Antiviral alternatives against important members of the subfamily Parvovirinae: a review.

Parvoviruses are responsible for multiple diseases, and there is a critical need for effective antiviral therapies. Specific antiviral treatments for parvovirus infections are currently lacking, and the available options are mostly supportive and symptomatic. In recent years, significant research efforts have been directed toward understanding the molecular mechanisms of parvovirus replication and identifying potential targets for antiviral interventions. This review highlights the structure, pathogenesis, and treatment options for major viruses of the subfamily Parvovirinae, such as parvovirus B19 (B19V), canine parvovirus type 2 (CPV-2), and porcine parvovirus (PPV) and also describes different approaches in the development of antiviral alternatives against parvovirus, including drug repurposing, serendipity, and computational tools (molecular docking and artificial intelligence) in drug discovery. These advances greatly increase the likelihood of discoveries that will lead to potent antiviral strategies against different parvovirus infections.

Clinical and inflammatory response to antiviral treatments in dogs with parvoviral enteritis.

BACKGROUND: Canine parvoviral enteritis (CPE) is a fatal disease worldwide. The treatment of CPE is based mainly on supportive and symptomatic treatment. Antiviral addition to the treatment may result in a higher survival. OBJECTIVES: This study evaluated the effects of antiviral treatments with a standardized treatment (ST) on the clinical and inflammatory response of dogs with naturally occurring CPE. METHODS: Twenty-eight dogs with CPE caused by canine parvovirus type 2 were divided randomly into treatment groups. The ST group received fluid, antibiotic, antiemetic, and deworming treatments. The antiviral treatment groups received the same ST with an additional antiviral drug, recombinant feline interferon omega (rFeIFN-ω), oseltamivir (OSEL) or famciclovir (FAM). RESULTS: Compared to the healthy control, the tumor necrosis factor-α, interleukin-1ß, interferon (IFN)-α, IFN-γ, haptoglobin, and C-reactive protein values were high (p < 0.05) on day zero. At presentation, mild lymphopenia, neutropenia, and a high neutrophil to lymphocyte (LYM) ratio (NLR) were also observed. Adding rFeIFN-ω to the ST produced the best improvement in the clinical score with a decreased NLR, while leucocytes remained low and inflammatory markers stayed high on day three. The survival rates of the groups were 85.7% in ST+IFN, 71.4% in ST+OSEL, 71.4% in ST+FAM, and 57.1% in ST groups on day seven. CONCLUSIONS: Antiviral drugs may be valuable in treating CPE to improve the clinical signs and survival. In addition, the decrease in NLR in favor of LYM may be an indicator of the early prognosis before the improvement of leukocytes, cytokines, and acute phase proteins in CPE.

Algorithm for laboratory diagnostics of parvoviral infection in risk groups.

Parvovirus infection (PVI) is widespread, characterized by airborne, bloodborne and vertical transmission routes. Parvovirus B19 (PVB19) exhibits tropism to erythropoietic cells. According to the increased likelihood principle of PVB19 infection and the severity of the consequences, immunocompromised individuals, especially those with hematological manifestations of diseases, are in increased risk group. Based on the own research results and analysis of the published data, we have proposed specific algorithms for PVI laboratory testing in individual risk groups, taking into account the peculiarities of the development and infection manifestation in each group: in HIV-infected patients, in oncohematological patients with to whom allogeneic hematopoietic stem cell transplantation (allo-HSCT) have been prescribed (blood and bone marrow recipients), as well as in patients with chronic anemia of parasitic etiology. For each group, the main clinical or laboratory marker, treatment procedure, or patient physiological parameters have been determined, based on which it was recommended to test for PVI. For HIV-infected patients, the main criterion for PVI testing is persistent anemia. For oncohematological patients, the basis for PVI testing is allo-HSCT procedure, which is planned or performed for this particular patient. For malaria patients, the patient's age was considered as major criterion, since in malaria and PVI coinfected young children can lead to a fatal outcome. The proposed PVI diagnostics algorithms usein risk groups can help to predict the severe course of underlying disease associated with PVB19 infection, and timely correct the therapy used.

Interferon-ß Suppresses Transcriptionally Active Parvovirus B19 Infection in Viral Cardiomyopathy: A Subgroup Analysis of the BICC-Trial.

