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Leukocyte Tyrosine Kinase (Ltk) Is the Mendelian Determinant of the Axolotl Melanoid Color Variant
Kabangu et al., Genes. 2023.
https://www.mdpi.com/2073-4425/14/4/904
The diversity of color patterns among amphibians is largely explained by the differentiation of a few pigment cell types during development. Mexican axolotls have a variety of color phenotypes, from leucistic to highly melanistic. The melanoid axolotl is a Mendelian variant characterized by large numbers of melanophores, fewer xanthophores, and no iridophores. Studies of melanoid were influential in developing the single-origin hypothesis of pigment cell development, proposing that all three pigment cell types derive from a common progenitor cell, with pigment metabolites playing potential roles in directing the development of organelles that define different pigment cell types. Xanthine dehydrogenase (XDH) activity was identified as a mechanism for the permissive differentiation of melanophores at the expense of xanthophores and iridophores. The authors used bulked segregant RNA-Seq (including a region on chromosome 14q) to screen the axolotl genome for melanoid candidate genes and identify the associated locus. The region 14q contains gephyrin (Gphn), an enzyme that catalyzes the synthesis of the molybdenum cofactor that is required for XDH activity, and Ltk, a cell surface signaling receptor required for iridophore differentiation in zebrafish. Wild-type Ltk crispants present similar pigment phenotypes to melanoid, strongly implicating Ltk as the melanoid locus. The results support the idea of direct fate specification of pigment cells, as well as the single-origin hypothesis of pigment cell development. Supported by ORIP (P40OD019794, R24OD010435, R24OD021479).
Effect of the Snake Venom Component Crotamine on Lymphatic Endothelial Cell Responses and Lymph Transport
Si et al., Microcirculation. 2023.
https://onlinelibrary.wiley.com/doi/10.1111/micc.12775
The pathology of snake envenomation is closely tied to the severity of edema in the tissue surrounding the area of the bite. This study focused on one of the most abundant venom components in North American viper venom, crotamine, and the effects it has on the cells and function of the lymphatic system. The authors found that genes that encode targets of crotamine are highly present in lymphatic tissues and cells and that there is a differential distribution of those genes that correlates with phasic contractile activity. They found that crotamine potentiates calcium flux in human dermal lymphatic endothelial cells in response to stimulation with histamine and shear stress—but not alone—and that it alters the production of nitric oxide in response to shear, as well as changes the level of F-actin polymerization of those same cells. Crotamine alters lymphatic transport of large molecular weight tracers to local lymph nodes and is deposited within the node, mostly in the immediate subcapsular region. Results suggest that snake venom components may have an impact on the function of the lymphatic system and provide new targets for improved therapeutics to treat snakebites. Supported by ORIP (P40OD010960).
Longitudinal Characterization of Circulating Extracellular Vesicles and Small RNA During Simian Immunodeficiency Virus Infection and Antiretroviral Therapy
Huang et al., AIDS. 2023.
https://www.doi.org/10.1097/QAD.0000000000003487
Antiretroviral therapy is effective for controlling HIV infection but does not fully prevent early aging disorders or serious non-AIDS events among people with HIV. Using pigtail and rhesus macaques (sex not specified), researchers profiled extracellular vesicle small RNAs during different phases of simian immunodeficiency virus infection to explore the potential relationship between extracellular vesicle–associated small RNAs and the infection process. They reported that average particle counts correlated with infection, but the trend could not be explained fully by virions. These findings raise new questions about the distribution of extracellular vesicle RNAs in HIV latent infection. Supported by ORIP (U42OD013117), NIDA, NIMH, NIAID, NCI, and NINDS.
A Live Dengue Virus Vaccine Carrying a Chimeric Envelope Glycoprotein Elicits Dual DENV2–DENV4 Serotype-Specific Immunity
Young et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/36914616/
Dengue vaccine development is challenging because some virus-specific antibodies are protective, whereas others are implicated in enhanced viral replication and more severe disease. Current dengue tetravalent vaccines contain four live attenuated serotypes formulated to induce balanced protective immunity. To simplify live-virus vaccine design, investigators identified co-evolutionary constraints inherent in flavivirus virion assembly. They found that the chimeric virus replicated efficiently in vitro and in vivo and that a single inoculation induced type-specific neutralizing antibodies in male macaques. These findings can be applied to the development of bivalent live dengue vaccines that induce independent immunity to multiple serotypes. Supported by ORIP (P40OD012217) and NIAID.
Mechanism of STMN2 Cryptic Splice-Polyadenylation and its Correction for TDP-43 Proteinopathies
Baughn et al., Science. 2023.
