Examples of “Mn stress” include deficiency and overload -viewed either in isolation or in relation to other divalent metals-, which impact directly on Mn interactions with molecular structures, as well as situations of altered demand for Mn cofactor, such as oxidative stress, nitrosative stress and thermal stress.
“Stress responses” is meant as adaptations to perturbations of optimal Mn steady state levels that may affect host and/or microbe physiology. These adaptive responses comprise alarming and signaling, capture and storage, membrane transport, metabolic activity and detoxification, inter-cellular communication.
Manganese (Mn) is one of the most abundant trace metals found in the human body that is necessary for various functions, including immune response, regulation of blood sugar and cellular energetics, reproduction, digestion, bone growth, hemostasis and protection against various stresses. It is likewise essential for human health and to microbial ability to cause infection. As such Mn availability is tightly controlled both at tissue and cellular levels during health and infection.
Regular diet provides sufficient bioavailable Mn and deficiency is rarely observed; yet, experimental Mn shortage impairs innate immune surveillance. On the other hand excessive intake interferes with metallostasis (e.g., Fe, Zn, Mg co-factors), exerting toxicity and inflammation, notably in the brain. The majority of ingested Mn is thus normally excreted.
Mn homeostasis involves a variety of membrane transporters, which carry other metals as well (e.g., Fe, Zn or Ca), to maintain concentration gradients within cells and tissues. Mn blood levels (70-270 uM) are high compared to the intracellular cytoplasmic concentration of free Mn (micromolar range), because Mn is stored in subcellular compartments such as mitochondria and Golgi, where it acts as a co-factor for anti-oxidant defense and post-translational modifications of secreted proteins, respectively.
Few eukaryotic cytoplasmic enzymes are known to use Mn as a co-factor in vivo (e.g., arginase, glutamine synthase and some phosphatases). However, Mn may constitute the metal co-factor that is preferred over Mg or Fe for certain enzymatic activities, including signalling components, depending on environmental conditions such as oxidative stress and tissue necrosis. Consequently, cytoplasmic and nuclear metabolism or signalling may be regulated by Mn in various infectious settings.
During infection, microbial invaders encounter Mn poor conditions that challenge its use in vital cellular processes, including redox homeostasis maintenance, and can constitute a cue for the expression of virulence factors. Within the host, pathogens regulate Mn metabolism to resist anti-microbial products, such as oxygen and nitrogen based radicals, and allow growth by overcoming nutritional immunity and obtaining essential metals while avoiding acute metallotoxicity. From an evolutionary perspective this resulted in a tug of war between host defense functions and microbial virulence factors.
Host cell death is a frequent outcome as infection develops. Apart from apoptosis coupled to proficient efferocytosis that fosters proper recycling of apoptotic biomass, cell lysis following other forms of regulated death or secondary necrosis may lead to the passive release of intracellular Mn stores, creating a gradient in the surrounding tissue. In turn, Mn uptake by bystander cells may raise cytoplasmic levels to induce local apoptosis or more distally, to activate Mn-sensitive functions involved in host defense.
Mn hypothetical role as a ‘damage-associated element’, analogous to ‘damage-associated molecular patterns’, has interesting immunological correlates: large quantities of the Mn-chelator calprotectin are released as neutrophils reach inflamed tissues, which limits Mn acquisition by pathogens; in vitro exposure to sub-lethal concentrations of free Mn both sensitizes the cGAS-STING pathway in macrophages, leading to IFN-I secretion and expression of interferon-I stimulated genes, and promotes adjuvant activities of derived dendritic cells to elicit adaptive responses.
Current state of knowledge suggests that during infection, and in conjunction with other potential stressors, Mn availability broadly informs host-pathogen interactions. This emerging view instilled the proposed research topic to encourage contributions regarding novel role(s) of Mn in the context of infectious diseases that will detail the diversity of microbial adaptive strategies to obtain enough Mn for survival and growth; depict host processes that mediate and/or regulate nutritional immunity; demonstrate Mn use as specific signal or preferred substrate or co-factor by either protagonist; define the contribution of Mn pro-inflammatory effects to host immunity and their subversion by invasive pathogens; address potential benefits of using Mn compounds in translational strategies such as vaccinology and immunotherapy.
