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Dietary zinc deficiency promotes Acinetobacter baumannii lung infection via IL-13 in mice

Nature Microbiology volume 9, pages 3196–3209 (2024)Cite this article

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Abstract

Dietary zinc deficiency is a major risk factor for pneumonia. Acinetobacter baumannii is a leading cause of ventilator-associated pneumonia and a critical public health threat due to increasing rates of multidrug resistance. Patient populations at increased risk for A. baumannii pneumonia are also at increased risk of zinc deficiency. Here we established a mouse model of dietary zinc deficiency and acute A. baumannii pneumonia to test the hypothesis that host zinc deficiency contributes to A. baumannii pathogenesis. We showed that zinc-deficient mice have significantly increased A. baumannii burdens in the lungs, dissemination to the spleen and higher mortality. During infection, zinc-deficient mice produce more pro-inflammatory cytokines, including IL-13. Administration of IL-13 promotes A. baumannii dissemination in zinc-sufficient mice, while antibody neutralization of IL-13 protects zinc-deficient mice from A. baumannii dissemination and mortality during infection. These data highlight the therapeutic potential of anti-IL-13 antibody treatments, which are well tolerated in humans, for the treatment of pneumonia.

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Fig. 1: Dietary Zn deficiency increases A. baumannii burdens and lethality in lung infection.
Fig. 2: Dietary Zn deficiency does not change the level of Zn bioavailable to A. baumannii.
Fig. 3: Dietary Zn deficiency leads to increased pathology and immune cell recruitment.
Fig. 4: Zn-deficient mice produce higher levels of IL-13.
Fig. 5: IL-13 promotes dissemination during A. baumannii lung infection.

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Data availability

Flow cytometry files, Nanostring files and all data used to generate graphs are available via figshare at https://doi.org/10.6084/m9.figshare.26461594 (ref. 90).

Code availability

No custom code was developed or used to analyse data in the manuscript.

References

  1. Ikuta, K. S. et al. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 400, 2221–2248 (2022).

    Google Scholar 

  2. Murray, C. J. et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399, 629–655 (2022).

    CAS  Google Scholar 

  3. Koulenti, D., Tsigou, E. & Rello, J. Nosocomial pneumonia in 27 ICUs in Europe: perspectives from the EU-VAP/CAP study. Eur. J. Clin. Microbiol. Infect. Dis. 36, 1999–2006 (2017).

    CAS  PubMed  Google Scholar 

  4. Mohd Sazlly Lim, S., Zainal Abidin, A., Liew, S. M., Roberts, J. A. & Sime, F. B. The global prevalence of multidrug-resistance among Acinetobacter baumannii causing hospital-acquired and ventilator-associated pneumonia and its associated mortality: a systematic review and meta-analysis. J. Infect. 79, 593–600 (2019).

    CAS  PubMed  Google Scholar 

  5. Wong, D. et al. Clinical and pathophysiological overview of Acinetobacter infections: a century of challenge. Clin. Microbiol. Rev. 30, 409–447 (2017).

    CAS  PubMed  Google Scholar 

  6. Dijkshoorn, L., Nemec, A. & Seifert, H. An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii. Nat. Rev. Microbiol. 5, 939–951 (2007).

    CAS  PubMed  Google Scholar 

  7. Falagas, M. E., Karveli, E. A., Siempos, I. & Vardakas, K. Z. Acinetobacter infections: a growing threat for critically ill patients. Epidemiol. Infect. 136, 1009–1019 (2008).

    CAS  PubMed  Google Scholar 

  8. Sengstock, D. M. et al. Multidrug‐resistant Acinetobacter baumannii: an emerging pathogen among older adults in community hospitals and nursing homes. Clin. Infect. Dis. 50, 1611–1616 (2010).

    CAS  PubMed  Google Scholar 

  9. Anstey, N. M. et al. Community-acquired bacteremic Acinetobacter pneumonia in tropical Australia is caused by diverse strains of Acinetobacter baumannii, with carriage in the throat in at-risk groups. J. Clin. Microbiol. 40, 685–686 (2002).

