Phalora, P. | bioRxiv Science

bioRxiv2024

The Human T-cell Leukemia Virus capsid protein is a potential drug target

Human T-cell Leukemia Virus type 1 (HTLV-1) is an untreatable retrovirus that causes lethal malignancies and degenerative inflammatory conditions. Effective treatments have been delayed by substantial gaps in our knowledge of the fundamental virology, especially when compared to the closely related virus, HIV. A recently developed and highly effective anti-HIV strategy is to target the virus with drugs that interfere with capsid integrity and interactions with the host. Importantly, the first in class anti-capsid drug approved, lenacapavir, can provide long-acting pre-exposure prophylaxis. Such a property would provide a means to prevent the transmission of HTLV-1, but its capsid has not previously been considered as a drug target. Here we describe the first high-resolution crystal structures of the HTLV-1 capsid protein, define essential lattice interfaces, and identify a previously unknown ligand-binding pocket. We show that this pocket is essential for virus infectivity, providing a potential target for future anti-capsid drug development.

molecular biology↗

bioRxiv2022

MR1 dependent MAIT cell activation is regulated by autophagy associated proteins

The antigen presenting molecule, MR1, presents microbial metabolites to MAIT cells, a population of innate-like, anti-microbial T cells. It also presents an unidentified ligand to MR-1 restricted T cells in the setting of cancer. The cellular co-factors that regulate MR1 antigen presentation have yet to be fully defined. We performed a mass spectrometry-based proteomics screen to identify MR1 interacting proteins and discovered the selective autophagy receptor SQSTM1/p62. CRISPR-Cas9-mediated knock out of SQSTM1/p62 increased MAIT cell activation in the presence of E.coli but not the synthetic ligand 5-OP-RU whereas depletion of Atg5 and Atg7, key autophagy proteins, increased MAIT activation irrespective of the ligand used. This regulation appears to occur at an early step in the MR1 trafficking pathway. This data implicates distinct roles for autophagy associated proteins in the regulation of MR1 activity and highlights the contribution of the autophagy pathway to regulation of cellular antigen presentation.

cell biology↗

bioRxiv2017

Diverse Streptococcus pneumoniae strains drive a MAIT cell response through MR1-dependent and cytokine-driven pathways

Mucosal Associated Invariant T (MAIT) cells represent an innate T cell population of emerging significance. These abundant cells can recognize ligands generated by microbes utilizing the riboflavin synthesis pathway, presented via the major histocompatibility complex (MHC) class I-related molecule MR1 and binding of specific T cell receptors (TCR). They also possess an innate functional programme allowing microbial sensing in a cytokine-dependent, TCR-independent manner. Streptococcus pneumoniae is a major human pathogen that is also associated with commensal carriage, thus host control at the mucosal interface is critical. The recognition of S. pneumoniae strains by MAIT cells has not been defined, nor have the genomics and transcriptomics of the riboflavin operon (Rib genes). We examined the expression of Rib genes in S. pneumoniae at rest and in response to metabolic stress and linked this to MAIT cell activation in vitro. We observed robust recognition of S. pneumoniae strains at rest and following stress, using both TCR-dependent and TCR-independent pathways. The pathway used was highly dependent on the antigen-presenting cell, but was maintained across a wide range of clinically-relevant strains. The riboflavin operon was highly conserved across a range of 571 S. pneumoniae from 39 countries dating back to 1916, and different versions of the riboflavin operon were also identified in related Streptococcus species. These data indicate an important functional relationship between MAIT cells and S. pneumoniae,which may be tuned by local factors, including the metabolic state of the organism and the antigen-presenting cell that it encounters.\n\nAuthor SummaryStreptococcus pneumoniae is the leading cause of bacterial pneumonia, causes invasive diseases such as meningitis and bacteraemia, and is associated with significant morbidity and mortality, particularly in children and the elderly. Here, we demonstrate that a novel T cell population called Mucosal-associated invariant T (MAIT) cells is able to respond to a diverse range of S. pneumoniae strains. We found that this response was dependent on the T cell receptor (which recognises metabolites of the bacterial riboflavin biosynthesis pathway), cytokines, and the type of antigen-presenting cell. A population genomics approach was also used to assess the prevalence and diversity of the genes encoding the riboflavin biosynthesis pathway among a large and diverse collection of S. pneumoniae. These genes were highly conserved across a range of 571 S. pneumoniae from 39 countries dating back to 1916, and was also present in other related Streptococcus species. Given the low levels of MAIT cells in neonates and MAIT cell decline in the elderly, both of whom are at the highest risk of invasive pneumococcal disease, further understanding of the functional role of MAIT cells in host defense against this major pathogen may allow novel therapeutics or vaccines to be designed.

immunology↗