Human parvovirus B19 (B19V) is the predominant virus currently detected in endomyocardial biopsies (EMBs). Recent findings indicate that, specifically, transcriptionally active B19V with detectable viral RNA is of prognostic relevance in inflammatory viral cardiomyopathy. We aimed to evaluate B19V replicative status (viral RNA) and beneficial effects in a sub-collective of the prospective randomized placebo-controlled phase II multi-center BICC-Trial (Betaferon In Chronic Viral Cardiomyopathy) after interferon beta-1b (IFN-ß) treatment. EMBs of n = 64 patients with B19V mono-infected tissue were retrospectively analyzed. Viral RNA could be detected in n = 18/64 (28.1%) of B19V DNA positive samples (mean age 51.7 years, 12 male), of whom n = 13 had been treated with IFN-ß. Five patients had received placebo. PCR analysis confirmed in follow-up that EMBs significantly reduced viral RNA loads in n = 11/13 (84.6%) of IFN-ß treated patients (p = 0.001), independently from the IFN-ß dose, in contrast to the placebo group, where viral RNA load was not affected or even increased. Consequently, a significant improvement of left ventricular ejection fraction (LVEF) after treatment with IFN-ß was observed (LVEF mean baseline 51.6 ± 14.1% vs. follow-up 61.0 ± 17.5%, p = 0.03). In contrast, in the placebo group, worsening of LVEF was evaluated in n = 4/5 (80.0%) of patients. We could show for the first-time the beneficial effects from treatment with IFN-ß, suppressing B19V viral RNA and improving the hemodynamic course. Our results need further verification in a larger prospective randomized controlled trial.

Parvovirus B19-induced severe anemia in heart transplant recipient: A case report.

RATIONALE: Human parvovirus B19 (B19V) is a non-enveloped single-stranded DNA virus associated with a variety of human diseases. Reports of B19V infection after cardiac transplantation are relatively rare. PATIENT CONCERNS: We report a case of a 48-year-old women who underwent orthotopic heart transplant for dilated cardiomyopathy. She developed an anemia after cardiac transplantation. Anemia was most severe 2 months after surgery, with a decrease in reticulocyte count. Serological DNA test for parvovirus B19V was performed and the result was positive. DIAGNOSES: B19V infection. INTERVENTIONS AND OUTCOMES: Intravenous immunoglobulin administration resulted in a resolution of the anemia. The patient's blood test results showed a normal hemoglobin and reticulocyte count 1 year after surgery. LESSONS: Patients with parvovirus B19V infection may develop severe anemia after heart transplantation. The diagnosis mainly relies on viral DNA detection. Intravenous immunoglobulin is an effective treatment for viral infection.

Biomimetic amphiphilic FAAP NPs nanoparticles: Synthesis, characterization and antivirus activity.

Antiviral agents based on natural products have attracted substantial attention in clinical applications for their distinct biological activities,molecular structuralmultiformities, and low biotoxicities. Ferulic acid (FA) with apigenin propaneto form an esterified FA derivative (FAAP).Herein, we designed a CsPbBr3-modified chitosan oligosaccharide, a biomimetic nanoplatform that could load with FAAP. After self-assembly by combining FAAP with CsPbBr3-modified chitosan oligosaccharide (FAAP NPs), the resulting nanoparticles (FAAP NPs) showed high antioxidant and anti-inflammatory activities for enhancing the inhibition of porcineparvovirus.FAAP NPs exhibited no signs of acute toxicity in vitro or in vivo. DPPH and ABST are widely used for quantitative determination of antioxidant capacity. FAAP NPs exhibited excellent DPPH and ABTS radical scavenging abilities. In addition, we found that FAAP NPs inhibited PPV infection-induced PK-15 cell apoptosis, which was associated with regulating antioxidant and anti-inflammatory signaling pathways. Importantly, we showed that FAAP NPs blocked PPV infection-induced mitochondrial apoptosis in PK-15 cells via a p53/BH3 domain molecular-dependent mechanism.

Lipid metabolism is a novel and practical source of potential targets for antiviral discovery against porcine parvovirus.

How parvovirus manipulates host lipid metabolism to facilitate its propagation, pathogenicity and consequences for disease, is poorly characterized. Here, we addressed this question using porcine parvovirus (PPV) to understand the complex interactions of parvovirus with lipid metabolism networks contributing to the identification of novel and practical antiviral candidates. PPV significantly alters host lipid composition, characteristic of subclasses of phospholipids and sphingolipids, and induces lipid droplets (LDs) formation via regulating calcium-independent PLA2ß (iPLA2ß), phospholipase Cγ2 (PLCγ2), diacylglycerol kinase α (DKGα), phosphoinositide 3-kinase (PI3K), lysophosphatidic acid acyltransferase θ (LPAATθ), and sphingosine kinases (SphK1 and SphK2). PPV utilizes and exploits these enzymes as well as their metabolites and host factors including MAPKs (p38 and ERK1/2), protein kinase C (PKC) and Ca2+ to induce S phase arrest, apoptosis and incomplete autophagy, all benefit to PPV propagation. PPV also suppresses prostaglandin E2 (PGE2) synthesis via downregulating cyclooxygenase-1 (COX-1), indicating PPV hijacks COX-1-PGE2 axis to evade immune surveillance. Our data support a model where PPV to establishes an optimal environment for its propagation and pathogenicity via co-opting host lipid metabolism, being positioned as a source of potential targets.

