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Pathogenicity and virulence of human adenovirus F41: Possible links to severe hepatitis in children.Virulence Dec 2023Over 100 human adenoviruses (HAdVs) have been isolated and allocated to seven species, A-G. Species F comprises two members-HAdV-F40 and HAdV-F41. As their primary site... (Review)
Review
Over 100 human adenoviruses (HAdVs) have been isolated and allocated to seven species, A-G. Species F comprises two members-HAdV-F40 and HAdV-F41. As their primary site of infection is the gastrointestinal tract they have been termed, with species A, enteric adenoviruses. HAdV-F40 and HAdV-F41 are a common cause of gastroenteritis and diarrhoea in children. Partly because of difficulties in propagating the viruses in the laboratory, due to their restrictions on growth in many cell lines, our knowledge of the properties of individual viral proteins is limited. However, the structure of HAdV-F41 has recently been determined by cryo-electron microscopy. The overall structure is similar to those of HAdV-C5 and HAdV-D26 although with some differences. The sequence and arrangement of the hexon hypervariable region 1 (HVR1) and the arrangement of the C-terminal region of protein IX differ. Variations in the penton base and hexon HVR1 may play a role in facilitating infection of intestinal cells by HAdV-F41. A unique feature of HAdV-F40 and F41, among human adenoviruses, is the presence and expression of two fibre genes, giving long and short fibre proteins. This may also contribute to the tropism of these viruses. HAdV-F41 has been linked to a recent outbreak of severe acute hepatitis "of unknown origin" in young children. Further investigation has shown a very high prevalence of adeno-associated virus-2 in the liver and/or plasma of some cohorts of patients. These observations have proved controversial as HAdV-F41 had not been reported to infect the liver and AAV-2 has generally been considered harmless.
Topics: Humans; Child; Child, Preschool; Adenoviruses, Human; Virulence; Cryoelectron Microscopy; Adenovirus Infections, Human; Hepatitis; Hepatitis A; Phylogeny
PubMed: 37543996
DOI: 10.1080/21505594.2023.2242544 -
Diseases (Basel, Switzerland) Sep 2023Respiratory infections constitute a major reason for infants and children seeking medical advice and visiting health facilities, thus remaining a significant public...
Respiratory infections constitute a major reason for infants and children seeking medical advice and visiting health facilities, thus remaining a significant public threat with high morbidity and mortality. The predominant viruses causing viral respiratory infections are influenza A and B viruses (Flu-A, Flu-B), respiratory syncytial virus (RSV), adenovirus and coronaviruses. We aimed to record the proportion of RSV, SARS-CoV-2, influenza A/B and adenovirus cases with rapid antigen tests and validate the results with RT-PCR assays of upper respiratory specimens with a wide range of viral loads and (co)-infection patterns in children. Clinical samples were collected from early symptomatic children (presenting with fever and/or cough and/or headache within 5-7 days). The surveillance program was conducted in five private pediatric dispensaries and one pediatric care unit, from 10 January 2023 to 30 March 2023 in central Greece. The total sample of specimens collected was 784 young children and infants, of which 383 (48.8%) were female and 401 were male (51.2%). The mean age of participants was 7.3 + 5.5 years. The sensitivity of the FLU A & B test was 91.15% (95% CI: 84.33-95.67%), and the specificity was 98.96% (95% CI: 97.86-99.58%). The sensitivity and specificity of the adenovirus and RSV test was {92.45% (95% CI: 81.79-97.91%), 99.32% (95% CI: 98.41-99.78%)} and {92.59% (95% CI: 75.71-99.09%), 99.47% (95% CI: 98.65-99.86%)} respectively. Lastly, the sensitivity of the SARS-CoV-2 test was 100.00% (95% CI: 79.41-100.00%) and the specificity was 99.74% (95% CI: 99.06-99.97%). We recorded a proportion of 14.3% and 3.44% for influenza A and B, respectively, followed by a proportion of 6.9% for adenovirus, a proportion of 3.7% for RSV, and finally, a proportion of 2.3% for SARS-CoV-2. The combination of a new multiple rapid test with multiple antigens will probably be a useful tool with a financial impact for health systems targeting the early detection and appropriate treatment of respiratory infections in emergency departments in primary health care facilities.
PubMed: 37754318
DOI: 10.3390/diseases11030122 -
Microbiology Spectrum Aug 2023Enteroviruses are one of the most abundant viruses causing mild to serious acute infections in humans and also contributing to chronic diseases like type 1 diabetes....
