Biology subjects

Eshraghi, A.

Publications and source records attributed to Eshraghi, A..

2 recordsLinked to original sources

bioRxiv2025

Targeting deubiquitinating enzymes (DUBs) and ubiquitin pathway modulators to enhance host defense against bacterial infections

The rise of antibiotic-resistant bacterial pathogens poses a critical global health challenge, necessitating innovative therapeutic approaches. This study explores host-targeted therapies (HTTs) by focusing on deubiquitinating enzymes (DUBs), essential modulators of the ubiquitin-proteasome system (UPS) that regulate host-pathogen interactions during many bacterial infections. Using Salmonella-infected macrophages as a model, we identified UPS modulators that enhance bacterial clearance and observed significant changes in DUB expression, particularly USP25, USP46, and Otud7b. The small-molecule DUB inhibitor AZ-1 significantly reduced intracellular bacterial loads in vitro and mitigated early disease severity in a murine model by decreasing fecal bacterial loads and preserving host weight. However, AZ-1 alone did not achieve complete clearance of Salmonella and required combination with extracellular-targeting antibiotics for optimal efficacy. Notably, AZ-1 demonstrated broad-spectrum activity against multidrug-resistant pathogens, including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Transcriptomic analyses revealed infection-induced DUB regulation and highlighted pathways modulating immune responses, including TNF- secretion. These findings highlight the potential of targeting the UPS as a host-directed antimicrobial strategy and provide a foundation for developing innovative therapies to combat antimicrobial resistance.

microbiology↗

bioRxiv2024

Pathogenicity determinant protein E is a Francisella type VI secretion system effector protein that modulates host death

Francisella tularensis is a highly pathogenic Gram-negative intracellular bacterial pathogen and the etiologic agent of tularemia, a fatal zoonotic disease that poses a threat to global public health. F. tularensis virulence is mediated by genes on the Francisella pathogenicity island (FPI), which encodes a unique contractile secretion apparatus with functional and structural similarity to bacterial type VI secretion systems (T6SSs). T6SSs can inject effector proteins into host cells to facilitate invasion, intracellular proliferation, and pathogenesis; however, the identity and function of Francisella effectors are still unclear. In this study, we measured T6SS activity in a series of FPI deletion mutants to identify genes that are required for core apparatus activity. We found that Pathogenicity Determinant Protein E (PdpE) is not required for secretion of T6SS substrates or intramacrophage growth. Instead, PdpE forms a complex with another T6SS-secreted effector, PdpC, and limits death of infected host cells by attenuating the macrophage type I interferon response. Importantly, a {Delta}pdpE mutant more rapidly induces death in an established invertebrate in vivo model for Francisella infection. These data define the role of a previously uncharacterized substrate of the Francisella T6SS and provide new insights into host-Francisella interaction.

microbiology↗