Postnatal IVIG treatment for persistent anaemia in neonate due to congenital parvovirus infection.

Congenital parvovirus B19 infection is a rare but serious condition that can result in hydrops fetalis and fetal death. Due to the virus' cytotoxic effect on fetal red blood cell precursors, postnatal infection can cause a neonatal viremia and secondary pure red cell aplasia. Here, we describe a case of congenital parvovirus infection in a preterm infant complicated by hydrops fetalis and chronic anaemia that responded to postnatal treatment with intravenous immunoglobulin administered on day of life 44. After treatment, the anaemia resolved as the neonate exhibited interval increases in haemoglobin, haematocrit and reticulocyte count with no subsequent need for red blood cell transfusions.

Effects of astragalus polysaccharide on intestinal inflammatory damage in goslings infected with gosling plague.

1. This study explored the effects of Astragalus membranaceus polysaccharide (APS) on intestinal inflammatory damage of goslings infected with parvovirus ('gosling plague').2. A total of 90 healthy goslings were randomly divided into three groups; control, infected or APS treated, respectively. Goslings in the infection and APS treatment groups were inoculated with 0.3 ml allantoic fluid containing goose parvovirus (ELD50 = 1 × 103/0.3 ml) by intramuscular injection and the control group were injected with saline (0.3 ml) twice a day for 15 days.3. Blood serum and the jejunum were collected at 5, 10 and 15 days after the start of the experiment to detect the activities of SOD and GSH-Px, levels of MDA, sIgA, IL-1ß, IL-6 and TNF-α, the mRNA expression of IL-1ß, IL-6, LITAF, NF-κB, COX-2 and PGE2, pathological damage in the jejunum and serum IgG, IgM, C3, C4, IFN-γ levels.4. After APS treatment, SOD and GSH-Px activities increased, MDA content decreased; sIgA, IL-1ß, IL-6 and TNF-α protein content, and IL-1ß, IL-6, LITAF, NF-κB, COX-2 and PGE2 mRNA expression decreased in the jejunal tissue, serum IgG, IgM, C3, C4, IFN-γ significantly increased and pathological damage of jejunum significantly improved.5. In conclusion, APS reduced intestinal inflammatory damage in goslings infected with parvovirus by improving the immune and antioxidant functions of goslings.

Pure Red Cell Aplasia Related to Parvovirus B19 Infection in Simultaneous Pancreas and Kidney Recipient: A Case Report.

A 42-year-old woman received a simultaneous pancreas and kidney transplantation (SPK). Immunosuppression consisted of tacrolimus modified release, prednisone, mycophenolate mofetil (MMF), and thymoglobulin as induction. The function of both grafts was good. Eight months after SPK, the patient suffered from weakness and arthralgia. Normocytic anemia with reticulocytopenia was revealed. In a bone marrow examination, giant pronormoblasts were found. Immunohistochemical staining of bone marrow and serum examination were positive for Parvovirus B19 (Parvo B19) confirming diagnosis of pure red cell aplasia (PRCA).The treatment consisted of MMF withdrawal, red-cell transfusions, immunoglobulins subcutaneously (SCIg) and immunosuppression reduction. Rapid improvement was observed with the rise of reticulocyte count and hemoglobin. Two months after the achievement of remission, the low dose of everolimus was added considering the high risk of rejection and antiviral potential of mTOR inhibitors. Three months later, PRCA relapsed. Retherapy with SCIg was still effective. Subsequent SCIg was supplemented due to low reticulocyte count and recurrent herpes zoster. The replication of Parvo B19 was persistent (serum qualitative test). Everolimus was withdrawn after 9 months of therapy due to the recurrence of PRCA and serious infections. The observation period after PRCA diagnosis lasts for 15 months. The patient is in good condition with no anemia and excellent grafts function. In conclusion, pure red cell aplasia related to Parvo B19 infection should be considered in transplant recipients with normocytic anemia and reticulocytopenia. The treatment with immunoglobulin G and immunosuppression reduction is an effective therapy. The role of everolimus in Parvo B19 infection requires future studies.

Ferulic acid isolated from propolis inhibits porcine parvovirus replication potentially through Bid-mediate apoptosis.

