Role of autophagy machinery dysregulation in bacterial chondronecrosis with osteomyelitis

Ramser, Alison; Greene, Elizabeth S.; Alrubaye, Adnan A.K.; Wideman, Robert F.; Dridi, Sami

doi:10.1016/j.psj.2022.101750

Cited by 7 publications

(5 citation statements)

References 68 publications

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“…S. agnetis 908 has been shown to trigger an NLRP3 inflammasome response in osteoblast cultures [73]. Femoral head necrosis, one form of BCO, has been correlated with down-regulation of autophagy, and 908 decreases viability of, and expression of autophagy genes of, human fetal osteoblast cells [74]. We have also found that 908 survives in and escapes from chicken immortalized macrophage-like cells (unpublished).…”

Section: Discussionmentioning

confidence: 74%

Horizontal transfer of probable chicken-pathogenicity chromosomal islands betweenStaphylococcus aureusandStaphylococcus agnetis

Rhoads

Pummill

Ekesi

et al. 2023

Preprint

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Staphylococcus agnetis is an emerging pathogen in chickens but has been most commonly isolated from sub-clinical mastitis in bovines. Previous whole-genome analyses for known virulence genes failed to identify determinants for the switch from mild ductal infections in cattle to severe infections in poultry. We now report identification of a family of 15 kbp, 17-19 gene mobile genetic elements (MGEs) specific to chicken osteomyelitis and dermatitis isolates of S. agnetis. These MGEs can be present in multiple copies per genome. The MGE has been vectored on a Staphylococcus phage that separately lysogenized two S. agnetis osteomyelitis strains. The S. agnetis genome from a broiler breeder case of ulcerative dermatitis contains 2 orthologs of this MGE, not associated with a prophage. BLASTn and phylogenetic analyses show that there are closely related intact MGEs found in genomes of S. aureus. The genome from a 1980s isolate from chickens in Ireland contains 3 copies of this MGE. More recent chicken isolates descended from that genome (Poland 2009, Oklahoma 2010, and Arkansas 2018) contain 2 to 4 related copies. Many of the genes of this MGE can be identified in disparate regions of the genomes of other chicken isolates of S. aureus. BLAST searches of the NCBI databases detect no similar MGEs outside of S. aureus and S. agnetis. These MGEs encode no proteins related to those produced by Staphylococcus aureus Pathogenicity Islands, which have been associated with the transition of S. aureus from human to chicken hosts. Other than mobilization functions, most of the genes in these new MGEs annotate as hypothetical proteins. The MGEs we describe appear to represent a new family of Chromosomal Islands (CIs) shared amongst S. agnetis and S. aureus. Further work is needed to understand the role of these CIs/MGEs in pathogenesis. Analysis of horizontal transfer of genetic elements between isolates and species of Staphylococci provides clues to evolution of host-pathogen interactions as well as revealing critical determinants for animal welfare and human diseases.

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Section: Discussionmentioning

confidence: 74%

Horizontal transfer of probable chicken-pathogenicity chromosomal islands betweenStaphylococcus aureusandStaphylococcus agnetis

Rhoads

Pummill

Ekesi

et al. 2023

Preprint

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“…FHS is characterized by the detachment of GP and AC, occurring in tibia and femur (Durairaj et al, 2009;Packialakshmi et al, 2015). Although some studies have been published in the last years with FHS, FHN, and BCO, including by our group, there are few of them approaching the molecular mechanisms involved with these conditions, especially with early ages (Li et al, 2015;Paludo et al, 2017;Peixoto et al, 2019;Oliveira et al, 2020;Liu K. et al, 2021;Hul et al, 2021;Ramser et al, 2021Ramser et al, , 2022Goldoni et al, 2022;Santos et al, 2022). To the best of our knowledge, this paper is the first attempt to compare normal and FHS-affected femoral head transcriptome in broilers with 21 days of age.…”

Section: Discussionmentioning

confidence: 99%

“… Oliveira et al (2020) also pointed out that osteochondral downregulated genes are potentially triggering BCO in tibia of 42-day-old broilers. Most of the studies with FHN/FHS in chickens are focused on understanding the ossification processes and, generally, in animals older than 35 days of age ( Li et al, 2015 ; Paludo et al, 2017 ; Peixoto et al, 2019 ; Hul et al, 2021 ; Ramser et al, 2021 , 2022 ), since the highest incidences of this condition occur at these ages ( McNamee and Smyth, 2000 ; Paxton et al, 2014 ; Packialakshmi et al, 2015 ). Therefore, molecular mechanisms involved with femoral head separation in young age (21 days) broilers were identified using RNA sequencing, allowing highlighting genes and BP potentially related to the onset of this condition.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of growth plate genes involved with the onset of femoral head separation in young broilers