Examples of “Mn stress” include deficiency and overload -viewed either in isolation or in relation to other divalent metals-, which impact directly on Mn interactions with molecular structures, as well as situations of altered demand for Mn cofactor, such as oxidative stress, nitrosative stress and thermal stress.
“Stress responses” is meant as adaptations to perturbations of optimal Mn steady state levels that may affect host and/or microbe physiology. These adaptive responses comprise alarming and signaling, capture and storage, membrane transport, metabolic activity and detoxification, inter-cellular communication.
Manganese (Mn) is one of the most abundant trace metals found in the human body that is necessary for various functions, including immune response, regulation of blood sugar and cellular energetics, reproduction, digestion, bone growth, hemostasis and protection against various stresses. It is likewise essential for human health and to microbial ability to cause infection. As such Mn availability is tightly controlled both at tissue and cellular levels during health and infection.
Regular diet provides sufficient bioavailable Mn and deficiency is rarely observed; yet, experimental Mn shortage impairs innate immune surveillance. On the other hand excessive intake interferes with metallostasis (e.g., Fe, Zn, Mg co-factors), exerting toxicity and inflammation, notably in the brain. The majority of ingested Mn is thus normally excreted.
Mn homeostasis involves a variety of membrane transporters, which carry other metals as well (e.g., Fe, Zn or Ca), to maintain concentration gradients within cells and tissues. Mn blood levels (70-270 uM) are high compared to the intracellular cytoplasmic concentration of free Mn (micromolar range), because Mn is stored in subcellular compartments such as mitochondria and Golgi, where it acts as a co-factor for anti-oxidant defense and post-translational modifications of secreted proteins, respectively.
Few eukaryotic cytoplasmic enzymes are known to use Mn as a co-factor in vivo (e.g., arginase, glutamine synthase and some phosphatases). However, Mn may constitute the metal co-factor that is preferred over Mg or Fe for certain enzymatic activities, including signalling components, depending on environmental conditions such as oxidative stress and tissue necrosis. Consequently, cytoplasmic and nuclear metabolism or signalling may be regulated by Mn in various infectious settings.
During infection, microbial invaders encounter Mn poor conditions that challenge its use in vital cellular processes, including redox homeostasis maintenance, and can constitute a cue for the expression of virulence factors. Within the host, pathogens regulate Mn metabolism to resist anti-microbial products, such as oxygen and nitrogen based radicals, and allow growth by overcoming nutritional immunity and obtaining essential metals while avoiding acute metallotoxicity. From an evolutionary perspective this resulted in a tug of war between host defense functions and microbial virulence factors.
Host cell death is a frequent outcome as infection develops. Apart from apoptosis coupled to proficient efferocytosis that fosters proper recycling of apoptotic biomass, cell lysis following other forms of regulated death or secondary necrosis may lead to the passive release of intracellular Mn stores, creating a gradient in the surrounding tissue. In turn, Mn uptake by bystander cells may raise cytoplasmic levels to induce local apoptosis or more distally, to activate Mn-sensitive functions involved in host defense.
Mn hypothetical role as a ‘damage-associated element’, analogous to ‘damage-associated molecular patterns’, has interesting immunological correlates: large quantities of the Mn-chelator calprotectin are released as neutrophils reach inflamed tissues, which limits Mn acquisition by pathogens; in vitro exposure to sub-lethal concentrations of free Mn both sensitizes the cGAS-STING pathway in macrophages, leading to IFN-I secretion and expression of interferon-I stimulated genes, and promotes adjuvant activities of derived dendritic cells to elicit adaptive responses.
Current state of knowledge suggests that during infection, and in conjunction with other potential stressors, Mn availability broadly informs host-pathogen interactions. This emerging view instilled the proposed research topic to encourage contributions regarding novel role(s) of Mn in the context of infectious diseases that will detail the diversity of microbial adaptive strategies to obtain enough Mn for survival and growth; depict host processes that mediate and/or regulate nutritional immunity; demonstrate Mn use as specific signal or preferred substrate or co-factor by either protagonist; define the contribution of Mn pro-inflammatory effects to host immunity and their subversion by invasive pathogens; address potential benefits of using Mn compounds in translational strategies such as vaccinology and immunotherapy.