Common symptoms reported in adults with COVID-19 are fever, dry cough, and fatigue; severe cases have been associated with dyspnoea and bilateral ground-glass opacities on chest CT.3 In China, the ...SARS-CoV-2 reproductive number is estimated at 2.6 The combined case-fatality rate is 2% in China,7 and the risk of death is increased significantly in older people (approximately 15%).7 It is noteworthy that infants and children have not been featured prominently in COVID-19 case statistics. An analysis from China has shown that children younger than 10 years account for only 1% of COVID-19 cases,7 similar to the proportion for SARS-CoV and MERS-CoV epidemics.4,5 Infants and young children are typically at high risk for admission to hospital after respiratory tract infection with viruses such as respiratory syncytial virus and influenza virus.8 Immaturity of the respiratory tract and immune system is thought to contribute to severe viral respiratory disease in this age group.8 Therefore, the absence of paediatric patients with COVID-19 has perplexed clinicians, epidemiologists, and scientists. Patients were stratified by disease severity and were assessed in hospital (mean duration of hospitalisation, 14 SD 3 days) for secondary bacterial and fungal infection, sepsis, immune responses, and organ dysfunction (lung, liver, heart, and kidney).
The influenza universe in an mRNA vaccine Kelvin, Alyson A; Falzarano, Darryl
Science (American Association for the Advancement of Science),
11/2022, Letnik:
378, Številka:
6622
Journal Article
Recenzirano
An mRNA-lipid nanoparticle vaccine protects animals from 20 influenza lineages.
Kelvin and Zambon examines influenza imprinting in childhood and the influence on vaccine response later in life. First impressions are important and often long-lasting. The first influenza virus ...infection during childhood, termed immune imprinting, is recognized for its influence on subsequent infections and vaccinations. The imprinting event initiates a cascade of innate and adaptive immune responses leading to an immunological memory retained over a person's lifetime. Recent studies in Eurosurveillance report potential implications for vaccine responses. Skowronski et al. with the Canadian Sentinel Practitioner Surveillance Network and Kissling et al. with the Influenza Monitoring Vaccine Effectiveness (I-MOVE) in Europe observed evidence of an age-related cohort effect reducing vaccine protection during the 2018/19 influenza season, which they infer occurred as a result of an immunological imprinting event.
Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan ...dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics. After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics. Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics.
COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a disease affecting several organ systems. A model that captures all clinical ...symptoms of COVID-19 as well as long-haulers disease is needed. We investigated the host responses associated with infection in several major organ systems including the respiratory tract, the heart, and the kidneys after SARS-CoV-2 infection in Syrian hamsters. We found significant increases in inflammatory cytokines (IL-6, IL-1beta, and TNF) and type II interferons whereas type I interferons were inhibited. Examination of extrapulmonary tissue indicated inflammation in the kidney, liver, and heart which also lacked type I interferon upregulation. Histologically, the heart had evidence of myocarditis and microthrombi while the kidney had tubular inflammation. These results give insight into the multiorgan disease experienced by people with COVID-19 and possibly the prolonged disease in people with post-acute sequelae of SARS-CoV-2 (PASC).
On 31 December 2019 the Wuhan Health Commission reported a cluster of atypical pneumonia cases that was linked to a wet market in the city of Wuhan, China. The first patients began experiencing ...symptoms of illness in mid-December 2019. Clinical isolates were found to contain a novel coronavirus with similarity to bat coronaviruses. As of 28 January 2020, there are in excess of 4,500 laboratory-confirmed cases, with > 100 known deaths. As with the SARS-CoV, infections in children appear to be rare. Travel-related cases have been confirmed in multiple countries and regions outside mainland China including Germany, France, Thailand, Japan, South Korea, Vietnam, Canada, and the United States, as well as Hong Kong and Taiwan. Domestically in China, the virus has also been noted in several cities and provinces with cases in all but one provinence. While zoonotic transmission appears to be the original source of infections, the most alarming development is that human-to-human transmission is now prevelant. Of particular concern is that many healthcare workers have been infected in the current epidemic. There are several critical clinical questions that need to be resolved, including how efficient is human-to-human transmission? What is the animal reservoir? Is there an intermediate animal reservoir? Do the vaccines generated to the SARS-CoV or MERS-CoV or their proteins offer protection against 2019-nCoV? We offer a research perspective on the next steps for the generation of vaccines. We also present data on the use of in silico docking in gaining insight into 2019-nCoV Spike-receptor binding to aid in therapeutic development. Diagnostic PCR protocols can be found at https://www.who.int/health-topics/coronavirus/laboratory-diagnostics-for-novel-coronavirus.
