COVID-19 and Alzheimer's Disease: What Is the Connection?

Wang et al. found that elderly COVID-19 patients were at risk of AD. The following facts suggest a possible explanation: reactivation of herpes simplex virus type 1 (HSV1) and other herpesviruses can occur in SARS-CoV-2 patients; in cell cultures, HSV1 infection causes occurrence of many AD-like features, as does reactivation of latent HSV1 after addition of certain infectious agents; recurrent experimental reactivation of HSV1-infected mice leads to formation of the main features of AD brains, and to cognitive decline. These suggest that COVID-19 results in repeated reactivation of HSV1 in brain, with subsequent accumulation of damage and eventual development of AD.

Orobanche crenata Forssk. Extract Affects Human Breast Cancer Cell MCF-7 Survival and Viral Replication.

BACKGROUND: Breast cancer (BC) is the leading cause of death worldwide. The severity of BC strictly depends on the molecular subtype. The less aggressive hormone-positive subtype is treated with adjuvant endocrine therapy (AET), which causes both physical and psychological side effects. This condition strongly impacts the adherence and persistence of AET among oncologic patients. Moreover, viral infections also constitute a serious problem for public health. Despite their efficacy, antiviral agents present several therapeutic limits. Accordingly, in the present work, we investigated the antitumor and antiviral activities of Orobanche crenata Forssk. (O. crenata), a parasitic plant, endemic to the Mediterranean basin, traditionally known for its beneficial properties for human health. METHODS: The MTT assay was carried out to evaluate the cytotoxic effect of O. crenata leaf extract (OCLE) on human breast cancer cells (MCF-7 and MDA-MB-231) and the primary HFF-1 cell line. The lactic dehydrogenase (LDH) assay was performed on MCF-7 cells to analyze necrotic cell death. The antioxidant effect of OCLE was evaluated by intracellular determination of the reactive oxygen species and thiol groups, by DPPH and ABTS assays. The antiviral activity of OCLE was determined against Poliovirus 1, Echovirus 9, Human respiratory syncytial virus, Adenovirus type 2 and type 5, Coxsackievirus B1 (CoxB1) and B3 (CoxB3), Herpes simplex type 1 (HSV-1) and type 2 (HSV-2), and ß-Coronavirus by the plaque reduction assay. RESULTS: The extract, after 24 h of incubation, did not affect MDA-MB-231 and HFF-1 cell viability. However, at the same time point, it showed a dose-dependent inhibitory effect on MCF-7 cells, with an increase in LDH release. OCLE exhibited free radical scavenging activity and significantly increased non-protein thiol levels in MCF-7 cells. OCLE effectively inhibited HSV-1, HSV-2, CoxB1, and CoxB3 replication. CONCLUSIONS: The overall results showed an interesting inhibitory effect of OCLE on both MCF-7 cell survival and viral replication.

Stromal and endothelial herpes simplex virus keratitis reactivation in the convalescent period of COVID-19 - A case report.

A 73-year-old lady presented with a white spot and redness in the left eye for 1 month and had been treated elsewhere as a case of fungal keratitis. She had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection 2 months before. Her past ocular history and examination gave a probable diagnosis of herpetic stromal and endothelial keratitis. She responded to oral acyclovir and topical steroid, leading to resolution of stromal edema and inflammation. Anterior chamber fluid polymerase chain reaction (PCR) confirmed pathogen herpes simplex virus (HSV)-1. HSV ocular reactivation after coronavirus disease 2019 (COVID-19) has been reported currently. The present report will add knowledge about this potential opportunistic ophthalmic infection during the recovery phase of COVID-19 disease.

HSV-1 reactivation is associated with an increased risk of mortality and pneumonia in critically ill COVID-19 patients.

BACKGROUND: Data in the literature about HSV reactivation in COVID-19 patients are scarce, and the association between HSV-1 reactivation and mortality remains to be determined. Our objectives were to evaluate the impact of Herpes simplex virus (HSV) reactivation in patients with severe SARS-CoV-2 infections primarily on mortality, and secondarily on hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP) and intensive care unit-bloodstream infection (ICU-BSI). METHODS: We conducted an observational study using prospectively collected data and HSV-1 blood and respiratory samples from all critically ill COVID-19 patients in a large reference center who underwent HSV tests. Using multivariable Cox and cause-specific (cs) models, we investigated the association between HSV reactivation and mortality or healthcare-associated infections. RESULTS: Of the 153 COVID-19 patients admitted for ≥ 48 h from Feb-2020 to Feb-2021, 40/153 (26.1%) patients had confirmed HSV-1 reactivation (19/61 (31.1%) with HSV-positive respiratory samples, and 36/146 (24.7%) with HSV-positive blood samples. Day-60 mortality was higher in patients with HSV-1 reactivation (57.5%) versus without (33.6%, p = 0.001). After adjustment for mortality risk factors, HSV-1 reactivation was associated with an increased mortality risk (hazard risk [HR] 2.05; 95% CI 1.16-3.62; p = 0.01). HAP/VAP occurred in 67/153 (43.8%) and ICU-BSI in 42/153 (27.5%) patients. In patients with HSV-1 reactivation, multivariable cause-specific models showed an increased risk of HAP/VAP (csHR 2.38, 95% CI 1.06-5.39, p = 0.037), but not of ICU-BSI. CONCLUSIONS: HSV-1 reactivation in critically ill COVID-19 patients was associated with an increased risk of day-60 mortality and HAP/VAP.

