Influenza D virus (FLUDV) was isolated from diseased pigs with respiratory disease symptoms in 2011, and since then the new virus has also been spread to cattle. Little is known about the susceptibility of other agricultural animals and poultry to FLUDV. This study was designed to determine if other farm animals such as goats, sheep, chickens, and turkey are possible hosts to this newly emerging influenza virus. 648 goat and sheep serum samples and 250 chicken and turkey serum samples were collected from 141 small ruminant and 25 poultry farms from different geographical locations in the United States and Canada. Serum samples were examined using the hemagglutination inhibition (HI) assay and the sheep and goat samples were further analyzed using the serum neutralization assay. Results of this study showed FLUDV antibodies were detected in 13.5% (17/126) of the sampled sheep farms, and 5.2% (29/557) of tested sheep serum samples were positive for FLUDV antibodies. For the goat results, the FLUDV antibodies were detected in 13.3% (2/15) of the sampled farms, and 8.8% (8/91) of the tested goat serum samples were positive for FLUDV antibodies. Furthermore, all tested poultry serum samples were negative for FLUDV antibodies. Our data demonstrated that sheep and goat are susceptible to FLUDV virus and multiple states in U.S. have this virus infection already in these two species. This new finding highlights a need for future surveillance of FLUDV virus in small ruminants toward better understanding both the origin and natural reservoir of this new virus.

Influenza Influenza viruses are classified as genera A, B, and C, in accordance with the antigenic differences in their nucleoproteins (NP) and matrix 1 (M1) proteins (28). Influenza A (IAV) and B (IBV) viruses can result in severe upper respiratory disease in humans, while influenza C viruses (ICV) cause relatively mild disease (9, 23). Among influenza viruses, IAV and IBV are very similar in terms of genome structure and organization. IBV, along with influenza A(H3N2) and A(H1N1) viruses [including A(H1N1)pdm09 virus], cause seasonal influenza epidemics annually (9, 23). In the United States alone during 1976 to 2007, approximately 3,000 to 49,000 deaths each year have been attributed to these epidemics (42). Some reports indicate that in older children and healthy adults, influenza A(H3N2) virus is responsible for the most severe cases, followed by IBV, while influenza A(H1N1) virus infections tend to manifest as the mildest cases of illness (1,5,23,25). In some seasons, however, IBV may be the predominate strain responsible for influenza activities. This was best exemplified by the 1979-1980 season, in which IBV was the predominant strain circulating in the United States; therefore, it was responsible for influenza outbreaks and excess pneumonia and influenza deaths nationwide (39). Furthermore, IBV has been reported to be associated with central nervous system complications, such as Reye's syndrome and encephalitis in children (1).IBVs continue to circulate worldwide alongside IAVs. Actively circulating IBVs are divided into two genetically and antigenically

Summary Influenza D virus (IDV) is a newly described influenza type of the Orthomyxoviridae virus family that was first isolated from diseased swine in 2011 and has subsequently been detected in cattle around the world in 2014. In addition, serological evidence for IDV infection in humans has been recently established. Despite all the progress, the full range of susceptible hosts for this novel virus has yet to be determined, but includes swine, bovine, small ruminants and human. This study was designed to determine if equine is a possible host to this newly emerging influenza virus. Three hundred and sixty-four equine serum samples were collected in 2015 from 141 farms within the Midwestern United States. Serum samples were examined using hemagglutination inhibition (HI) assay against two established IDV lineages (D/OK and D/660) and one IDV-related human ICV lineage (C/JHB). Results of this study showed 44 (44 of 364, 12%) samples positive for antibodies against D/OK, 39 (39 of 364, 11%) samples positive for antibodies against D/660, and 41 (41 of 364, 11%) samples positive for antibodies against C/JHB. A subset of these samples was further confirmed via microtitre neutralization (MN) assay. Our data demonstrated that horses are susceptible to two lineages of IDV, and that these viruses were present in equine populations throughout multiple Midwestern states of the United States. These findings continue to support the need for further surveillance of IDV viruses in agricultural species to work towards a better understanding of the full host range and natural reservoirs of influenza D virus.

Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs.

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