Mpox (formerly Monkeypox), a zoonotic illness caused by the Mpox virus, belongs to the Orthopoxvirus genus in the family Poxviridae. To design and develop effective antiviral therapeutics against DNA ...viruses, the DNA‐dependent RNA polymerase (DdRp) of poxviruses has emerged as a promising drug target. In the present study, we modeled the three‐dimensional (3D) structure of DdRp using a template‐based homology approach. After modeling, virtual screening was performed to probe the molecular interactions between 1755 Food and Drug Administration‐approved small molecule drugs (≤500 molecular weight) and the DdRp of Mpox. Based on the binding affinity and molecular interaction patterns, five drugs, lumacaftor (−11.7 kcal/mol), conivaptan (−11.7 kcal/mol), betulinic acid (−11.6 kcal/mol), fluspirilene (−11.3 kcal/mol), and imatinib (−11.2 kcal/mol), have been ranked as the top drug compounds interacting with Mpox DdRp. Complexes of these shortlisted drugs with DdRp were further evaluated using state‐of‐the‐art all‐atoms molecular dynamics (MD) simulations on 200 nanoseconds followed by principal component analysis (PCA). MD simulations and PCA results revealed highly stable interactions of these small drugs with DdRp. After due validation in wet‐lab using available in vitro and in vivo experiments, these repurposed drugs can be further utilized for the treatment of contagious Mpox virus. The outcome of this study may establish a solid foundation to screen repurposed and natural compounds as potential antiviral therapeutics against different highly pathogenic viruses.
Seasonal influenza viruses are typically restricted to the human upper respiratory tract whereas influenza viruses with greater pathogenic potential often also target extra-pulmonary organs. Infants, ...pregnant women, and breastfeeding mothers are highly susceptible to severe respiratory disease following influenza virus infection but the mechanisms of disease severity in the mother-infant dyad are poorly understood. Here we investigated 2009 H1N1 influenza virus infection and transmission in breastfeeding mothers and infants utilizing our developed infant-mother ferret influenza model. Infants acquired severe disease and mortality following infection. Transmission of the virus from infants to mother ferrets led to infection in the lungs and mother mortality. Live virus was also found in mammary gland tissue and expressed milk of the mothers which eventually led to milk cessation. Histopathology showed destruction of acini glandular architecture with the absence of milk. The virus was localized in mammary epithelial cells of positive glands. To understand the molecular mechanisms of mammary gland infection, we performed global transcript analysis which showed downregulation of milk production genes such as Prolactin and increased breast involution pathways indicated by a STAT5 to STAT3 signaling shift. Genes associated with cancer development were also significantly increased including JUN, FOS and M2 macrophage markers. Immune responses within the mammary gland were characterized by decreased lymphocyte-associated genes CD3e, IL2Ra, CD4 with IL1β upregulation. Direct inoculation of H1N1 into the mammary gland led to infant respiratory infection and infant mortality suggesting the influenza virus was able to replicate in mammary tissue and transmission is possible through breastfeeding. In vitro infection studies with human breast cells showed susceptibility to H1N1 virus infection. Together, we have shown that the host-pathogen interactions of influenza virus infection in the mother-infant dyad initiate immunological and oncogenic signaling cascades within the mammary gland. These findings suggest the mammary gland may have a greater role in infection and immunity than previously thought.
Influenza A and B infections are a worldwide health concern to both humans and animals. High genetic evolution rates of the influenza virus allow the constant emergence of new strains and cause ...illness variation. Since human influenza infections are often complicated by secondary factors such as age and underlying medical conditions, strain or subtype specific clinical features are difficult to assess. Here we infected ferrets with 13 currently circulating influenza strains (including strains of pandemic 2009 H1N1 H1N1pdm and seasonal A/H1N1, A/H3N2, and B viruses). The clinical parameters were measured daily for 14 days in stable environmental conditions to compare clinical characteristics. We found that H1N1pdm strains had a more severe physiological impact than all season strains where pandemic A/California/07/2009 was the most clinically pathogenic pandemic strain. The most serious illness among seasonal A/H1N1 and A/H3N2 groups was caused by A/Solomon Islands/03/2006 and A/Perth/16/2009, respectively. Among the 13 studied strains, B/Hubei-Wujiagang/158/2009 presented the mildest clinical symptoms. We have also discovered that disease severity (by clinical illness and histopathology) correlated with influenza specific antibody response but not viral replication in the upper respiratory tract. H1N1pdm induced the highest and most rapid antibody response followed by seasonal A/H3N2, seasonal A/H1N1 and seasonal influenza B (with B/Hubei-Wujiagang/158/2009 inducing the weakest response). Our study is the first to compare the clinical features of multiple circulating influenza strains in ferrets. These findings will help to characterize the clinical pictures of specific influenza strains as well as give insights into the development and administration of appropriate influenza therapeutics.
The Chikungunya virus infection zones have now quickly spread from Africa to parts of Asia, North America and Europe. Originally thought to trigger a disease of only mild symptoms, recently ...Chikungunya virus caused large-scale fatalities and widespread economic loss that was linked to recent virus genetic mutation and evolution. Due to the paucity of information on Chikungunya immunological progression, we investigated the serum levels of 13 cytokines/chemokines during the acute phase of Chikungunya disease and 6- and 12-month post-infection follow-up from patients of the Italian outbreak. We found that CXCL9/MIG, CCL2/MCP-1, IL-6 and CXCL10/IP-10 were significantly raised in the acute phase compared to follow-up samples. Furthermore, IL-1β, TNF-α, Il-12, IL-10, IFN-γ and IL-5 had low initial acute phase levels that significantly increased at later time points. Analysis of symptom severity showed association with CXCL9/MIG, CXCL10/IP-10 and IgG levels. These data give insight into Chikungunya disease establishment and subsequent convalescence, which is imperative to the treatment and containment of this quickly evolving and frequently re-emerging disease.
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