-19, we are developing a novel agent with first-in-class mechanism-of-actions that address both the viral infection and the overactive immune system in the pathogenesis of the disease. Unlike virus-directed therapeutics that may lose efficacy due to viral mutations and immunosuppressants that require ideal timing to be effective, this agent, with its unique host-directed antiviral and anti-inflammatory actions, can work against all variants of the virus, be effective during all stages of the disease, and even resolve post-disease damage and complications. A further development of the compound will provide an important tool in the fight against COVID-19, its complications, as well as future outbreaks of new viruses.