Manganese Stress Responses During Infection

Editors

Mathieu F. Cellier

Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique, Université du Québec

Thomas Kehl-Fie

University of Illinois at Urbana-Champaign

Amy Elizabeth Palmer

University of Colorado Boulder

Impact

N. gonorrhoeae (Narasimhan et al., 2022), C. jejuni (Alqurashi et al., 2021), S. Typhimurium (Eriksson et al., 1998; Cotruvo and Stubbe, 2010; Panosa et al., 2010; Cotruvo and Stubbe, 2011; Martin and Imlay, 2011), C. trachomatis (Jiang et al., 2007), A. ureae (Rose et al., 2019), S. sanguinis (Makhlynets et al., 2014), S. pneumoniae (Jayachandran et al., 2021), S. pyogenes (Roca et al., 2008), B. cereus (John et al., 2022), B. subtilis (Zhang and Stubbe, 2011), B. anthracis (Grāve et al., 2020), M. tuberculosis (Hammerstad et al., 2014). Although the RNR of C. diphtheriae has not been directly characterized, it is very likely that it is manganese-dependent, as two close non-pathogenic relatives, C. glutamicum and C. ammoniagenes, have been demonstrated to be manganese-dependent RNRs (Abbouni et al., 2009; Cox et al., 2010).

Review

03 February 2023

Why is manganese so valuable to bacterial pathogens?

Jan Čapek

and

Branislav Večerek

Apart from oxygenic photosynthesis, the extent of manganese utilization in bacteria varies from species to species and also appears to depend on external conditions. This observation is in striking contrast to iron, which is similar to manganese but essential for the vast majority of bacteria. To adequately explain the role of manganese in pathogens, we first present in this review that the accumulation of molecular oxygen in the Earth’s atmosphere was a key event that linked manganese utilization to iron utilization and put pressure on the use of manganese in general. We devote a large part of our contribution to explanation of how molecular oxygen interferes with iron so that it enhances oxidative stress in cells, and how bacteria have learned to control the concentration of free iron in the cytosol. The functioning of iron in the presence of molecular oxygen serves as a springboard for a fundamental understanding of why manganese is so valued by bacterial pathogens. The bulk of this review addresses how manganese can replace iron in enzymes. Redox-active enzymes must cope with the higher redox potential of manganese compared to iron. Therefore, specific manganese-dependent isoenzymes have evolved that either lower the redox potential of the bound metal or use a stronger oxidant. In contrast, redox-inactive enzymes can exchange the metal directly within the individual active site, so no isoenzymes are required. It appears that in the physiological context, only redox-inactive mononuclear or dinuclear enzymes are capable of replacing iron with manganese within the same active site. In both cases, cytosolic conditions play an important role in the selection of the metal used. In conclusion, we summarize both well-characterized and less-studied mechanisms of the tug-of-war for manganese between host and pathogen.

5,058 views

10 citations

Original Research

13 October 2022

Nramp: Deprive and conquer?

M. F. M. Cellier

2,398 views

2 citations

Schematic overview of the regulatory network for maintaining Mn homeostasis and its usage in bacterial cells. Total intracellular levels of Mn are controlled by 1) regulated import and efflux through dedicated Mn-specific transporters located in the inner membrane (refer to Figure 1A for representative transporter classes). In addition, 2) extracellular binding proteins (T6SS effector proteins) can capture extracellular Mn and deliver it to other uptake machinery (Yang et al., 2021). Mn-sensing regulatory factors control expression of Mn homeostasis genes, primarily encoding transporters, via conformational changes when bound to Mn. These include 3) protein transcription factors that transcriptionally regulate gene expression, as well as 4) RNA-based Mn-sensing riboswitch elements which provide post-transcriptional regulation via altering accessibility of the ribosome binding site (RBS) or an anti-termination event that allows transcription read-through of the coding region of the mRNA (not shown). Other post-transcriptional regulatory mechanism that affect mRNA stability and/or translation include 5) RNA-binding proteins (RBPs) such as CvfD (Sinha et al., 2020) and 6) sRNAs such as RsaC (Lalaouna et al., 2019). RBPs can act directly on mRNAs by binding to motifs present in the mRNA and/or enable sRNAs to base-pair with a mRNA. It is not currently known whether CvfD and RsaC require other factors to mediate their effects. In contrast to riboswitches, sRNAs do not typically directly sense environmental signals by binding ligands, but instead are expressed under specific environmental conditions (e.g., high or low Mn levels). Fluctuating intracellular Mn levels serve as an important role post-translationally, after nascent Mn-using proteins are synthesized. 7) The intracellular labile metal pool can influence the metallation status and activity of Mn-enzymes, such as PhpP, CspB, and Pgm (Martin et al., 2017b; McFarland et al., 2021). Such enzymes are active when bound to Mn, but become inactive with loss of metal or when replaced with Zn; reduced activity is observed with other metal cations. This process might also be aided by metal chaperone delivery factors during Mn deficient bacterial growth (not shown). 8) Metal-dependent protein factors, such as proteases, can directly control protein levels, as when the YqgP protease degrades the Mg transporter MgtA (Began et al., 2020). Other examples include Mn-binding transcription factors (PerR and Irr) that become oxidized when bound to Fe or heme, which leads to their degradation (not shown) (Lee and Helmann, 2006; Ahn and Baker, 2016; Nam et al., 2020). 9) Activated Mn-enzymes YdiU and PhpP may cause global physiological responses by modulating the activities of non-metal binding proteins via post-translational protein modifications, UMPylation and dephosphorylation, respectively (Martin et al., 2017b; Yang et al., 2020). Mn ions are designated as pink spheres; Zn as grey spheres.