Enhanced Antiviral Function of Magnesium Chloride-Modified Heparin on a Broad Spectrum of Viruses.

Previous studies reported on the broad-spectrum antiviral function of heparin. Here we investigated the antiviral function of magnesium-modified heparin and found that modified heparin displayed a significantly enhanced antiviral function against human adenovirus (HAdV) in immortalized and primary cells. Nuclear magnetic resonance analyses revealed a conformational change of heparin when complexed with magnesium. To broadly explore this discovery, we tested the antiviral function of modified heparin against herpes simplex virus type 1 (HSV-1) and found that the replication of HSV-1 was even further decreased compared to aciclovir. Moreover, we investigated the antiviral effect against the new severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and measured a 55-fold decreased viral load in the supernatant of infected cells associated with a 38-fold decrease in virus growth. The advantage of our modified heparin is an increased antiviral effect compared to regular heparin.

High rate of HSV-1 reactivation in invasively ventilated COVID-19 patients: Immunological findings.

SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome with the need of invasive ventilation. Pulmonary herpes simplex-1 (HSV-1) reactivation in invasively ventilated patients is a known phenomenon. To date very little is known about the frequency and the predisposing factors of HSV-1 reactivation in COVID-19. Therefore, we evaluated our cohort of invasively ventilated COVID-19 patients with severe pneumonia for HSV-1 in respiratory specimens and combined these results with functional immunomonitoring of the peripheral blood. Tracheal secretions and bronchial lavages were screened by PCR for HSV-1 positivity. Comprehensive immunophenotyping and quantitative gene expression analysis of Interferon-stimulated genes (IFI44L, MX1, RSAD2, ISIG15 and IFIT1) and IL-1 beta were performed in whole blood. Time course of infection beginning at symptom onset was grouped into three phases ("early" phase 1: day 1-10, "middle" phase 2: day 11-30 and "late" phase 3: day 31-40). Pulmonary HSV-1 reactivation was exclusively observed in the later phases 2 and 3 in 15 of 18 analyzed patients. By FACS analysis a significant increase in activated CD8 T cells (CD38+HLADR+) in phase 2 was found when compared with phase 1 (p<0.05). Expression of Interferon-stimulated genes (IFI44L, RSAD2 ISIG15, MX1, IFIT1) was significantly lower after HSV-1 detection than before. Taken together, reactivation of HSV-1 in the later phase of SARS-CoV-2- infection occurs in parallel with a drop of antiviral innate responsiveness as shown by decreased expression of Interferon-stimulated genes and a concurrent increase of highly activated CD38+HLADR+ CD8 T cells.

HSV-1 and Zika Virus but Not SARS-CoV-2 Replicate in the Human Cornea and Are Restricted by Corneal Type III Interferon.

Here, we report our studies of immune-mediated regulation of Zika virus (ZIKV), herpes simplex virus 1 (HSV-1), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the human cornea. We find that ZIKV can be transmitted via corneal transplantation in mice. However, in human corneal explants, we report that ZIKV does not replicate efficiently and that SARS-CoV-2 does not replicate at all. Additionally, we demonstrate that type III interferon (IFN-λ) and its receptor (IFNλR1) are expressed in the corneal epithelium. Treatment of human corneal explants with IFN-λ, and treatment of mice with IFN-λ eye drops, upregulates antiviral interferon-stimulated genes. In human corneal explants, blockade of IFNλR1 enhances replication of ZIKV and HSV-1 but not SARS-CoV-2. In addition to an antiviral role for IFNλR1 in the cornea, our results suggest that the human cornea does not support SARS-CoV-2 infection despite expression of ACE2, a SARS-CoV-2 receptor, in the human corneal epithelium.

Nanoscale Structural Characterization of Individual Viral Particles Using Atomic Force Microscopy Infrared Spectroscopy (AFM-IR) and Tip-Enhanced Raman Spectroscopy (TERS).

Viruses are infections species that infect a large spectrum of living systems. Although displaying a wide variety of shapes and sizes, they are all composed of nucleic acid encapsulated into a protein capsid. After virions enter the host cell, they replicate to produce multiple copies of themselves. They then lyse the host, releasing virions to infect new cells. The high proliferation rate of viruses is the underlying cause of their fast transmission among living species. Although many viruses are harmless, some of them are responsible for severe diseases such as AIDS, viral hepatitis, and flu. Traditionally, electron microscopy is used to identify and characterize viruses. This approach is time- and labor-consuming, which is problematic upon pandemic proliferation of previously unknown viruses, such as H1N1 and COVID-19. Herein, we demonstrate a novel diagnosis approach for label-free identification and structural characterization of individual viruses that is based on a combination of nanoscale Raman and infrared spectroscopy. Using atomic force microscopy-infrared (AFM-IR) spectroscopy, we were able to probe structural organization of the virions of Herpes Simplex Type 1 viruses and bacteriophage MS2. We also showed that tip-enhanced Raman spectroscopy (TERS) could be used to reveal protein secondary structure and amino acid composition of the virus surface. Our results show that AFM-IR and TERS provide different but complementary information about the structure of complex biological specimens. This structural information can be used for fast and reliable identification of viruses. This nanoscale bimodal imaging approach can be also used to investigate the origin of viral polymorphism and study mechanisms of virion assembly.