    PubMed  PubMed Central  Google Scholar 

  10. Anstey, N. M., Currie, B. J. & Withnall, K. M. Community-acquired Acinetobacter pneumonia in the Northern Territory of Australia. Clin. Infect. Dis. 14, 83–91 (1992).

    CAS  PubMed  Google Scholar 

  11. Falagas, M. E., Karveli, E. A., Kelesidis, I. & Kelesidis, T. Community-acquired Acinetobacter infections. Eur. J. Clin. Microbiol. Infect. Dis. 26, 857–868 (2007).

    CAS  PubMed  Google Scholar 

  12. Sharma, A., Shariff, M., Thukral, S. S. & Shah, A. Chronic community-acquired Acinetobacter pneumonia that responded slowly to rifampicin in the anti-tuberculous regime. J. Infect. 51, e149–e152 (2005).

    PubMed  Google Scholar 

  13. Fraker, P. J., King, L. E., Laakko, T. & Vollmer, T. L. The dynamic link between the integrity of the immune system and zinc status. J. Nutr. 130, 1399S–1406S (2000).

    CAS  PubMed  Google Scholar 

  14. Fraker, P. J. & King, L. E. Reprogramming of the immune system during zinc deficiency. Annu. Rev. Nutr. 24, 277–298 (2004).

    CAS  PubMed  Google Scholar 

  15. Haase, H. & Rink, L. Multiple impacts of zinc on immune function. Metallomics 6, 1175–1180 (2014).

    CAS  PubMed  Google Scholar 

  16. Rink, L. & Haase, H. Zinc homeostasis and immunity. Trends Immunol. 28, 1–4 (2007).

    CAS  PubMed  Google Scholar 

  17. Girodon, F. et al. Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. MIN. VIT. AOX. geriatric network. Arch. Intern. Med. 159, 748–754 (1999).

    CAS  PubMed  Google Scholar 

  18. Girodon, F. et al. Effect of micronutrient supplementation on infection in institutionalized elderly subjects: a controlled trial. Ann. Nutr. Metab. 41, 98–107 (1997).

    CAS  PubMed  Google Scholar 

  19. Prasad, A. S. et al. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am. J. Clin. Nutr. 85, 837–844 (2007).

    CAS  PubMed  Google Scholar 

  20. Meydani, S. N. et al. Serum zinc and pneumonia in nursing home elderly. Am. J. Clin. Nutr. 86, 1167–1173 (2007).

    CAS  PubMed  Google Scholar 

  21. Barnett, J. B., Hamer, D. H. & Meydani, S. N. Low zinc status: a new risk factor for pneumonia in the elderly? Nutr. Rev. 68, 30–37 (2010).

    PubMed  Google Scholar 

  22. Prasad, A. S. et al. Zinc deficiency in elderly patients. Nutrition 9, 218–224 (1993).

    CAS  PubMed  Google Scholar 

  23. Wakimoto, P. & Block, G. Dietary intake, dietary patterns, and changes with age: an epidemiological perspective. J. Gerentol. A 56, 65–80 (2001).

    Google Scholar 

  24. Kiabi, F., Alipour, A., Darvishi-Khezri, H., Aliasgharian, A. & Zeydi, A. Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: a secondary analysis of a prospective, observational study. Indian J. Crit. Care Med. 21, 34–39 (2017).

    CAS  Google Scholar 

  25. Boudreault, F. et al. Zinc deficiency primes the lung for ventilator-induced injury. JCI Insight 2, e86507 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. Palmer, L. D. & Skaar, E. P. Transition metals and virulence in bacteria. Annu. Rev. Genet. 50, 67–91 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Zackular, J. P. et al. Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection. Nat. Med. 22, 1330–1334 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Juttukonda, L. J. et al. Dietary Manganese Promotes Staphylococcal Infection of the Heart. Cell Host Microbe 22, 531–542.e8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lopez, C. A. & Skaar, E. P. The impact of dietary transition metals on host–bacterial interactions. Cell Host Microbe 23, 737–748 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bauckman, K. A. et al. Dietary restriction of iron availability attenuates UPEC pathogenesis in a mouse model of urinary tract infection. Am. J. Phys. 316, F814–F822 (2019).

