Biology subjects

Mansour, M. K.

Publications and source records attributed to Mansour, M. K..

3 recordsLinked to original sources

bioRxiv2021

Photoinactivation of catalase sensitizes Candida albicans and Candida auris to ROS-producing agents and immune cells

Nearly all organisms found in nature have evolved and developed their own specific strategies to cope with reactive oxygen species (ROS). Catalase, a heme-containing tetramer protein expressed in a broad range of aerobic fungi, has been utilized as an essential enzymatic ROS detoxifying mechanism, and shows remarkable efficiency in degrading hydrogen peroxide (H2O2) for fungal cell survival and host invasion. Here, we demonstrate that catalase inactivation with blue light renders fungal cells highly susceptible to ROS attack, thus resembling a strength-to-weakness optical switch. To unveil catalase as the underlying molecular target of blue light and its inactivation mechanism, we systematically compared wild-type Candida albicans to a catalase-deficient mutant strain for susceptibility to ROS in the absence/presence of 410 nm treatment. Upon testing on a wide range of fungal species and strains, we found that intracellular catalase could be effectively and universally inactivated by 410 nm blue light. We find that the photoinactivation of catalase in combination with ROS-generating agents is highly effective and potent in achieving full eradication of multiple fungal species and strains, including multiple clinical strains of Candida auris, the causative agent of the global fungal epidemic. In addition, photoinactivation of catalase is shown to facilitate macrophage killing of intracellular Candida albicans. The antifungal efficacy of catalase photoinactivation is further validated using a Candida albicans-induced mouse model of skin abrasion. Taken together, our findings offer a novel catalase-photoinactivation approach to address multidrug-resistant Candida infections.

microbiology↗

bioRxiv2021

tiRNA signaling via stress-regulated vesicle transfer in the hematopoietic niche

Extracellular vesicles transfer complex biologic material between cells, whose role in in-vivo organismal physiology is poorly defined. Here, we demonstrate that osteoblastic cells in the bone marrow elaborate extracellular vesicles that are taken up by hematopoietic progenitor cells in vivo. Genotoxic or infectious stress rapidly increased stromal-derived extracellular vesicle transfer to granulocyte-monocyte progenitors. Stimulating osteoblastic cells with parathyroid hormone or activating its receptor enhanced extracellular vesicle transfer, myeloid recovery post radiation and improved animal survival from Candida sepsis. The extracellular vesicles contained tiRNAs known to modulate protein translation. 5-ti-Pro-CGG-1 was preferentially abundant in osteoblast-derived extracellular vesicles and when transferred to granulocyte macrophage progenitors, increased protein translation, cell proliferation and myeloid differentiation. Therefore, EV-mediated tiRNA transfer provides a stress modulated signaling axis distinct from conventional cytokine-driven stress responses. One sentence summaryStress regulated tiRNA transfer alters hematopoiesis

cell biology↗

bioRxiv2021

Neutrophils require SKAP2 for reactive oxygen species production following C-type lectin and Candida stimulation

Signaling cascades that convert the recognition of pathogens to efficient inflammatory responses by immune cells, specifically neutrophils, are critical for host survival. SKAP2, an adaptor protein, is required for reactive oxygen species (ROS) generation following stimulation by integrins, formyl peptide receptors and gram-negative bacteria Klebsiella pneumoniae and Yersinia pseudotuberculosis in vitro (Nguyen et al., 2020, Shaban et al., 2020, Boras et al., 2017). SKAP2 is also required for the host defense against K. pneumoniae and{Delta} yopH Y. pseudotuberculosis infection in vivo in mouse models (Shaban et al., 2020, Nguyen et al., 2020). Another class of pattern recognition receptors (PRR) is the C-type lectin receptors (CLR), such as Dectin-1, Dectin-2 and Mincle, that are critical to trigger innate immune responses. Using neutrophils from murine HoxB8-immortalized progenitors, we show that SKAP2 is crucial for maximal ROS response to purified CLR agonists and to the fungal pathogens Candida glabrata and C. albicans, as well as for robust killing of C. glabrata. Skap2-/- murine neutrophils failed to generate ROS and exhibited reduced cellular adhesion in response to trehalose-6,6-dibehenate (TDB), furfurman, and curdlan, Mincle, Dectin-2, and Dectin-1 agonists, respectively. TDB, furfurman, and curdlan stimulation also led to SKAP2-independent integrin conformational changes, showing that inside-out signaling by these CLRs to integrin occurs in the absence of SKAP2. Pyk2 phosphorylation was significantly reduced after infection with C. glabrata in Skap2-/- neutrophils, while Syk phosphorylation was unaffected by the loss of SKAP2. These data strengthen the importance of SKAP2 in the activation of neutrophil ROS production by PRRs to include CLRs and extend the role of SKAP2 in host defense beyond antibacterial immunity to include Candida species.

immunology↗