Propolis from honeybee hives, which is a traditional Chinese medicine, is widely used in veterinary clinics. Many compounds have been identified and isolated from propolis. Ferulic acid (FA), one of the propolis components, previous studies have proven that it has antiviral effects. To study the mechanism of FA antiviral effects, experiments such as immunofluorescence, quantitative real-time PCR and immunoblotting were introduced. In porcine kidney (PK-15) cells, PPV infection induced the expression of the proapoptotic genes Bid, Bad, Bim and Bak, disrupted mitochondrial membrane potential, promoted mitochondria-mediated, caspase-dependent apoptotic signaling and induced apoptosis. Furthermore, the infected PK-15 cells had increased intracellular reactive oxygen species (ROS) generation. FA treatment, however, reversed these effects and increased cell viability. FA treatment also significantly decreased the PPV-induced expression of Bid, Cyt-c and Apaf-1, suggesting that ROS were involved in the activation of the mitochondria-mediated apoptosis pathway. This in vitro study showed that the antiviral activity of FA was probably associated with inhibiting the replication of PPV by blocking proapoptotic factors such as Bid, Bcl-2 and Mcl-1, and attenuating the mitochondria-mediated response by inhibiting the activation of the Bid-related signaling pathway. Pharmacological inhibitors inhibited PPV-induced apoptosis by blocking Bid, and also suppressed the expression of Caspase family proteins in ppv-induced apoptosis. Taken together, our results suggested that PPV induced PK-15 cell apoptosis via activation of Bid and Bid-related signaling pathways and that the mitochondria act as the mediators of these pathways. FA effectively and extensively attenuated this PPV action, and thus is a potential antiviral agent against PPV.

Infecção por parvovírus B19 em receptores de transplante renal: série de caso / Parvovirus B19 infection in kidney transplant recipients: a case series

Os receptores de transplante renal são mais suscetíveis a infecções, entre elas o parvovírus B19, que pode ser transmitido por via respiratória, adquirido por meio do enxerto ou por reativação de infecção latente. A anemia normocítica normocrômica, com diminuição dos reticulócitos e resistência ao tratamento com eritropoietina, é a principal forma de apresentação da infecção por parvovírus B19 em transplante renal. O diagnóstico requer alto índice de suspeição clínica e realização de testes diagnósticos selecionados. Tratamento com imunoglobulina e suspensão dos imunossupressores durante a infecção mostraram-se eficazes. Os autores relatam sua experiência com cinco casos de infecção por parvovírus B19 em receptores de transplante renal de um hospital universitário. Os aspectos clínicos, diagnósticos e terapêuticos são revistos.

Kidney transplant recipients are more susceptible to infections, including by parvovirus B19, spread through the respiratory tract, acquired through the graft or reactivation of latent infection. Normocytic normochromic anemia, with decreased reticulocytes and resistance to erythropoietin treatment, is the most common presentation of Parvovirus B19 infection in renal transplant. Diagnosis requires a higher clinical suspicion and the performance of selected diagnostic tests. Treatment with immunoglobulin and suspension of immunosuppressive therapy during the infection may be effective. The authors report five cases of PB19 infection in kidney transplant patients at a hospital. The clinical, diagnostic, and treatment features are reviewed.

New Insights into Parvovirus Research.

The family Parvoviridae includes an ample and most diverse collection of viruses. Exploring the biological diversity and the inherent complexity in these apparently simple viruses has been a continuous commitment for the scientific community since their first discovery more than fifty years ago. The Special Issue of 'Viruses' dedicated to the 'New Insights into Parvovirus Research' aimed at presenting a 'state of the art' in many aspects of research in the field, at collecting the newest contributions on unresolved issues, and at presenting new approaches exploiting systemic (-omic) methodologies.

Expectoration of bronchial casts in association with Ramipril treatment.

We report of a 26-year-old female patient who was referred to our centre with congestive heart failure (CHF). Acute myocarditis with a high Parvovirus B19 virus load was diagnosed by myocardial biopsy. CHF improved after start of ramipril 5 mg/d, metoprolol, diuretics, immunoglobins, and a 24-hour infusion of levosimendan. Soon after initiation of medical therapy, the patient started to expectorate bronchial casts with varying frequencies (three times per week to five times daily). Thorough pneumological workup, including histology of the casts, microbiology, and a CT scan of the lungs, did not reveal any cause for bronchial cast formation. Inhalative corticoids were started without any benefit. Two years later, cardiac catheterisation demonstrated normalised left ventricular function. LV end-diastolic pressure, however, was still elevated at 14 mmHg. Endomyocardial biopsies at this time were negative for virus genome. Finally, we changed afterload reduction therapy from ramipril to candesartan. Within 24 hours, expectoration of bronchial casts terminated. Four weeks later, re-exposition to ramipril prompted immediate re-appearance of cast formation, which again stopped with switching back to candesartan. Finally, we were to prove that treatment with ramipril resulted in bronchial cast formation in this patient.