    CAS  Google Scholar 

  31. Monteith, A. J., Miller, J. M., Beavers, W. N., Juttukonda, L. J. & Skaar, E. P. Increased dietary manganese impairs neutrophil extracellular trap formation rendering neutrophils ineffective at combating Staphylococcus aureus. Infect. Immun. 90, e0068521 (2022).

    PubMed  Google Scholar 

  32. Nairz, M. et al. Genetic and dietary iron overload differentially affect the course of Salmonella Typhimurium infection. Front. Cell Infect. Microbiol. 7, 110 (2017).

    PubMed  PubMed Central  Google Scholar 

  33. Noto, J. M. et al. Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans. J. Clin. Invest. 123, 479–492 (2013).

    CAS  PubMed  Google Scholar 

  34. Strand, T. A. et al. Pneumococcal pulmonary infection, septicaemia and survival in young zinc-depleted mice. Br. J. Nutr. 86, 301–306 (2001).

    CAS  PubMed  Google Scholar 

  35. Strand, T. A. et al. Effects of zinc deficiency and pneumococcal surface protein A immunization on zinc status and the risk of severe infection in mice. Infect. Immun. 71, 2009–2013 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Eijkelkamp, B. A. et al. Dietary zinc and the control of Streptococcus pneumoniae infection. PLoS Pathog. 15, e1007957 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Alquethamy, S. F. et al. The role of zinc efflux during Acinetobacter baumannii infection. ACS Infect. Dis. 6, 150–158 (2020).

    CAS  PubMed  Google Scholar 

  38. Fraker, P. J., Caruso, R. & Kierszenbaum, F. Alteration of the immune and nutritional status of mice by synergy between zinc deficiency and infection with Trypanosoma cruzi. J. Nutr. 112, 1224–1229 (1982).

    CAS  PubMed  Google Scholar 

  39. Fraker, P. J., Haas, S. M. & Luecke, R. W. Effect of zinc deficiency on the immune response of the young adult A/J mouse. J. Nutr. 107, 1889–1895 (1977).

    CAS  PubMed  Google Scholar 

  40. King, L. E., Osati-Ashtiani, F. & Fraker, P. J. Apoptosis plays a distinct role in the loss of precursor lymphocytes during zinc deficiency in mice. J. Nutr. 132, 974–979 (2002).

    CAS  PubMed  Google Scholar 

  41. King, L. E. & Fraker, P. J. Zinc deficiency in mice alters myelopoiesis and hematopoiesis. J. Nutr. 132, 3301–3307 (2002).

    CAS  PubMed  Google Scholar 

  42. Liu, M. J. et al. ZIP8 regulates host defense through zinc-mediated inhibition of NF-κB. Cell Rep. 3, 386–400 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hesse, L. E., Lonergan, Z. R., Beavers, W. N. & Skaar, E. P. The Acinetobacter baumannii Znu system overcomes host-imposed nutrient zinc limitation. Infect. Immun. 87, e00746-19 (2019).

    PubMed  PubMed Central  Google Scholar 

  44. Hood, M. I. et al. Identification of an Acinetobacter baumannii zinc acquisition system that facilitates resistance to calprotectin-mediated zinc sequestration. PLoS Pathog. 8, e1003068 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Mortensen, B. L., Rathi, S., Chazin, W. J. & Skaar, E. P. Acinetobacter baumannii response to host-mediated zinc limitation requires the transcriptional regulator Zur. J. Bacteriol. 196, 2616–2626 (2014).

    PubMed  PubMed Central  Google Scholar 

  46. Bao, S. & Knoell, D. L. Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L433–L441 (2006).

    CAS  PubMed  Google Scholar 

  47. Bao, S. & Knoell, D. L. Zinc modulates cytokine-induced lung epithelial cell barrier permeability. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L1132–L1141 (2006).

    CAS  PubMed  Google Scholar 

  48. Gomez, N. N. et al. Overexpression of inducible nitric oxide synthase and cyclooxygenase-2 in rat zinc-deficient lung: involvement of a NF-κB dependent pathway. Nitric Oxide 14, 30–38 (2006).

