Microbial Metallomics

Nutritional Immunity and Host–Pathogen Dynamics

Nutritional immunity is a host-driven defense mechanism that restricts access to essential nutrients, particularly trace metals like iron and zinc, to invading pathogens. First conceptualized in the 1970s, subsequent research has demonstrated that micronutrients are critical for both host health and microbial survival.[1][2] Host mechanisms to limit pathogen access include sequestration, transport, and regulation of metal ions, while pathogens counteract these restrictions with strategies such as high-affinity uptake systems and production of chelators like siderophores.[1] This constant interplay between host defenses and microbial countermeasures underscores the delicate balance between nutrient availability and immune function, which directly shapes disease outcomes.

The relevance of nutritional immunity has been amplified by insights from microbial metallomics, a field that investigates the role of metal ions in microbial physiology and host–microbiota interactions.[3][4] Metallomic studies show that trace metals such as iron, zinc, copper, and manganese not only serve as enzymatic cofactors but also act as modulators of immune signaling pathways, influencing macrophage activation, neutrophil function, and pathogen detoxification.[3] However, controversies remain regarding how pathogens circumvent host nutritional strategies, with significant variation observed in siderophore specificity and efficiency, as well as in microbial transport systems that hijack host metal-binding proteins.[1][5]

Clinical Implications and Therapeutic Potential

The expanding understanding of nutritional immunity opens new therapeutic avenues. Interventions targeting microbial metal transport pathways, as well as host-directed approaches such as metal supplementation or chelation therapy, hold promise for modulating immune responses.[6][7] Yet, dysregulation of trace metals can either exacerbate or mitigate disease outcomes, emphasizing the need for context-dependent strategies tailored to specific pathogens and host conditions.

The significance of nutritional immunity is particularly relevant in contemporary contexts, such as respiratory infections and COVID-19, where micronutrient status (for example, zinc sufficiency) has been suggested to influence susceptibility and severity.[8][9]While evidence remains heterogeneous, these findings highlight the translational importance of nutritional immunity in guiding clinical practice, infection control, and therapeutic innovation.

Historical Background

The concept of nutritional immunity was first articulated in the 1970s and remains central to understanding host–pathogen interactions.[1] Early studies revealed the importance of iron sequestration in restricting microbial growth and highlighted the role of host proteins such as transferrin and lactoferrin. As early as the 2000s, research on siderophores—high‑affinity iron chelators produced by bacteria—illuminated how pathogens circumvent host iron withholding and how this contributes to virulence.[1][3]

Notably, research has highlighted that both micronutrients and macronutrients are integral to immune function; deficiencies in zinc, iron, copper, and other trace elements can impair immune responses and increase infection susceptibility.[2][10] The gut microbiota also plays a vital role in modulating systemic immunity and is directly influenced by metal availability and dietary composition.[11] The expansion of microbial metallomics has further integrated these insights by quantifying metal pools and tracking metal‑binding proteins to connect metal homeostasis with immune signaling and microbial survival.[4][3] These insights have paved the way for targeted therapies that manipulate metal availability as adjuncts to antimicrobial treatment.[10][6]

Mechanisms of Nutritional Immunity

Role of Trace Elements in Immune Function

Zinc is essential for immune cell development, signaling, and antimicrobial functions; deficiency leads to impaired barrier integrity and increased infection risk.[7][12] The host may withhold zinc from pathogens through S100 proteins and metallothioneins, while pathogens deploy high‑affinity transporters to acquire zinc in limiting environments.[5][12] Iron is sequestered by host proteins such as transferrin, lactoferrin, and ferritin to reduce microbial access; pathogens often counter with siderophores and specialized receptors.[1][13] Toxic heavy metals (e.g., cadmium, mercury, lead, nickel) can disrupt immune signaling and alter microbiota composition, with consequences for both local and systemic immunity.[11][15]

Interplay Between Nutritional Immunity and Pathogen Strategies

Pathogens adapt to metal‑restricted niches using specialized importers, storage proteins, and detoxification systems.[5] For instance, siderophore modification can enable evasion of host lipocalin‑2, while manganese and copper homeostasis buffer oxidative stress in phagolysosomes.[5] The arms race around metal acquisition and intoxication shapes virulence, tissue tropism, and immune evasion.[5][5]