Enteroviruses are one of the most abundant viruses causing mild to serious acute infections in humans and also contributing to chronic diseases like type 1 diabetes. Presently, there are no approved antiviral drugs against enteroviruses. Here, we studied the potency of vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAF mutant-related melanoma, as an antiviral against enteroviruses. We showed that vemurafenib prevented enterovirus translation and replication at low micromolar dosage in an RAF/MEK/ERK-independent manner. Vemurafenib was effective against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect was related to a cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevented infection efficiently in acute cell models, eradicated infection in a chronic cell model, and lowered virus amounts in pancreas and heart in an acute mouse model. Altogether, instead of acting through the RAF/MEK/ERK pathway, vemurafenib affects the cellular PI4KB and, hence, enterovirus replication, opening new possibilities to evaluate further the potential of vemurafenib as a repurposed drug in clinical care. Despite the prevalence and medical threat of enteroviruses, presently, there are no antivirals against them. Here, we show that vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAF mutant-related melanoma, prevents enterovirus translation and replication. Vemurafenib shows efficacy against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect acts through cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevents infection efficiently in acute cell models, eradicates infection in a chronic cell model, and lowers virus amounts in pancreas and heart in an acute mouse model. Our findings open new possibilities to develop drugs against enteroviruses and give hope for repurposing vemurafenib as an antiviral drug against enteroviruses.
Topics: Animals; Mice; Humans; Vemurafenib; Enterovirus; 1-Phosphatidylinositol 4-Kinase; Proto-Oncogene Proteins B-raf; Melanoma; Protein Kinase Inhibitors; Enterovirus Infections; Mitogen-Activated Protein Kinase Kinases; Mutation
PubMed: 37436162
DOI: 10.1128/spectrum.00552-23 -
International Journal of Antimicrobial... May 2024Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem...
Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem cell transplantation (HSCT). Immunosuppressors are used universally to prevent graft-vs-host disease in HSCT and graft rejection in SOT. The long-term use of these drugs is associated with a high risk of infection, but there is also evidence of their specific interference with viral infection. This study evaluated the antiviral activity of immunosuppressors commonly used in clinical practice in SOT and HSCT recipients in vitro to determine whether their use could be associated with reduced risk of HAdV and HCMV infection. Cyclophosphamide, tacrolimus, cyclosporine, mycophenolic acid, methotrexate, everolimus and sirolimus presented antiviral activity, with 50% inhibitory concentration (IC) values at low micromolar and sub-micromolar concentrations. Mycophenolic acid and methotrexate showed the greatest antiviral effects against HAdV (IC=0.05 µM and 0.3 µM, respectively) and HCMV (IC=10.8 µM and 0.02 µM, respectively). The combination of tacrolimus and mycophenolic acid showed strong synergistic antiviral activity against both viruses, with combinatory indexes (CI) of 0.02 and 0.25, respectively. Additionally, mycophenolic acid plus cyclosporine, and mycophenolic acid plus everolimus/sirolimus showed synergistic antiviral activity against HAdV (CI=0.05 and 0.09, respectively), while methotrexate plus cyclosporine showed synergistic antiviral activity against HCMV (CI=0.29). These results, showing antiviral activity in vitro against both HAdV and HCMV, at concentrations below the human C values, may be relevant for the selection of specific immunosuppressant therapies in patients at risk of HAdV and HCMV infections.
Topics: Humans; Immunosuppressive Agents; Antiviral Agents; Adenoviruses, Human; Cytomegalovirus; Drug Synergism; Inhibitory Concentration 50; Mycophenolic Acid; Tacrolimus; Cyclosporine; Cytomegalovirus Infections
PubMed: 38401774
DOI: 10.1016/j.ijantimicag.2024.107116 -
EMBO Molecular Medicine Dec 2023The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused more than 700 million confirmed infections and ~7 million fatalities...
The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused more than 700 million confirmed infections and ~7 million fatalities worldwide since its emergence in December 2019. SARS-CoV-2 is part of a family of positive-sense, enveloped RNA viruses known as coronaviruses. Today, at least seven human coronaviruses have been identified and are known to cause respiratory tract illnesses with varying severity. The COVID-19 pandemic spurred the generation of a vast amount of scientific knowledge on coronaviruses in record time, leading to a broad understanding of host immunity against SARS-CoV-2, and the rapid development of life-saving vaccines (mainly mRNA and adenovirus- or inactivated virus-based vaccines). Real world data on licensed SARS-CoV-2 vaccines have shown that efficacy ranges from 50 to 95% depending on viral variants, pre-infections, and vaccine formulations, regimens, and combinations. While vaccination does markedly decrease the chances of infection and severe disease, breakthrough symptomatic and asymptomatic infections have occurred due to the emergence of immune escape virus variants. Therefore, despite these early successes, a better understanding of the mechanisms of protective immunity against infection is essential for the development of longer lasting and more efficient vaccines against SARS-CoV-2 and future coronaviruses.
