High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases.

Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah-/- mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.

Two Distinct Illnesses Consistent With MIS-C in a Pediatric Patient.

Multisystem inflammatory syndrome in children (MIS-C) is a severe inflammatory response described in children after infection with severe acute respiratory syndrome coronavirus 2. We present a case of a 9-year-old African American boy with 2 distinct illnesses that were both consistent with MIS-C. He first presented in the early stages of our understanding of MIS-C with predominantly neurologic and gastrointestinal symptoms and demonstrated elevated inflammatory markers consistent with MIS-C. He was treated with intravenous immunoglobulin with complete resolution of signs and symptoms. After 7 months of good health, he returned with a second, distinct illness characterized by fever, rash, gastrointestinal symptoms, and elevated inflammatory markers that met the criteria for MIS-C. In addition, we identified new dilatation of the left anterior descending coronary artery. He improved rapidly after treatment with intravenous immunoglobulin, aspirin, and steroids. Our report highlights the need to achieve a better understanding of this entity's pathogenesis and clinical course and to improve anticipatory guidance for children with MIS-C.

Implementation of an Early Childhood Healthy Eating and Physical Activity Program in New South Wales, Australia: Munch & Move.

Background: Childhood obesity is an important public health issue. Approximately 20% of 2-4 year olds are overweight or obese, meaning 1 in 5 Australian children start school above a healthy weight. In the state of New South Wales (NSW) the combined prevalence of childhood overweight and obesity is significantly higher among children from low socioeconomic status backgrounds and children from regional, rural and remote areas. This paper describes implementation of a healthy eating and active play program (Munch & Move) for center-based early childhood education and care (ECEC) services aimed at influencing healthy behaviors in young children in NSW, Australia. It shows changes over time including a focus on disadvantaged, Aboriginal and remote communities. It also discusses the challenges and future opportunities for the program. Methods: Routine data in relation to service delivery (reach) and implementation indicators are collected by Local Health District staff. Fifteen implementation indicators (known as practices) were introduced to monitor the implementation of Munch & Move (six related to promoting and encouraging healthy eating, four related to improving physical activity, two related to small screen recreation; and three related to quality of service delivery). Results: As of 30 June 2017, 88.4% of ECEC services have staff trained in Munch & Move. Of the 15 practices related to promoting and encouraging healthy eating, increasing physical activity and improving the quality of service delivery 13 practices saw significant improvements between 2012 and 2017. This was consistent for services with a high proportion of Aboriginal children and for services in disadvantaged and remote communities. There has been a statistically significant increase in the proportion (37.6-81.0%, p < 0.0001) and type of ECEC services (preschools 36.1-81.3%, p < 0.0001, long day care 38.6-81.0%, p < 0.0001, and occasional care 34.0-74.6%, p < 0.0001) that have implemented the program since 2012 as well as in services with a high proportion of Aboriginal children (33.6-85.2% p < 0.0001), services in disadvantaged communities (37.4-83.3% p < 0.001), and services in remote communities (27.8-59.4% p < 0.0139). Discussion: This paper demonstrates that Munch & Move has seen large improvements in the delivery of training, practice achievements and program adoption in ECEC services across NSW including services in disadvantaged and remote communities and that have a higher proportion of Aboriginal children.

Codesign of the Population Health Information Management System to measure reach and practice change of childhood obesity programs.

INTRODUCTION: Childhood obesity prevalence is an issue of international public health concern and governments have a significant role to play in its reduction. The Healthy Children Initiative (HCI) has been delivered in New South Wales (NSW), Australia, since 2011 to support implementation of childhood obesity prevention programs at scale. Consequently, a system to support local implementation and data collection, analysis and reporting at local and state levels was necessary. The Population Health Information Management System (PHIMS) was developed to meet this need. Design and development: A collaborative and iterative process was applied to the design and development of the system. The process comprised identifying technical requirements, building system infrastructure, delivering training, deploying the system and implementing quality measures. Use of PHIMS: Implementation of PHIMS resulted in rapid data retrieval and reporting against agreed performance measures for the HCI. The system has 150 users who account for the monitoring and reporting of more than 6000 HCI intervention sites (early childhood services and primary schools). LESSONS LEARNT: Developing and implementing PHIMS presented a number of complexities including: applying an information technology (IT) development methodology to a traditional health promotion setting; data access and confidentiality issues; and managing system development and deployment to intended timelines and budget. PHIMS was successfully codesigned as a flexible, scalable and sustainable IT solution that supports state-wide HCI program implementation, monitoring and reporting.

