LEPTOTROMBIDIUM DELIENSE INFESTATION IN DOMESTIC DOGS FROM INDIA, A VECTOR OF SCRUB TYPHUS: A CASE REPORT

Scrub typhus is a vector-borne, zoonotic disease caused by Orientia tsutsugamushi. Several members of the genus Leptotrombidium have gained importance due to their potential role as vectors as well as reservoirs for O. tsutsugamushi. The larvae of Leptotrombidium species are primary parasites of ground-dwelling rodents. However, changes in climate, and host specificity makes them adapt to other animals and play a role in the perpetuation of various (re)- emerging pathogens between animals and humans. Two male mongrel dogs aged six months were presented to the College of Veterinary Sciences and Animal Husbandry, Central Agricultural University, Mizoram, India with a history of skin lesions and intense pruritus. Routine skin scraping examination of samples revealed the presence of Leptotrombidium deliense larvae. Considering the public health importance of L. deliense infestation, an attempt was made to screen the dogs for O. tsutsugamushi and other haemoprotozoans. Microscopic and molecular tests were negative for haemoprotozoan parasites and O. tsutsugamushi, respectively. Both the dogs were successfully treated with parenteral ivermectin and topical fipronil spra

Master Transcription Factor Reprogramming Unleashes Selective Translation Promoting Castration Resistance and Immune Evasion in Lethal Prostate Cancer

Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprogramming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5\u27 untranslated regions. Indeed, translation of the androgen receptor and major histocompatibility complex I (MHC-I) through this motif is sensitive to eIF3B amount. Notably, pharmacologic targeting of eIF3B-dependent translation in preclinical models sensitizes prostate cancer to ADT and anti-PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy-refractory lethal prostate cancer and provide a druggable mechanism that may transcend into effective combined therapeutic strategies. SIGNIFICANCE: Our study shows that specialized eIF3B-dependent translation of specific mRNAs released upon downregulation of the master transcription factor MITF confers castration resistance and immune evasion in lethal prostate cancer. Pharmacologic targeting of this mechanism delays castration resistance and increases immune-checkpoint efficacy. This article is featured in Selected Articles from This Issue, p. 2489

Structure, Substrate Specificity and Role of Lon Protease in Bacterial Pathogenesis and Survival

Proteases are the group of enzymes that carry out proteolysis in all forms of life and play an essential role in cell survival. By acting on specific functional proteins, proteases affect the transcriptional and post-translational pathways in a cell. Lon, FtsH, HslVU and the Clp family are among the ATP-dependent proteases responsible for intracellular proteolysis in bacteria. In bacteria, Lon protease acts as a global regulator, governs an array of important functions such as DNA replication and repair, virulence factors, stress response and biofilm formation, among others. Moreover, Lon is involved in the regulation of bacterial metabolism and toxin–antitoxin systems. Hence, understanding the contribution and mechanisms of Lon as a global regulator in bacterial pathogenesis is crucial. In this review, we discuss the structure and substrate specificity of the bacterial Lon protease, as well as its ability to regulate bacterial pathogenesis

Structure, Substrate Specificity and Role of Lon Protease in Bacterial Pathogenesis and Survival

Proteases are the group of enzymes that carry out proteolysis in all forms of life and play an essential role in cell survival. By acting on specific functional proteins, proteases affect the transcriptional and post-translational pathways in a cell. Lon, FtsH, HslVU and the Clp family are among the ATP-dependent proteases responsible for intracellular proteolysis in bacteria. In bacteria, Lon protease acts as a global regulator, governs an array of important functions such as DNA replication and repair, virulence factors, stress response and biofilm formation, among others. Moreover, Lon is involved in the regulation of bacterial metabolism and toxin–antitoxin systems. Hence, understanding the contribution and mechanisms of Lon as a global regulator in bacterial pathogenesis is crucial. In this review, we discuss the structure and substrate specificity of the bacterial Lon protease, as well as its ability to regulate bacterial pathogenesis