Biology subjects

Salminen, T. A.

Publications and source records attributed to Salminen, T. A..

4 recordsLinked to original sources

bioRxiv2025

Interrogating the genus Yersinia to define the rules of lipopolysaccharide lipid A structure associated with pathogenicity.

Pathogen recognition by the immune system relies on germline-encoded pathogen recognition receptors which identify conserved pathogen-associated molecular patterns (PAMPs) such as the lipid A section of the lipopolysaccharide (LPS). The assumption that pathogens and mammalian-associated bacteria remodel their lipid A PAMP because of host-microbe co-evolution is a long held-belief of microbial pathogenesis. We set out to test this fundamental principle by interrogating a Gram-negative genus presenting evidence of evolutionary events linked to the acquisition of essential virulence traits, resulting in pathogenic and non-pathogenic species. The genus Yersinia fulfil these requirements; the acquisition of the pYV virulence plasmid is one of the evolutionary events associated with virulence. At 37{degrees}C, only pathogenic Yersinia switch to deacylated lipid A, a modification that diminishes TLR4/MD-2 recognition and reduces inflammation. An engineered chimeric pathogenic Yersinia strain expressing the non-pathogenic lipid A profile efficiently engages with TLR4, demonstrating it is sufficient to switch the acylation pattern to modify the recognition by TLR4 and subsequent activation of inflammation. The lipid As of pathogenic and non-pathogenic species are modified with aminoarabinose and palmitate; therefore, only the reduced acylation of the lipid A PAMP is a trait associated with virulence. The decorations of lipid A do not alter TLR4 engagement but confer resistance to antimicrobial peptides. The chimeric pathogenic Yersinia strain expressing the non-pathogenic lipid A profile allows to ascertain whether the switch in the lipid A PAMP affects virulence. This strain showed enhanced motility due to an upregulation of the flhDC master regulator, and impaired cellular invasion through downregulation of rovA, a key invasion regulator. The expression and function of pYV-encoded virulence factors Yops and YadA were not affected. Nonetheless, the chimeric strain was attenuated in vivo, demonstrating that virulence factors cannot overcome a switch in the lipid A PAMP associated with pathogenicity.

microbiology↗

bioRxiv2024

Secreted Clever-1 Modulates T Cell Responses and Impacts Cancer Immunotherapy Efficacy

Clever-1 functions as a scavenger and adhesion receptor, promoting tolerogenic activities in macrophages and subsets of endothelial cells, thereby contributing to cancer progression. High Clever-1 expression associates with resistance to immune checkpoint inhibitors and combined targeting of Clever-1 with anti-PD-1 enhances response in refractory mouse tumor models. A Clever-1-targeting humanized IgG4 antibody, bexmarilimab, is investigated in clinical trials as a macrophage-reprogramming therapy to treat solid tumors (NCT03733990) and hematological malignancies (NCT05428969). Here we describe a secreted form of (s)Clever-1 enriched in plasma of cancer patients, that was decreased upon bexmarilimab treatment. With the production of a recombinant sClever-1, mimicking the one found in human plasma, we show that sClever-1 can selectively bind activated T cells and disrupt T cell receptor signalling leading to impaired Th1 expansion. We demonstrate that sClever-1 binds to insulin growth factor 2 receptor (IGF2R) on T cells via its mannose-6-phosphate modification and further show that sClever-1 contributes to the immunosuppressive properties of macrophage-secreted extracellular vesicles, driving T cell tolerance and impairing anti-PD-1 efficacy. These findings suggest that Clever-1 exerts a systemic immunosuppressive effect independently of the cells it is expressed on, highlighting its potential as a target in cancer immunotherapy and a valuable biomarker for disease detection.

immunology↗

bioRxiv2023

Proton motive force dissipation drives flavodiiron proteins to the thylakoid membrane for ferredoxin-powered O2 photoreduction