Microbial Metallomics

Microbial metallomics examines the distribution, speciation, and dynamics of metal ions in microbes, integrating proteomics and bioinorganic chemistry to define metal‑dependent pathways relevant to infection and symbiosis.[4][3]

Metal Acquisition and Homeostasis

Microbes regulate metal uptake, storage, and export to maintain homeostasis under host‑imposed metal limitation or intoxication, with systems tuned to iron, zinc, manganese, and copper.[3]

Interactions with Heavy Metals

Environmental and dietary exposures to heavy metals alter microbial communities and host immunity by reshaping metal pools and redox states, emphasizing the need to consider both essential and toxic metals in disease contexts.[11][16] Advances in metallomics have clarified how metal–protein networks adapt in response to host defense and microbial competition.[3]

Nutritional Immunity and Microbial Metal Handling

In the lung and other tissues, metal availability governs immune cell antimicrobial functions (e.g., copper‑ and zinc‑mediated killing) and pathogen survival strategies.[17][1] Understanding these processes informs the development of interventions that harness or modulate metal fluxes during infection.

Therapeutic Implications

Targeting pathogen metal acquisition (e.g., siderophore pathways) and leveraging host metal sequestration or intoxication mechanisms represent promising strategies. Systems‑level profiling of pathogen metalloproteomes and host metal‑binding proteins may reveal biomarkers and therapeutic targets.[4][3]

Intersection of Nutritional Immunity and Microbial Metallomics

Integrated analyses show that host metal sequestration and microbial counterstrategies are tightly intertwined, with macrophage metal effector functions (e.g., copper/zinc bursts) intersecting pathogen detoxification and acquisition modules.[4][18] Metallomic profiling of microbiota communities highlights how dietary and environmental metals shape microbial networks and host immunity.[5][18] Moreover, bacterial resistance mechanisms to heavy metals (e.g., efflux, sequestration, enzymatic detoxification) are integral to pathogen survival in metal‑rich inflammatory niches.[20][21] The gut microbiota intricately influences nutritional immunity and metal metabolism, with implications for systemic inflammation and infection outcomes.[16][22]

Clinical Relevance

Clinical and translational studies indicate that metal imbalances can contribute to immune dysregulation, tolerance, and autoimmunity, while infections can alter systemic metal distribution (e.g., hepcidin‑mediated iron sequestration).[19] Zinc status, for example, has been associated with outcomes in viral infections, though causal interpretations remain debated.[8] Nutritional immunity frameworks help explain tissue‑specific disease processes and can inform personalized interventions combining diet, supplementation, and therapies targeting metal handling.[16][9] In respiratory disease, for instance, copper and zinc fluxes in innate immune cells modulate antimicrobial activity and pathogen persistence—emphasizing the need for context‑specific strategies.[17][13]