Virulent PB1-F2 residues: effects on fitness of H1N1 influenza A virus in mice and changes during evolution of human influenza A viruses.

Specific residues of influenza A virus (IAV) PB1-F2 proteins may enhance inflammation or cytotoxicity. In a series of studies, we evaluated the function of these virulence-associated residues in the context of different IAV subtypes in mice. Here, we demonstrate that, as with the previously assessed pandemic 1968 (H3N2) IAV, PB1-F2 inflammatory residues increase the virulence of H1N1 IAV, suggesting that this effect might be a universal feature. Combining both inflammatory and cytotoxic residues in PB1-F2 enhanced virulence further, compared to either motif alone. Residues from these virulent motifs have been present in natural isolates from human seasonal IAV of all subtypes, but there has been a trend toward a gradual reduction in the number of virulent residues over time. However, human IAV of swine and avian origin tend to have more virulent residues than do the human-adapted seasonal strains, raising the possibility that donation of PB1 segments from these zoonotic viruses may increase the severity of some seasonal human strains. Our data suggest the value of surveillance of virulent residues in both human and animal IAV to predict the severity of influenza season.

A novel cytotoxic sequence contributes to influenza A viral protein PB1-F2 pathogenicity and predisposition to secondary bacterial infection.

Enhancement of cell death is a distinguishing feature of H1N1 influenza virus A/Puerto Rico/8/34 protein PB1-F2. Comparing the sequences (amino acids [aa] 61 to 87 using PB1-F2 amino acid numbering) of the PB1-F2-derived C-terminal peptides from influenza A viruses inducing high or low levels of cell death, we identified a unique I68, L69, and V70 motif in A/Puerto Rico/8/34 PB1-F2 responsible for promotion of the peptide's cytotoxicity and permeabilization of the mitochondrial membrane. When administered to mice, a 27-mer PB1-F2-derived C-terminal peptide with this amino acid motif caused significantly greater weight loss and pulmonary inflammation than the peptide without it (due to I68T, L69Q, and V70G mutations). Similar to the wild-type peptide, A/Puerto Rico/8/34 elicited significantly higher levels of macrophages, neutrophils, and cytokines in the bronchoalveolar lavage fluid of mice than its mutant counterpart 7 days after infection. Additionally, infection of mice with A/Puerto Rico/8/34 significantly enhanced the levels of morphologically transformed epithelial and immune mononuclear cells recruited in the airways compared with the mutant virus. In the mouse bacterial superinfection model, both peptide and virus with the I68, L69, and V70 sequence accelerated development of pneumococcal pneumonia, as reflected by increased levels of viral and bacterial lung titers and by greater mortality. Here we provide evidence suggesting that the newly identified cytotoxic sequence I68, L69, and V70 of A/Puerto Rico/8/34 PB1-F2 contributes to the pathogenesis of both primary viral and secondary bacterial infections.

Immunopathogenic and antibacterial effects of H3N2 influenza A virus PB1-F2 map to amino acid residues 62, 75, 79, and 82.

The influenza A virus protein PB1-F2 has been linked to the pathogenesis of both primary viral and secondary bacterial infections. H3N2 viruses have historically expressed full-length PB1-F2 proteins with either proinflammatory (e.g., from influenza A/Hong Kong/1/1968 virus) or noninflammatory (e.g., from influenza A/Wuhan/359/1995 virus) properties. Using synthetic peptides derived from the active C-terminal portion of the PB1-F2 protein from those two viruses, we mapped the proinflammatory domain to amino acid residues L62, R75, R79, and L82 and then determined the role of that domain in H3N2 influenza virus pathogenicity. PB1-F2-derived peptides containing that proinflammatory motif caused significant morbidity, mortality, and pulmonary inflammation in mice, manifesting as increased acute lung injury and the presence of proinflammatory cytokines and inflammatory cells in the lungs compared to peptides lacking this motif, and better supported bacterial infection with Streptococcus pneumoniae. Infections of mice with an otherwise isogenic virus engineered to contain this proinflammatory sequence in PB1-F2 demonstrated increased morbidity resulting from primary viral infections and enhanced development of secondary bacterial pneumonia. The presence of the PB1-F2 noninflammatory (P62, H75, Q79, and S82) sequence in the wild-type virus mediated an antibacterial effect. These data suggest that loss of the inflammatory PB1-F2 phenotype that supports bacterial superinfection during adaptation of H3N2 viruses to humans, coupled with acquisition of antibacterial activity, contributes to the relatively diminished frequency of severe infections seen with seasonal H3N2 influenza viruses in recent decades compared to their first 2 decades of circulation.