    CAS  PubMed  Google Scholar 

  49. Truong-Tran, A. Q., Carter, J., Ruffin, R. E. & Zalewski, P. D. The role of zinc in caspase activation and apoptotic cell death. Biometals 14, 315–330 (2001).

    CAS  PubMed  Google Scholar 

  50. Manicone, A. M. Role of the pulmonary epithelium and inflammatory signals in acute lung injury. Expert Rev. Clin. Immunol. 5, 63–75 (2009).

    PubMed  PubMed Central  Google Scholar 

  51. Quimby, F. & Luong, R. in The Mouse in Biomedical Research Vol. 3, 171–216 (Elsevier, 2007).

  52. Van Dyken, S. J. & Locksley, R. M. Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu. Rev. Immunol. 31, 317–343 (2013).

    PubMed  PubMed Central  Google Scholar 

  53. Palmer, L. D. et al. The innate immune protein S100A9 protects from T-helper cell type 2-mediated allergic airway inflammation. Am. J. Respir. Cell Mol. Biol. 61, 459–468 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Giannouli, M. et al. Virulence-related traits of epidemic Acinetobacter baumannii strains belonging to the international clonal lineages I–III and to the emerging genotypes ST25 and ST78. BMC Infect. Dis. 13, 282 (2013).

    PubMed  PubMed Central  Google Scholar 

  55. Ozyildirim, S. & Baltaci, S. B. Cardiovascular diseases and zinc. Biol. Trace Elem. Res. 201, 1615–1626 (2023).

    CAS  PubMed  Google Scholar 

  56. Rosenblum, H., Wessler, J. D., Gupta, A., Maurer, M. S. & Bikdeli, B. Zinc deficiency and heart failure: a systematic review of the current literature. J. Card. Fail. 26, 180–189 (2020).

    PubMed  Google Scholar 

  57. Hartl, D. et al. Pulmonary TH2 response in Pseudomonas aeruginosa-infected patients with cystic fibrosis. J. Allergy Clin. Immunol. 117, 204–211 (2006).

    CAS  PubMed  Google Scholar 

  58. Tiringer, K. et al. A Th17- and Th2-skewed cytokine profile in cystic fibrosis lungs represents a potential risk factor for Pseudomonas aeruginosa infection. Am. J. Respir. Crit. Care Med. 187, 621–629 (2013).

    CAS  PubMed  Google Scholar 

  59. Matsukawa, A. et al. Expression and contribution of endogenous IL-13 in an experimental model of sepsis. J. Immunol. 164, 2738–2744 (2000).

    CAS  PubMed  Google Scholar 

  60. Cronan, M. R. et al. A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization. Cell 184, 1757–1774.e14 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Lundahl, M. L. et al. Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses. eLife 11, e74690 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Prasad, A. S. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J. Infect. Dis. 182 Suppl 1, S62–S68 (2000).

    CAS  PubMed  Google Scholar 

  63. Chowdhury, D. et al. Metallothionein 3 controls the phenotype and metabolic programming of alternatively activated macrophages. Cell Rep. 27, 3873–3886.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Subramanian Vignesh, K. et al. IL-4 induces metallothionein 3- and SLC30A4-dependent increase in intracellular Zn2+ that promotes pathogen persistence in macrophages. Cell Rep. 16, 3232–3246 (2016).

    CAS  PubMed  Google Scholar 

  65. Spencer, S. P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Wilhelm, C. et al. Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection. J. Exp. Med. 213, 1409–1418 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Yokota-Nakatsuma, A. et al. Retinoic acid prevents mesenteric lymph node dendritic cells from inducing IL-13-producing inflammatory Th2 cells. Mucosal Immunol. 7, 786–801 (2014).

    CAS  PubMed  Google Scholar 

  68. Ahmed, A. M. S. et al. Association between serum vitamin D, retinol and zinc status, and acute respiratory infections in underweight and normal-weight children aged 6–24 months living in an urban slum in Bangladesh. Epidemiol. Infect. 144, 3494–3506 (2016).

    CAS  PubMed  Google Scholar 

  69. González-Martínez, H. et al. Expression of cytokine mRNA in lymphocytes of malnourished children. J. Clin. Immunol. 28, 593–599 (2008).

