Amphibian skin is a mucosal surface in direct and continuous contact with a microbially diverse and laden aquatic and/or terrestrial environment. As such, frog skin is an important innate immune organ and first line of defence against pathogens in the environment. Critical to the innate immune functions of frog skin are the maintenance of physical, chemical, cellular, and microbiological barriers and the complex network of interactions that occur across all the barriers. Despite the global decline in amphibian populations, largely as a result of emerging infectious diseases, we understand little regarding the cellular and molecular mechanisms that underlie the innate immune function of amphibian skin and defence against pathogens. In this review, we discuss the structure, cell composition and cellular junctions that contribute to the skin physical barrier, the antimicrobial peptide arsenal that, in part, comprises the chemical barrier, the pattern recognition receptors involved in recognizing pathogens and initiating innate immune responses in the skin, and the contribution of commensal microbes on the skin to pathogen defence. We briefly discuss the influence of environmental abiotic factors (natural and anthropogenic) and pathogens on the immunocompetency of frog skin defences. Although some aspects of frog innate immunity, such as antimicrobial peptides are well-studied; other components and how they contribute to the skin innate immune barrier, are lacking. Elucidating the complex network of interactions occurring at the interface of the frog's external and internal environments will yield insight into the crucial role amphibian skin plays in host defence and the environmental factors leading to compromised barrier integrity, disease, and host mortality.

Hypoxia is a driver of cell movement in processes such as development and tumor progression. The cellular response to hypoxia involves a transcriptional program mediated by hypoxiainducible factors, but translational control has emerged as a significant contributor. In this study, we demonstrate that a cell-cell adhesion molecule, cadherin-22, is upregulated in hypoxia via mTORC1-independent translational control by the initiation factor eIF4E2. We identify new functions of cadherin-22 as a hypoxia-specific cell-surface molecule involved in cancer cell migration, invasion and adhesion. Silencing eIF4E2 or cadherin-22 significantly impaired MDA-MB-231 breast carcinoma and U87MG glioblastoma cell migration and invasion only in hypoxia, while reintroduction of the respective exogenous gene restored the normal phenotype. Cadherin-22 was evenly distributed throughout spheroids and required for their formation and support of a hypoxic core. Conversely, E-cadherin translation was repressed by hypoxia and only expressed in the oxygenated cells of U87MG spheroids. Furthermore, immunofluorescence on paraffinembedded human tissue from 40 glioma and 40 invasive ductal breast carcinoma patient specimens revealed that cadherin-22 expression colocalized with areas of hypoxia and significantly correlated with tumor grade and progression-free survival or stage and tumor size, respectively. This study broadens our understanding of tumor progression and metastasis by highlighting cadherin-22 as a potential new target of cancer therapy to disable hypoxic cancer cell motility and adhesion.

Antimicrobial peptides (AMPs) are small, usually cationic, and amphiphilic molecules that play a crucial role in molecular and cellular host defense against pathogens, tissue damage, and infection. AMPs are present in all metazoans and several have been discovered in teleosts. Some teleosts, such as salmonids, have undergone whole genome duplication events and retained a diverse AMP repertoire. Salmonid AMPs have also been shown to possess diverse and potent antibacterial, antiviral, and antiparasitic activity and are induced by a variety of factors, including dietary components and specific molecules also known as pathogen-associated molecular patterns (PAMPs), which may activate downstream signals to initiate transcription of AMP genes. Moreover, a multitude of cell lines have been established from various salmonid species, making it possible to study host-pathogen interactions in vitro, and several of these cell lines have been shown to express various AMPs. In this review, the structure, function, transcriptional regulation, and immunomodulatory role of salmonid AMPs are highlighted in health and disease. It is important to characterize and understand how salmonid AMPs function as this may lead to a better understanding of host-pathogen interactions with implications for aquaculture and medicine.

The skin epithelial layer acts as an important immunological barrier against pathogens and is capable of recognizing and responding to pathogen associated molecular patterns (PAMPs) in human and mouse models. Although presumed, it is unknown whether amphibian skin epithelial cells exhibit the ability to respond to PAMPs such as viral double-stranded RNA (dsRNA). To address this, two cell lines from the dorsal skin (Xela DS2) and ventral skin (Xela VS2) of the African clawed frog (Xenopus laevis) were established. Xela DS2 and Xela VS2 cells have an epithelial-like morphology, express genes associated with epithelial cells, and lack senescence-associated beta-galactosidase activity. Cells grow optimally in 70% Leibovitz's L-15 medium supplemented with 15% fetal bovine serum at 26°C. Upon treatment with poly(I:C), a synthetic viral dsRNA analogue and known type I interferon inducer, Xela DS2 and Xela VS2 exhibit marked upregulation of key pro-inflammatory and antiviral transcripts suggesting frog epithelial cells participate in the recognition of extracellular viral dsRNA and production of local inflammatory signals; similar to human and mouse models. Currently, these are the only known Xenopus laevis skin epithelial-like cell lines and will be important for future research in amphibian epithelial cell biology, initial host-pathogen interactions, and rapid screening of the effects of environmental stressors, including contaminants, on frog skin epithelial cells.

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18The skin epithelial layer acts as an important immunological barrier against pathogens 19 and is capable of recognizing and responding to pathogen associated molecular patterns 20 (PAMPs) in human and mouse models. Although presumed, it is unknown whether amphibian 21 skin epithelial cells exhibit the ability to respond to PAMPs such as viral double-stranded RNA 22(dsRNA). To address this, two cell lines from the dorsal skin (Xela DS2) and ventral skin (Xela 23 VS2) of the African clawed frog (Xenopus laevis) were established. Xela DS2 and Xela VS2 24 cells have an epithelial-like morphology, express genes associated with epithelial cells, and lack 25 senescence-associated beta-galactosidase activity. Cells grow optimally in 70% Leibovitz's L-15 26 medium supplemented with 15% fetal bovine serum at 26°C. Upon treatment with poly(I:C), a 27 synthetic viral dsRNA analogue and known type I interferon inducer, Xela DS2 and Xela VS2 28 exhibit marked upregulation of key pro-inflammatory and antiviral transcripts suggesting frog 29 epithelial cells participate in the recognition of extracellular viral dsRNA and production of local 30 inflammatory signals; similar to human and mouse models. Currently, these are the only known 31Xenopus laevis skin epithelial-like cell lines and will be important for future research in 32 amphibian epithelial cell biology, initial host-pathogen interactions, and rapid screening of the 33 effects of environmental stressors, including contaminants, on frog skin epithelial cells. 34 35