Topics: Humans; COVID-19; COVID-19 Vaccines; SARS-CoV-2; Pandemics; Vaccination; Adaptive Immunity
PubMed: 37966373
DOI: 10.15252/emmm.202216345 -
Cardiology in ReviewCOVID-19 is a prothrombotic and cardiac-damaging disease. There are 4 vaccines against COVID-19 currently approved in North America, including the mRNA vaccines by...
COVID-19 is a prothrombotic and cardiac-damaging disease. There are 4 vaccines against COVID-19 currently approved in North America, including the mRNA vaccines by Pfizer and Moderna, and the adenovirus vector vaccines by Johnson and Johnson and AstraZeneca. These vaccines have been proven effective in reducing morbidity and preventing mortality in patients who were exposed to COVID-19 infection, but the vaccines have also been associated with complications. Vaccine-induced thrombotic thrombocytopenia (VITT) has a similar pathogenesis to heparin-induced thrombocytopenia, with an inappropriate immune response leading to platelet activation, consumption of platelets, and thrombosis. It appears to be more common with the adenovirus vector vaccines. Secondary immune thrombocytopenic purpura has been reported with all COVID-19 vaccines and is distinct from VITT because there is no sign of platelet activation or thrombotic events. Myocarditis and pericarditis are often reported in young males following mRNA vaccines and is often associated with a full recovery. The long-term effects of VITT, secondary immune thrombocytopenic purpura, myocarditis, and pericarditis secondary to COVID-19 vaccines have yet to be elucidated. Continued surveillance for these complications after vaccination is crucial for accurate diagnosis and effective management. Patients should consult their physicians regarding repeated vaccine doses after experiencing an adverse effect.
PubMed: 35576367
DOI: 10.1097/CRD.0000000000000457 -
Planta Medica Aug 2023The emergence and re-emergence of viruses has highlighted the need to develop new broad-spectrum antivirals to mitigate human infections. Pursuing our search for new...
The emergence and re-emergence of viruses has highlighted the need to develop new broad-spectrum antivirals to mitigate human infections. Pursuing our search for new bioactive plant-derived molecules, we study several diterpene derivatives synthesized from jatropholones A and B and carnosic acid isolated from and , respectively. Here, we investigate the antiviral effect of the diterpenes against human adenovirus (HAdV-5) that causes several infections for which there is no approved antiviral therapy yet. Ten compounds are evaluated and none of them present cytotoxicity in A549 cells. Only compounds 2, 5 and 9 inhibit HAdV-5 replication in a concentration-dependent manner, without virucidal activity, whereas the antiviral action takes place after virus internalization. The expression of viral proteins E1A and Hexon is strongly inhibited by compounds 2 and 5 and, in a lesser degree, by compound 9. Since compounds 2, 5 and 9 prevent ERK activation, they might exert their antiviral action by interfering in the host cell functions required for virus replication. Besides, the compounds have an anti-inflammatory profile since they significantly inhibit the levels of IL-6 and IL-8 produced by THP-1 cells infected with HAdV-5 or with an adenoviral vector. In conclusion, diterpenes 2, 5 and 9 not only exert antiviral activity against adenovirus but also are able to restrain pro-inflammatory cytokines induced by the virus.
Topics: Humans; Antiviral Agents; Adenoviridae Infections; Adenoviridae; Adenoviruses, Human; Diterpenes; Virus Replication
PubMed: 36940926
DOI: 10.1055/a-2058-3635 -
Current Opinion in Virology Aug 2023The world is in need of next-generation COVID-19 vaccines. Although first-generation injectable COVID-19 vaccines continue to be critical tools in controlling the... (Review)
Review
The world is in need of next-generation COVID-19 vaccines. Although first-generation injectable COVID-19 vaccines continue to be critical tools in controlling the current global health crisis, continuous emergence of SARS-CoV-2 variants of concern has eroded the efficacy of these vaccines, leading to staggering breakthrough infections and posing threats to poor vaccine responders. This is partly because the humoral and T-cell responses generated following intramuscular injection of spike-centric monovalent vaccines are mostly confined to the periphery, failing to either access or be maintained at the portal of infection, the respiratory mucosa (RM). In contrast, respiratory mucosal-delivered vaccine can induce immunity encompassing humoral, cellular, and trained innate immunity positioned at the respiratory mucosa that may act quickly to prevent the establishment of an infection. Viral vectors, especially adenoviruses, represent the most promising platform for RM delivery that can be designed to express both structural and nonstructural antigens of SARS-CoV-2. Boosting RM immunity via the respiratory route using multivalent adenoviral-vectored vaccines would be a viable next-generation vaccine strategy.