    PubMed  Google Scholar 

  70. González-Torres, C. et al. Effect of malnutrition on the expression of cytokines involved in Th1 cell differentiation. Nutrients 5, 579–593 (2013).

    PubMed  PubMed Central  Google Scholar 

  71. Rodríguez, L. et al. Assessment by flow cytometry of cytokine production in malnourished children. Clin. Vaccine Immunol. 12, 502–507 (2005).

    Google Scholar 

  72. Collins, N. & Belkaid, Y. Control of immunity via nutritional interventions. Immunity 55, 210–223 (2022).

    CAS  PubMed  Google Scholar 

  73. Matera, M. G., Ora, J., Calzetta, L., Rogliani, P. & Cazzola, M. Investigational anti IL-13 asthma treatments: a 2023 update. Expert Opin. Investig. Drugs 32, 373–386 (2023).

    CAS  PubMed  Google Scholar 

  74. Brightling, C. E. et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir. Med. 3, 692–701 (2015).

    CAS  PubMed  Google Scholar 

  75. Busse, W. W. et al. Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma. Eur. Respir. J. 53, 1800948 (2019).

    CAS  PubMed  Google Scholar 

  76. Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088–1098 (2011).

    CAS  PubMed  Google Scholar 

  77. Hanania, N. A. et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir. Med. 4, 781–796 (2016).

    CAS  PubMed  Google Scholar 

  78. Nair, P. & O’Byrne, P. M. The interleukin-13 paradox in asthma: effective biology, ineffective biologicals. Eur. Respir. J. 53, 1802250 (2019).

    CAS  PubMed  Google Scholar 

  79. Panettieri, R. A. et al. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respir. Med. 6, 511–525 (2018).

    CAS  PubMed  Google Scholar 

  80. Piper, E. et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur. Respir. J. 41, 330–338 (2013).

    CAS  PubMed  Google Scholar 

  81. Scheerens, H. et al. The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge. Clin. Exp. Allergy. 44, 38–46 (2014).

    CAS  PubMed  Google Scholar 

  82. Simpson, E. L. et al. Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: a randomized, placebo-controlled phase II trial (TREBLE). J. Am. Acad. Dermatol. 78, 863–871.e11 (2018).

    CAS  PubMed  Google Scholar 

  83. Lonergan, Z. R. et al. An Acinetobacter baumannii, zinc-regulated peptidase maintains cell wall integrity during immune-mediated nutrient sequestration. Cell Rep. 26, 2009–2018.e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Nairn, B. L. et al. The response of Acinetobacter baumannii to zinc starvation. Cell Host Microbe 19, 826–836 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Palmer, L. D. et al. Modulating isoprenoid biosynthesis increases lipooligosaccharides and restores Acinetobacter baumannii resistance to host and antibiotic stress. Cell Rep. 32, 108129 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Lonergan, Z. R., Palmer, L. D. & Skaar, E. P. Histidine utilization is a critical determinant of Acinetobacter pathogenesis. Infect. Immun. 88, e00118–e00120 (2020).

    PubMed  PubMed Central  Google Scholar 

  87. Wijers, C. D. M. et al. Identification of two variants of Acinetobacter baumannii 17978 with distinct genotypes and phenotypes. Infect. Immun. https://doi.org/10.1128/iai.00454-21 (2021).

  88. Iacono, M. et al. Whole-genome pyrosequencing of an epidemic multidrug-resistant Acinetobacter baumannii strain belonging to the European clone II group. Antimicrob. Agents Chemother. 52, 2616–2625 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Sheldon, J. R. & Skaar, E. P. Acinetobacter baumannii can use multiple siderophores for iron acquisition, but only acinetobactin is required for virulence. PLoS Pathog. 16, e1008995 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Palmer, L. D. et al. Dataset for ‘Dietary zinc deficiency promotes Acinetobacter baumannii lung infection via IL-13 in mice’. figshare https://doi.org/10.6084/m9.figshare.26461594 (2024).