References

  1. Huang SW, Lim SK, Yu YA, et al. Overcoming the nutritional immunity by engineering iron‑scavenging bacteria for cancer therapy. eLife. 2024;12:RP90798. https://doi.org/10.7554/eLife.90798.
  2. Zastrow ML. Illuminating metal ions in the gut microbiota (seminar). Colorado State University, Department of Chemistry; 2023. Available at: https://www.chem.colostate.edu/seminars/melissa-zastrow/.
  3. Tourkochristou E, Triantos C, Mouzaki A. The Influence of Nutritional Factors on Immunological Outcomes. Front Immunol. 2021;12:665968. https://doi.org/10.3389/fimmu.2021.665968.
  4. Skaar EP, Raffatellu M. Metals in infectious diseases and nutritional immunity. Metallomics. 2015;7(6):926‑928. https://doi.org/10.1039/C5MT90021B.
  5. Zhu Q, Zhou R, Sun H, et al. Toxic and essential metals: metabolic interactions with the gut microbiota and their health implications. Front Nutr. 2024;11:1448388. https://doi.org/10.3389/fnut.2024.1448388.
  6. Nutritional Immunity and Metallomic Signatures: Metal Competition at the Host–Pathogen Interface. Microbiome Signatures; 2025. Available at: https://microbiomesignatures.com/research-feeds/nutritional-immunity-and-metallomic-signatures/.
  7. Díaz‑Ochoa VE, Jellbauer S, Klaus S, Raffatellu M. Transition metal ions at the crossroads of mucosal immunity and microbial pathogenesis. Front Cell Infect Microbiol. 2014;4:2. https://doi.org/10.3389/fcimb.2014.00002.
  8. Xia P, Lian S, Wu Y, et al. Zinc is an important inter‑kingdom signal between the host and microbe. Vet Res. 2021;52(1):39. https://doi.org/10.1186/s13567-021-00913-1.
  9. Doaei S, Mardi A, Zare M. Role of micronutrients in the modulation of immune system and platelet activating factor in patients with COVID‑19; a narrative review. Front Nutr. 2023;10:1207237. https://doi.org/10.3389/fnut.2023.1207237.
  10. Branch AH, Stoudenmire JL, Seib KL, Cornelissen CN. Acclimation to Nutritional Immunity and Metal Intoxication Requires Zinc, Manganese, and Copper Homeostasis in the Pathogenic Neisseriae. Front Cell Infect Microbiol. 2022;12:909888. https://doi.org/10.3389/fcimb.2022.909888.
  11. Munteanu C, Schwartz B. The relationship between nutrition and the immune system. Front Nutr. 2022;9:1082500. https://doi.org/10.3389/fnut.2022.1082500.
  12. Hood MI, Skaar EP. Nutritional immunity: transition metals at the pathogen–host interface. Nat Rev Microbiol. 2012;10(8):525‑537. https://doi.org/10.1038/nrmicro2836.
  13. Giambò F, Italia S, Teodoro M, et al. Influence of toxic metal exposure on the gut microbiota (Review). World Acad Sci J. 2021;3:19. https://doi.org/10.3892/wasj.2021.90.
  14. Maciel‑Fiuza MF, Müller GC, Campos DMS, et al. Role of gut microbiota in infectious and inflammatory diseases. Front Microbiol. 2023;14:1098386. https://doi.org/10.3389/fmicb.2023.1098386.
  15. Balamurugan BS, Marimuthu MMC, Sundaram VA, et al. Micro nutrients as immunomodulators in the ageing population: a focus on inflammation and autoimmunity. Immunity & Ageing. 2024;21:88. https://doi.org/10.1186/s12979-024-00492-7.
  16. Murdoch CC, Skaar EP. Nutritional immunity: the battle for nutrient metals at the host–pathogen interface. Nat Rev Microbiol. 2022;20(11):657‑670. https://doi.org/10.1038/s41579-022-00745-6.
  17. Healy C, Muñoz‑Wolf N, Strydom K, et al. Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease. Respir Res. 2021;22(1):124. https://doi.org/10.1186/s12931-021-01722-y.
  18. Stafford SL, Bokil NJ, Achard MES, et al. Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper. Biosci Rep. 2013;33(4):e00049. https://doi.org/10.1042/BSR20130014.
  19. Weiss G. Impact of Metals on Immune Response and Tolerance, and Modulation of Metal Metabolism during Infection. In: Trace Metals and Infectious Diseases. Strüngmann Forum Reports. The MIT Press; 2015. Available at: https://www.ncbi.nlm.nih.gov/books/NBK569673/.
  20. Nnaji ND, Anyanwu CU, Miri T, Onyeaka H. Mechanisms of Heavy Metal Tolerance in Bacteria: A Review. Sustainability. 2024;16(24):11124. https://doi.org/10.3390/su162411124.
  21. Singh S, Chaudhry N, Wani MY, et al. Nutritional Immunity, Zinc Sufficiency, and COVID‑19 Mortality in Socially Similar European Populations. Front Immunol. 2021;12:699389. https://doi.org/10.3389/fimmu.2021.699389.
  22. Non-scholarly source. Maldonado‑Contreras A. A healthy microbiome builds a strong immune system that could help defeat COVID‑19. The Conversation. January 25, 2021. Available at: https://theconversation.com/a-healthy-microbiome-builds-a-strong-immune-system-that-could-help-defeat-covid-19-145668.