Human parvovirus B19 (B19V) is a single-stranded non-enveloped DNA virus of the family Parvoviridae that has been associated with various autoimmune disorders. Systemic sclerosis (SSc) is an autoimmune connective tissue disorder with high mortality and has been linked to B19V infection. However, the precise mechanism underlying the B19V contribution to the development of SSc remains uncertain. This study investigated the impacts of the functional B19V-VP1 unique region (VP1u) in macrophages and bleomycin (BLE)-induced SSc mice. Cell experimental data showed that significantly decreased viability and migration of both B19V-VP1u-treated U937 and THP-1 macrophages are detected in the presence of celastrol. Significantly increased MMP9 activity and elevated NF-kB, MMP9, IL-6, TNF-α, and IL-1β expressions were detected in both B19V-VP1u-treated U937 and THP-1 macrophages. Conversely, celastrol revealed an inhibitory effect on these molecules. Notably, celastrol intervened in this pathogenic process by suppressing the sPLA2 activity of B19V-VP1u and subsequently reducing the inflammatory response. Notably, the administration of B19V-VP1u exacerbated BLE-induced skin fibrosis in mice, with augmented expressions of TGF-β, IL-6, IL-17A, IL-18, and TNF-α, ultimately leading to α-SMA and collagen I deposits in the dermal regions of BLE-induced SSc mice. Altogether, this study sheds light on parvovirus B19 VP1u linked to scleroderma and aggravated dermal fibrosis.

Neutrophil extracellular traps (NETs) formation, namely NETosis, is implicated in antiphospholipid syndrome (APS)-related thrombosis in various autoimmune disorders such as systemic lupus erythematosus (SLE) and APS. Human parvovirus B19 (B19V) infection is closely associated with SLE and APS and causes various clinical manifestations such as blood disorders, joint pain, fever, pregnancy complications, and thrombosis. Additionally, B19V may trigger the production of autoantibodies, including those against nuclear and phospholipid components. Thus, exploring the connection between B19V, NETosis, and thrombosis is highly relevant. An in vitro NETosis model using differentiated HL-60 neutrophil-like cells (dHL-60) was employed to investigate the effect of B19V-VP1u IgG on NETs formation. A venous stenosis mouse model was used to test how B19V-VP1u IgG-mediated NETs affect thrombosis in vivo. The NETosis was observed in the dHL-60 cells treated with rabbit anti-B19V-VP1u IgG and was inhibited in the presence of either 8-Br-cAMP or CGS216800 but not GSK484. Significantly elevated reactive oxygen species (ROS), myeloperoxidase (MPO), and citrullinated histone (Cit-H3) levels were detected in the dHL60 treated with phorbol myristate acetate (PMA), human aPLs IgG and rabbit anti-B19V-VP1u IgG, respectively. Accordingly, a significantly larger thrombus was observed in a venous stenosis-induced thrombosis mouse model treated with PMA, human aPLs IgG, rabbit anti-B19V-VP1u IgG, and human anti-B19V-VP1u IgG, respectively, along with significantly increased amounts of Cit-H3-, MPO- and CRAMP-positive infiltrated neutrophils in the thrombin sections. This research highlights that anti-B19V-VP1u antibodies may enhance the formation of NETosis and thrombosis and implies that managing and treating B19V infection could lower the risk of thrombosis.

Background/Objectives: Influenza is a major global health challenge, causing thousands of deaths annually. Antiviral drugs, particularly oseltamivir, a neuraminidase inhibitor, have become essential therapeutic options due to their oral bioavailability and efficacy. Previous studies suggest a potential association between oseltamivir use and the onset of diabetes mellitus. However, further investigation is needed to establish a definitive link. Methods: This retrospective cohort study utilized data from the Taiwan National Health Insurance Research Database (NHIRD), including 1,631,968 patients (815,984 oseltamivir users) between 1 January 2009 and 28 December 2018. All statistical analyses were performed using SAS 9.4M8 software (SAS Institute Inc., Cary, NC, USA). Results: Cox proportional hazards regression and multivariate analyses revealed a statistically significant association between oseltamivir use and overall diabetes risk (HR = 1.027, p = 0.0186). While no significant association was observed for Type 1 diabetes (HR = 1.021; p = 0.06795), oseltamivir users showed a higher incidence of Type 2 diabetes (HR = 1.024; p < 0.05). Oseltamivir was also linked to increased risks of comorbidities, including dyslipidemia (HR = 1.295, p < 0.0001), chronic liver disease (HR = 1.446, p < 0.0001), hypertension (HR = 1.586, p < 0.0001), and obesity (HR = 2.949, p < 0.0001). Conclusions: Oseltamivir is associated with an increased risk of Type 2 diabetes but not Type 1, and related comorbidities.

Background/Objectives: Evidence has indicated an increased risk of stroke in individuals with influenza infection, and the administration of Oseltamivir revealed a lower stroke risk in these individuals. However, the impacts of Oseltamivir and stroke remain limited. Methods: The data used in this retrospective cohort study were extracted from the Taiwan National Health Insurance Research Database (NHIRD), which included 281,420 Oseltamivir users and 13,394,652 patients between 1 January 2009 and 31 December 2018. The Oseltamivir group was younger (age 40.1 ± 15.3 years) and had a lower prevalence of comorbidities compared to the non-user group (age 46.2 ± 16.0 years). Stroke incidence and mortality were compared using multivariable Cox proportional hazards models. Results: We compared the incidence of ischemic stroke among individuals without a history of ischemic stroke, stratified by Oseltamivir use. After adjusting for age, sex, and comorbidities, Oseltamivir use was not associated with a significantly different risk of stroke (adjusted HR = 1.02, 95% CI: 0.96–1.08; p = 0.511). The mortality among individuals with a history of ischemic stroke, being Oseltamivir users (n = 2502), exhibited a lower cumulative mortality rate compared to non-users (4.08% vs. 6.45%). The association remained significant after multivariable adjustment, with an adjusted hazard ratio for mortality of 0.74 (95% CI: 0.61–0.89; p = 0.002). Conclusions: In this large population-based cohort of patients without a history of ischemic stroke, Oseltamivir use during influenza infection was not associated with stroke incidence after adjusting for age, sex, and comorbidities. Notably, Oseltamivir use in patients with a history of ischemic stroke was associated with reduced all-cause mortality, suggesting a potential survival benefit that warrants further investigation.