et al. 2022

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Femoral head separation (FHS) is characterized by the detachment of growth plate (GP) and articular cartilage, occurring in tibia and femur. However, the molecular mechanisms involved with this condition are not completely understood. Therefore, genes and biological processes (BP) involved with FHS were identified in 21-day-old broilers through RNA sequencing of the femoral GP. 13,487 genes were expressed in the chicken femoral head transcriptome of normal and FHS-affected broilers. From those, 34 were differentially expressed (DE; FDR ≤0.05) between groups, where all of them were downregulated in FHS-affected broilers. The main BP were enriched in receptor signaling pathways, ossification, bone mineralization and formation, skeletal morphogenesis, and vascularization. RNA-Seq datasets comparison of normal and FHS-affected broilers with 21, 35 and 42 days of age has shown three shared DE genes (FBN2, C1QTNF8, and XYLT1) in GP among ages. Twelve genes were exclusively DE at 21 days, where 10 have already been characterized (SHISA3, FNDC1, ANGPTL7, LEPR, ENSGALG00000049529, OXTR, ENSGALG00000045154, COL16A1, RASD2, BOC, GDF10, and THSD7B). Twelve SNPs were associated with FHS (p < 0.0001). Out of those, 5 were novel and 7 were existing variants located in 7 genes (RARS, TFPI2, TTI1, MAP4K3, LINK54, and AREL1). We have shown that genes related to chondrogenesis and bone differentiation were downregulated in the GP of FHS-affected young broilers. Therefore, these findings evince that candidate genes pointed out in our study are probably related to the onset of FHS in broilers.

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“…The inability to reliably detect all FHN through gate scoring, the lack of a mec anistic understanding, and the absence of confirmed progression of the disease have mad FHN one of the most challenging physiological obstacles in poultry. The phenotype FHN is clear: bacterial infection by highly pathogenic, opportunistic bacteria of weak bo in often high-performing broilers resulting in chondronecrosis and osteomyelitis [31,32 The mechanism by which bacteria induce FHN has also begun to be investigated, wi molecular pathways such as autophagy and mitochondrial function being implicate [33,34]. An understanding of the systemic effects of FHN as well as a foundation for no invasive biomarkers have also been established via the evaluation of the cytokine an chemokine profiles in the blood and bone of normal and FHN-affected broilers [10].…”

Section: Discussionmentioning

confidence: 99%

Bone Metabolite Profile Differs between Normal and Femur Head Necrosis (FHN/BCO)-Affected Broilers: Implications for Dysregulated Metabolic Cascades in FHN Pathophysiology

Ramser

Hawken²,

Greene

et al. 2023

Metabolites

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Femur head necrosis (FHN), also known as bacterial chondronecrosis with osteomyelitis (BCO), has remained an animal welfare and production concern for modern broilers regardless of efforts to select against it in primary breeder flocks. Characterized by the bacterial infection of weak bone, FHN has been found in birds without clinical lameness and remains only detectable via necropsy. This presents an opportunity to utilize untargeted metabolomics to elucidate potential non-invasive biomarkers and key causative pathways involved in FHN pathology. The current study used ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC–HRMS) and identified a total of 152 metabolites. Mean intensity differences at p < 0.05 were found in 44 metabolites, with 3 significantly down-regulated and 41 up-regulated in FHN-affected bone. Multivariate analysis and a partial least squares discriminant analysis (PLS-DA) scores plot showed the distinct clustering of metabolite profiles from FHN-affected vs. normal bone. Biologically related molecular networks were predicted using an ingenuity pathway analysis (IPA) knowledge base. Using a fold-change cut off of −1.5 and 1.5, top canonical pathways, networks, diseases, molecular functions, and upstream regulators were generated using the 44 differentially abundant metabolites. The results showed the metabolites NAD+, NADP+, and NADH to be downregulated, while 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and histamine were significantly increased in FHN. Ascorbate recycling and purine nucleotides degradation were the top canonical pathways, indicating the potential dysregulation of redox homeostasis and osteogenesis. Lipid metabolism and cellular growth and proliferation were some of the top molecular functions predicted based on the metabolite profile in FHN-affected bone. Network analysis showed significant overlap across metabolites and predicted upstream and downstream complexes, including AMP-activated protein kinase (AMPK), insulin, collagen type IV, mitochondrial complex, c-Jun N-terminal kinase (Jnk), extracellular signal-regulated kinase (ERK), and 3β-hydroxysteroid dehydrogenase (3β HSD). The qPCR analysis of relevant factors showed a significant decrease in AMPKα2 mRNA expression in FHN-affected bone, supporting the predicted downregulation found in the IPA network analysis. Taken as a whole, these results demonstrate a shift in energy production, bone homeostasis, and bone cell differentiation that is distinct in FHN-affected bone, with implications for how metabolites drive the pathology of FHN.

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Role of autophagy machinery dysregulation in bacterial chondronecrosis with osteomyelitis

Cited by 7 publications

References 68 publications

Horizontal transfer of probable chicken-pathogenicity chromosomal islands betweenStaphylococcus aureusandStaphylococcus agnetis

Horizontal transfer of probable chicken-pathogenicity chromosomal islands betweenStaphylococcus aureusandStaphylococcus agnetis

Downregulation of growth plate genes involved with the onset of femoral head separation in young broilers

Bone Metabolite Profile Differs between Normal and Femur Head Necrosis (FHN/BCO)-Affected Broilers: Implications for Dysregulated Metabolic Cascades in FHN Pathophysiology

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