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Acknowledgements

We thank members of the Palmer Laboratory and Skaar Laboratory for critical reading of the manuscript. We thank the VUMC Flow Cytometry Shared Resource, S. Joyce, A. Kumar and D. Newcomb for help with flow cytometry; M. Allaman and Vanderbilt Digestive Disease Research Center for assistance with the Luminex assay; the VUMC Vanderbilt Technologies for Advanced Genomics core for Nanostring transcript quantification; and the VUMC Translational Pathology Shared Resource for tissue histology. This work was funded by National Institutes of Health grants R01 AI101171 and R01 AI17829 to E.P.S.; F31 AI136255 to Z.R.L.; T32 HL094296 to T. Blackwell (L.D.P.); F32 AI122516, K99 HL143441 and R00 HL143441 to L.D.P.; and NIH P30 DK058404 to Vanderbilt Digestive Disease Research Center. Additional funding was provided by the Ernest W. Goodpasture professorship to E.P.S., the Jane Coffin Childs Memorial Fund for Medical Research fellowship to Z.R.L., the American Heart Association Predoctoral Fellowship to L.J.J. and the Parker B. Francis fellowship program to L.D.P.

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Author notes

  1. Lillian J. Juttukonda

    Present address: Boston Children’s Hospital, Boston, MA, USA

  2. Zachery R. Lonergan

    Present address: Rutgers University, New Brunswick, NJ, USA

  3. Dziedzom A. Bansah

    Present address: American University of the Caribbean, Cupecoy, Sint Maarten

  4. Christopher Pinelli

    Present address: NAMSA, Minneapolis, MN, USA

  5. Kelli L. Boyd

    Present address: Gilead Sciences, Inc., Foster City, CA, USA

  6. These authors jointly supervised this work: Lauren D. Palmer, Eric P. Skaar.

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, USA

    Lauren D. Palmer, Dziedzom A. Bansah, Xiaomei Ren & John H. Geary

  2. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    Kacie A. Traina, Lillian J. Juttukonda, Zachery R. Lonergan, Christopher Pinelli, Kelli L. Boyd, Tzushan S. Yang & Eric P. Skaar

  3. Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA

    Kacie A. Traina, Lillian J. Juttukonda, Zachery R. Lonergan, Christopher Pinelli, Kelli L. Boyd, Tzushan S. Yang & Eric P. Skaar

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Contributions

Conceptualization was performed by L.D.P., L.J.J. and E.P.S. Methodology was performed by L.J.J. and L.D.P. Investigation was performed by L.D.P., K.A.T., L.J.J., Z.R.L., D.A.B., X.R., J.H.G., C.P., K.L.B. and T.S.Y. Writing of the original draft was performed by L.D.P.; reviewing and editing was performed by L.D.P., K.A.T., L.J.J., Z.R.L., D.A.B., X.R., J.H.G., C.P., K.L.B., T.S.Y. and E.P.S. Visualization was performed by L.D.P. Supervision and funding acquisition were performed by L.D.P. and E.P.S.

Corresponding authors

Correspondence to Lauren D. Palmer or Eric P. Skaar.

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Nature Microbiology thanks George Deepe Jr, Holger Heine and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Model of dietary zinc (Zn) deficiency and A. baumannii pneumonia in female mice.

(A) Model of dietary manipulation and A. baumannii 17978 infection in female C57BL/6J mice. (B) Body weight of female mice fed control Zn diet or low Zn diet (n = 10; mean ± SEM are shown). (C) Percent weight gain at the time of infection (n = 10 12-week old female mice; p by two-sided Student’s t test). (D) Survival following intranasal infection with A. baumannii 17978 (n = 10 12-week old female mice; p two-sided by Mantel-Cox test).

Extended Data Fig. 2 Metal levels in Zn sufficient and Zn deficient mice during A. baumannii pneumonia at 24 hpi.

(A–D) Total iron (Fe) and copper (Cu) levels in the lungs and serum (Ctrl Zn mock, n = 5; Low Zn mock, n = 5; Ctrl Zn infected, n = 5; Low Zn infected, n = 4; p by one-way ANOVA with Sidak’s multiple comparisons; mice were male 9-week old C57BL/6J). (E, F) WT and ∆znuC A. baumannii 17978 growth in lysogeny broth (LB) with and without additional Zn (1.25 mM ZnCl2; n = 3 per group; p by two-sided Student’s t-test; data are representative of at least two independent experiments). (G) Survival of male 9-week old C57BL/6J mice fed control Zn or low Zn diet and infected with a 1:1 mix of WT and ∆znuC A. baumannii 17978 (Ctrl Zn, n = 14, Low Zn, n = 12; p by two-sided Mantel-Cox test). Graphs show mean ± SEM.