Parvoviral infection with systemic impact and renal consequences.

Parvovirus infection is usually asymptomatic especially in immunocompetent adults. When symptomatic it can range from mild to life threatening depending on the patient's age and comorbidities. We report a case of a 40-year-old male patient with parvovirus infection who presented a purpuric rash in distal extremities, acute kidney injury, type II mixed cryoglobulinaemia and hypocomplementaemia. His renal biopsy showed a mesangioproliferative glomerulonephritis with positive immunoreactivity to C3, IgM and C1q. Parvovirus B19 was detected in the biopsy tissue by PCR. He was treated with prednisolone with total remission after 1 month. We discuss the diagnosis of kidney lesion due to parvovirus in an immunocompetent person, which is a very rare condition and its association with the cryoglobulinaemia diagnosis.

Human parvovirus B19 in solid organ transplantation: Guidelines from the American society of transplantation infectious diseases community of practice.

Clinical manifestations of human parvovirus B19 infection can vary widely and may be atypical in solid organ transplant (SOT) recipients. However, disease is apparent when there is destruction of erythrocyte progenitor cells leading to severe acute or chronic anemia with lack of an appropriate reticulocyte response in the setting of active parvovirus B19 infection. Serology may not reliably establish the diagnosis. High-level viremia is more likely to be associated with symptomatic disease. Conversely, ongoing DNAemia after infection may not be clinically significant, if detected at low levels. Despite lack of robust data, intravenous immunoglobulin (IVIG) is frequently used for the treatment of SOT recipients with symptomatic parvovirus B19 infection. Although the optimal dosage and duration of IVIG is not known, most patients receive a total of 2 g/kg over a period of 2-5 days. A daily dose of 1 g/kg or more seems to be associated with higher incidence of toxicity. Application of standard and droplet isolation precautions remains the cornerstone for preventing human parvovirus B19 transmission. Additional research is needed to assess the efficacy of current and novel therapies and to develop a safe and effective parvovirus B19 vaccine.

Kawasaki disease triggered by parvovirus infection: an atypical case report of two siblings.

BACKGROUND: There are reports of the familial occurrence of Kawasaki disease but only a few reports described Kawasaki disease in siblings. However, the familial cases were not simultaneous. In these patients the idea of infective agents as trigger must be considered. CASE PRESENTATION: We describe two siblings with atypical presentations of Kawasaki disease; the sister was first diagnosed as having parvovirus infection with anemia and the brother was diagnosed as having myocarditis. The first patient was a 9-month-old Caucasian girl with fever, conjunctivitis, rash, and pharyngitis, and later she had cervical adenopathy, diarrhea and vomiting, leukocytosis, and anemia, which were explained by positive immunoglobulin M against parvovirus. However, coronary artery lesions with aneurysms were documented at day 26 after fever onset. An infusion of intravenous immunoglobulin and high doses of steroids were not efficacious to resolve the coronary lesions. She was treated with anakinra, despite a laboratory test not showing inflammation, with prompt and progressive improvement of coronary lesions. Her 7-year-old Caucasian brother presented vomiting and fever at the same time as she was unwell, which spontaneously resolved after 4 days. Four days later, he again presented with fever with abdominal pain, associated with tachypnea, stasis at the pulmonary bases, tachycardia, gallop rhythm, hypotension, secondary anuria, and hepatomegaly. An echocardiogram revealed a severe hypokinesia, with a severe reduction of the ejection fraction (20%). He had an increase of immunoglobulin M anti-parvovirus, tested for the index case of his sister, confirming the suspicion of viral myocarditis. He received dopamine, dobutamine, furosemide plus steroids, with a progressive increase of the ejection fraction to 50%. However, evaluating his sister's history, the brother showed a myocardial dysfunction secondary to Kawasaki shock syndrome. CONCLUSIONS: We report on familial Kawasaki disease in two siblings which had the same infectious trigger (a documented parvovirus infection). The brother was diagnosed as having post-viral myocarditis. However, in view of the two different and simultaneous evolutions, the girl showed Kawasaki disease with late coronary artery lesions and aneurysms, whereas the brother showed Kawasaki shock syndrome with myocardial dysfunction. We stress the effectiveness of anakinra in non-responder Kawasaki disease and the efficacy on coronary aneurysms.