Loss of the RNA-binding protein TDP-43 from the nuclei of affected neurons is a hallmark of neurodegeneration in TDP-43 proteinopathies (e.g., amyotrophic lateral sclerosis, frontotemporal dementia). Loss of functional TDP-43 is accompanied by misprocessing of the stathmin-2 (STMN2) RNA precursor. Investigators determined the elements through which TDP‑43 regulates STMN2 pre‑mRNA processing and identified steric binding antisense oligonucleotides that are capable of restoring normal STMN2 protein and RNA levels. This approach is potentially applicable for human therapy. Supported by ORIP (U42OD010921), NIA, NCI, NIGMS, and NINDS.
Spike and Nsp6 Are Key Determinants of SARS-CoV-2 Omicron BA.1 Attenuation
Chen et al., Nature. 2023.
https://pubmed.ncbi.nlm.nih.gov/36630998/
The ability of the SARS-CoV-2 virus to mutate and create variants of concern demands new vaccines to control the COVID-19 pandemic. The SARS-CoV-2 Omicron variant was shown to be more immune evasive and less virulent than current major variants. The spike (S) protein in this variant carries many mutations that drive these phenotypes. Researchers generated a chimeric recombinant SARS-CoV-2 virus encoding the S gene of Omicron (BA.1 lineage) in an ancestral SARS-CoV-2 isolate and compared it with the naturally circulating Omicron variant. The Omicron S-bearing virus escaped vaccine-induced humoral immunity, owing to mutations in the receptor-binding motif. The recombinant virus replicated efficiently in distal lung cell lines and in K18-hACE2 mice. Moreover, mutations induced in non-structural protein 6 (nsp6) in addition to the S protein were sufficient to restate the attenuated phenotype of Omicron. These findings indicate that the pathogenicity of Omicron is determined by mutations both inside and outside of the S gene. Supported by ORIP (S10OD026983, S10OD030269).
In-Depth Virological and Immunological Characterization of HIV-1 Cure after CCR5A32/A32 Allogeneic Hematopoietic Stem Cell Transplantation
Jensen et al., Nature Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/36807684/
Evidence suggests that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure HIV-1, but the immunological and virological correlates are unknown. Investigators performed a longitudinal virological and immunological analysis of the peripheral blood and tissue compartments of a 53-year-old male patient more than 9 years after CCR5Δ32/Δ32 allogeneic HSCT and 48 months after analytical treatment interruption. Sporadic traces of HIV-1 DNA were detected in peripheral T cell subsets and tissue-derived samples, but repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice of both sexes did not reveal replication-competent virus. This case provides new insights that could guide future cure strategies. Supported by ORIP (P51OD011092) and NIAID.
PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS
Hung et al., Cell . 2023.
https://doi.org/10.1016/j.cell.2023.01.005
Investigators showed that pharmacological suppression of PIKFYVE activity reduces pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of amyotrophic lateral sclerosis (ALS). Upon PIKFYVE inhibition, exocytosis is activated to transport aggregation-prone proteins out of the cells, a process that does not require stimulating macroautophagy or the ubiquitin-proteosome system. These findings suggest therapeutic potential to manage multiple forms of ALS. Supported by ORIP (S10OD021553) and NINDS.
SIV Infection Regulates Compartmentalization of Circulating Blood Plasma miRNAs within Extracellular Vesicles (EVs) and Extracellular Condensates (ECs) and Decreases EV-Associated miRNA-128
Kopcho et al., Viruses. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10059597/
MicroRNAs (miRNAs) are thought to be involved in HIV pathogenesis, but the effect of HIV on the compartmentalization of miRNAs within extracellular particles is unclear. Researchers sequenced the small RNA population of paired EVs and ECs from male rhesus macaques. They showed that extracellular miRNAs in blood plasma are not restricted to any type of extracellular particles but are associated with lipid‑based carriers, with a significant proportion associated with ECs. Further, simian immunodeficiency virus (SIV) infection altered the miRNAome profile of EVs and revealed miR‑128‑3p as a potential target of infection. This work suggests that EV‑ and EC‑associated miRNAs potentially could serve as biomarkers for various diseases. Supported by ORIP (P51OD011104, P51OD011133), NIAID, and NIDA.
Genome Structures Resolve the Early Diversification of Teleost Fishes
Parey et al., Science. 2023.
https://pubmed.ncbi.nlm.nih.gov/36758078/
The early evolution of teleost fishes remains an unanswered question among evolutionary biologists. The three earliest branching clades of crown teleosts are Elopomorpha (e.g., tarpons, eels), Osteoglossomorpha (e.g., arapaima, elephantnose fish), and Clupeocephala (e.g., zebrafish, medaka). Building on recently described genome assemblies in Elopomorpha, the authors explored teleost phylogeny using independent gene sequencing and chromosomal rearrangement phylogenomic approaches. They found that Elopomorpha and Osteoglossomorpha comprise a monophyletic sister group to all other teleosts. This report highlights the value of combining different levels of genome-wide information to solve complex phylogenies and will serve as a basis for new investigations into the genomic and functional evolution of teleosts. Supported by ORIP (R01OD011116).