Mini Review

15 July 2022

Regulation of Bacterial Manganese Homeostasis and Usage During Stress Responses and Pathogenesis

Julia E. Martin

and

Lauren S. Waters

2,055 views

6 citations

Review

12 July 2022

Manganese Utilization in Salmonella Pathogenesis: Beyond the Canonical Antioxidant Response

Siva R. Uppalapati

and

Andres Vazquez-Torres

3,607 views

3 citations

Review

27 June 2022

Divalent Metal Uptake and the Role of ZIP8 in Host Defense Against Pathogens

Derrick R. Samuelson

, 1 more and

Daren L. Knoell

Manganese (Mn) and Zinc (Zn) are essential micronutrients whose concentration and location within cells are tightly regulated at the onset of infection. Two families of Zn transporters (ZIPs and ZnTs) are largely responsible for regulation of cytosolic Zn levels and to a certain extent, Mn levels, although much less is known regarding Mn. The capacity of pathogens to persevere also depends on access to micronutrients, yet a fundamental gap in knowledge remains regarding the importance of metal exchange at the host interface, often referred to as nutritional immunity. ZIP8, one of 14 ZIPs, is a pivotal importer of both Zn and Mn, yet much remains to be known. Dietary Zn deficiency is common and commonly occurring polymorphic variants of ZIP8 that decrease cellular metal uptake (Zn and Mn), are associated with increased susceptibility to infection. Strikingly, ZIP8 is the only Zn transporter that is highly induced following bacterial exposure in key immune cells involved with host defense against leading pathogens. We postulate that mobilization of Zn and Mn into key cells orchestrates the innate immune response through regulation of fundamental defense mechanisms that include phagocytosis, signal transduction, and production of soluble host defense factors including cytokines and chemokines. New evidence also suggests that host metal uptake may have long-term consequences by influencing the adaptive immune response. Given that activation of ZIP8 expression by pathogens has been shown to influence parenchymal, myeloid, and lymphoid cells, the impact applies to all mucosal surfaces and tissue compartments that are vulnerable to infection. We also predict that perturbations in metal homeostasis, either genetic- or dietary-induced, has the potential to impact bacterial communities in the host thereby adversely impacting microbiome composition. This review will focus on Zn and Mn transport via ZIP8, and how this vital metal transporter serves as a “go to” conductor of metal uptake that bolsters host defense against pathogens. We will also leverage past studies to underscore areas for future research to better understand the Zn-, Mn- and ZIP8-dependent host response to infection to foster new micronutrient-based intervention strategies to improve our ability to prevent or treat commonly occurring infectious disease.

3,160 views

12 citations

Review

21 June 2022

Managing Manganese: The Role of Manganese Homeostasis in Streptococcal Pathogenesis

Shifu Aggarwal

and

Muthiah Kumaraswami

Pathogenic streptococci require manganese for survival in the host. In response to invading pathogens, the host recruits nutritional immune effectors at infection sites to withhold manganese from the pathogens and control bacterial growth. The manganese scarcity impairs several streptococcal processes including oxidative stress defenses, de novo DNA synthesis, bacterial survival, and virulence. Emerging evidence suggests that pathogens also encounter manganese toxicity during infection and manganese excess impacts streptococcal virulence by manganese mismetallation of non-cognate molecular targets involved in bacterial antioxidant defenses and cell division. To counter host-imposed manganese stress, the streptococcal species employ a sophisticated sensory system that tightly coordinates manganese stress-specific molecular strategies to negate host induced manganese stress and proliferate in the host. Here we review the molecular details of host-streptococcal interactions in the battle for manganese during infection and the significance of streptococcal effectors involved to bacterial pathophysiology.

Manganese (Mn) homeostasis during streptococcal infections. During infection, neutrophils release calprotectin (CP) at infection sites (left panel). CP sequesters Mn from the invading pathogen to inhibit streptococcal growth. The intracellular Mn deficiency impairs the activity of Mn-dependent superoxide dismutases (SOD) and ribonucleotide reductases (RNR), which leads to defective antioxidant defenses against superoxide (O2−) and de novo DNA synthesis, respectively. The CP-imposed Mn deficiency is sensed by Mn-sensing metalloregulator, MtsR, and the Mn-free MtsR relieves the repression of ABC family Mn importer mtsABC. The Mn uptake during nutrient-limiting growth conditions in streptococci is mediated primarily by ABC transporters. In some streptococcal species, secondary transporters belonging to NRAMP- and ZIP-family transporters are also involved in Mn acquisition. During Mn sufficiency (middle panel), MtsR binds to Mn, interacts with promoters, and represses the expression of target genes including mtsABC. The optimal Mn levels in the cytosol promotes the activity of SOD and RNR. During Mn toxicity (right panel), the Mn efflux pump MntE detoxifies bacterial cytosol of excess Mn and promotes streptococcal survival. In the absence of MntE, high cytosolic Mn levels lead to mismetallation of peroxide sensing regulator (PerR) with Mn and results in defective antioxidant responses. Furthermore, Mn mismetallated PhpP phosphatase dephosphorylates cell division kinases StkP and MapZ, which causes improper cell division and altered bacterial cell morphologies.

2,260 views

8 citations