Extended Data Fig. 3 Lung barrier measures, myocardial necrosis, and flow cytometry gating.

(A) Wet lung weight at 24 hpi of 9-week old male C57BL/6J mice (Ctrl Zn mock, n = 5; Low Zn mock, n = 5; Ctrl Zn infected, n = 5; Low Zn infected, n = 4; p by one-way ANOVA with Sidak’s multiple comparisons). (B, C) Serum albumin in bronchial alveolar lavage fluid (BALF) at 16 hpi (Ctrl Zn mock, n = 2, Low Zn mock, n = 2; Ctrl Zn infected, n = 4; Low Zn infected, n = 5) and 24 hpi (Ctrl Zn mock, n = 2; Low Zn mock, n = 2; Ctrl Zn infected, n = 3; Low Zn infected, n = 4). p by one-way ANOVA with Sidak’s multiple comparisons, mice were 9-week old male C57BL/6J. (D) Representative images of myocardial necrosis clusters in hearts of 12-week old male C57BL/6J mice. (E) Myocardial necrosis scoring, n = 5, p by two-sided Mann-Whitney test. (F) Gating strategy using a representative male C57BL/6J mouse fed low Zn diet and infected with A. baumannii 17978. Abbreviations: FSC-H, forward scatter height; eos., eosinophils; Alv. Mac., alveolar macrophages; DC, dendritic cell; FMO, fluorescence minus one. Graphs show mean ± SEM for parametric data and median for non-parametric data.

Extended Data Fig. 4 Bacterial burdens, IL-13 abundance, and quantification of viable cells in investigating IL-13 production.

(A) A. baumannii 17978 CFU in the lungs of 9-week old male C57BL/6J mice shown in Fig. 4a,b (Ctrl Zn, n = 5; Low Zn, n = 4). (B) IL-13 abundance in the lung samples shown in Fig. 4 measured by Luminex (Ctrl Zn mock, n = 5; Low Zn mock, n = 5; Ctrl Zn infected, n = 5; Low Zn infected, n = 4). p by Kruskal-Wallis with Dunn’s multiple comparisons). (C) Lungs of 9-week old male C57BL/6J mice fed ctrl Zn or low Zn diet were digested and restimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin for 6 h and viable cells were enumerated pre- and post-restimulation by trypan blue exclusion with a hemocytometer (Ctrl Zn mock, n = 3; Low Zn mock, n = 3; Ctrl Zn infected, n = 7; Low Zn infected, n = 7; p by two-sided ratio paired t test with Holm-Sidak’s multiple comparisons). (D) IL-13 abundance in spleen samples from 12-week old male (solid symbols) and female (divided symbols) C57BL/6J mice was measured by ELISA (6 hpi, Ctrl Zn, n = 9, Low Zn, n = 10; 16 hpi, n = 9; 24 hpi, n = 10; p by two-sided Mann-Whitney at each timepoint). Panels A, B, and D show median; Panel C shows mean ± SEM.

Extended Data Fig. 5 Survival curve for 24 h IL-13 neutralization experiment.

IgG and α-IL-13 were administered immediately prior to A. baumannii 17978 intranasal inoculation of 9-week old male C57BL/6J mice (Ctrl Zn isotype, n = 11; Low Zn isotype, n = 11; Ctrl Zn α-IL-13, n = 12, Low Zn α-IL-13, n = 10; p by two-sided Mantel-Cox test; data are combined from two independent experiments).

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Palmer, L.D., Traina, K.A., Juttukonda, L.J. et al. Dietary zinc deficiency promotes Acinetobacter baumannii lung infection via IL-13 in mice. Nat Microbiol 9, 3196–3209 (2024). https://doi.org/10.1038/s41564-024-01849-w

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