Flavodiiron proteins (FDPs) catalyse light-dependent reduction of oxygen to water in photosynthetic organisms, creating an electron sink on the acceptor side of Photosystem I that protects the photosynthetic apparatus. However, the identity of the electron donor(s) and the molecular mechanisms regulating FDP activity have remained elusive. To elucidate these issues, we employed spectroscopic and gas flux analysis of photosynthetic electron transport, bimolecular fluorescence complementation assays for in vivo protein-protein interactions in the model cyanobacterium Synechocystis sp. PCC 6803, as well as in silico surface charge modelling. We demonstrated that Ferredoxin-1 interacts with Flv1, Flv2, and Flv3, and is the main electron donor to FDP heterooligomers, which are responsible for the photoreduction of oxygen. Moreover, we revealed that association of FDP heterooligomers with thylakoid membranes is promoted by dissipation of the trans-thylakoid proton motive force, providing the first in vivo evidence of a self-regulatory feedback mechanism allowing dynamic control of FDP activity and maintenance of photosynthetic redox balance in fluctuating environments. Our findings have direct implications for rationally directing electron flux toward desired reactions in biotechnological applications.

plant biology↗

bioRxiv2019

Klebsiella pneumoniae type VI secretion system-mediated microbial competition is PhoPQ controlled and reactive oxygen species dependent

Klebsiella pneumoniae is recognized as an urgent threat to human health due to the increasing isolation of multidrug resistant strains. Hypervirulent strains are a major concern due to their ability to cause life-threating infections in healthy hosts. The type VI secretion system (T6SS) is widely implicated in microbial antagonism, and it mediates interactions with host eukaryotic cells in some cases. In silico search for genes orthologous to T6SS component genes and T6SS effector genes across 700 K. pneumoniae genomes shows extensive diversity in T6SS genes across the K. pneumoniae species. Temperature, oxygen tension, pH, osmolarity, iron levels, and NaCl regulate the expression of the T6SS encoded by a hypervirulent K. pneumoniae strain. Polymyxins and human defensin 3 also increase the activity of the T6SS. A screen for regulators governing T6SS uncover the correlation between the transcription of the T6SS and the ability to kill E. coli prey. Whereas H-NS represses the T6SS, PhoPQ, PmrAB, Hfq, Fur, RpoS and RpoN positively regulate the T6SS. K. pneumoniae T6SS mediates intra and inter species bacterial competition. This antagonism is only evident when the prey possess an active T6SS. The PhoPQ two component system governs the activation of K. pneumoniae T6SS in bacterial competitions. Mechanistically, PhoQ periplasmic domain, and the acid patch within, is essential to activate K. pneumoniae T6SS. Klebsiella T6SS also mediates anti-fungal competition. We have delineated the contribution of each of the individual VgrGs in microbial competition, and identified VgrG4 as a T6SS effector. Structurally, domain DUF2345 of VgrG4 is sufficient to intoxicate bacteria and yeast. ROS generation mediates the antibacterial effects of VgrG4, and the antitoxin Sel1E protects against the toxic activity of VgrG4. Our findings provide a better understanding of the regulation of the T6SS in bacterial competitions, and place ROS as an early event in microbial competition.\n\nAUTHOR SUMMARYKlebsiella pneumoniae has been singled out as an \"urgent threat to human health\" due to extremely drug resistant strains. Numerous studies investigate the molecular mechanisms underlying antibiotic resistance in K. pneumoniae, while others dissect the virulence strategies of this pathogen. However, there is still limited knowledge on the fitness of Klebsiella in the environment, and particularly the competition of Klebsiella with other species. Here, we demonstrated that Klebsiella exploits the type VI secretion system (T6SS) nanoweapon to kill bacterial competitors and fungi. K. pneumoniae perceives T6SS attacks from bacterial competitors, resulting in retaliation against the aggressive cell. The perception of the attack involved the sensor PhoPQ and led to the up-regulation of the T6SS. We identified one of the toxins deployed by the T6SS to antagonize other microbes, and revealed how Klebsiella protects itself from this toxin. Our findings provide a better understanding of the T6SS role in microbial competition and uncover new aspects on how bacteria regulate T6SS-mediated microbial antagonism.

microbiology↗