Topics: Humans; COVID-19; COVID-19 Vaccines; SARS-CoV-2; Vaccines; Vaccines, Combined; Adenoviridae; Respiratory Mucosa; Antibodies, Viral; Antibodies, Neutralizing; Viral Vaccines
PubMed: 37276833
DOI: 10.1016/j.coviro.2023.101334 -
Vaccine Oct 2023Porcine deltacoronavirus (PDCoV) is a novel swine enteropathogenic coronavirus that causes severe watery diarrhea, vomiting, dehydration and high mortality in piglets,...
Porcine deltacoronavirus (PDCoV) is a novel swine enteropathogenic coronavirus that causes severe watery diarrhea, vomiting, dehydration and high mortality in piglets, resulting in significant economic losses by the global pig industry. Recently, PDCoV has also shown the potential for cross-species transmission. However, there are currently few vaccine studies and no commercially available vaccines for PDCoV. Hence, here, two novel human adenovirus 5 (Ad5)-vectored vaccines expressing codon-optimized forms of the PDCoV spike (S) glycoprotein (Ad-PD-tPA-Sopt) and S1 glycoprotein (Ad-PD-oriSIP-S1opt) were constructed, and their effects were evaluated via intramuscular (IM) injection in BALB/c mice with different doses and times. Both vaccines elicited robust humoral and cellular immune responses; moreover, Ad-PD-tPA-Sopt-vaccinated mice after two IM injections with 10 infectious units (IFU)/mouse had significantly higher anti-PDCoV-specific neutralizing antibody titers. In contrast, the mice immunized with Ad-PD-tPA-Sopt via oral gavage (OG) did not generate robust systemic and mucosal immunity. Thus, IM Ad-PD-tPA-Sopt administration is a promising strategy against PDCoV and provides useful information for future animal vaccine development.
Topics: Humans; Animals; Swine; Mice; Adenovirus Vaccines; Vaccines; Glycoproteins; Immunity, Cellular; Adenoviridae; Swine Diseases; Coronavirus Infections
PubMed: 37777448
DOI: 10.1016/j.vaccine.2023.09.053 -
Current Opinion in Pediatrics Jun 2024Lower respiratory tract infections (LRTIs) are an important cause of child morbidity and mortality globally, especially in children under the age of 5 years in Africa.... (Review)
Review
PURPOSE OF REVIEW
Lower respiratory tract infections (LRTIs) are an important cause of child morbidity and mortality globally, especially in children under the age of 5 years in Africa. Respiratory viruses, including human adenoviruses (HAdVs), are common causes of LRTIs in children. This review aims to shed light on the epidemiology, clinical manifestations, sequelae, and treatment options specific to adenovirus respiratory infections in African children.
RECENT FINDINGS
Recent evidence has challenged the perception that adenovirus is a negligible cause of LRTIs. Studies show HAdV emerging as the third most common viral pathogen in fatal pneumonias among under-5 children in low-income and middle-income African countries, contributing to 5.5% of all pneumonia deaths and ranking second in hospital-associated viral pneumonia deaths. Predominant HAdV serotypes associated with disease differ by country and region, and have changed over time. Risk factors for increased disease severity and long-term respiratory sequelae in previously healthy African children with HAdV LRTIs are not well established.
SUMMARY
Although respiratory viruses, including HAdV, are recognized contributors to LRTIs, the prevalence and impact of adenovirus infections have been under-recognized and understated. Available data suggests that African children, particularly those under 5 years old, are at risk of severe sequelae from respiratory HAdV infections. Long-term sequelae, including bronchiectasis and postinfectious bronchiolitis obliterans, further underscore the significant impact of HAdV infections. However, the scarcity of comprehensive data hampers our understanding of the extent of the impact of HAdV infections on child lung health in Africa. We recommend scaled-up HAdV surveillance, ensuring its consistent inclusion in population-level LRTI assessments, and expanded and equitable access to diagnostics for early recognition of African children at risk of developing chronic sequelae and death. Enhanced understanding of adenovirus epidemiology and clinical outcomes and the availability of therapeutic options are essential for informed public health strategies and clinical care.
Topics: Humans; Africa; Adenovirus Infections, Human; Child, Preschool; Respiratory Tract Infections; Adenoviruses, Human; Infant; Risk Factors; Prevalence; Child
PubMed: 38465727
DOI: 10.1097/MOP.0000000000001335