Zinc, immune stress, and COVID-19: MT2A emerges as a cross-compartment marker linked to severity

In a PRISMA-guided meta-analysis of seven studies (1,972 hospitalized patients), zinc supplementation was linked to lower mortality. Integrating large public transcriptomic datasets across blood and respiratory tissues, they found the zinc-binding, redox-responsive gene MT2A consistently associated with disease severity, particularly in myeloid cells.

Host-directed therapies are attractive for emerging viral infections because they may remain useful even as viruses mutate. Zinc is a core micronutrient for antiviral immunity and redox balance, and low serum zinc has been repeatedly linked to worse COVID-19 outcomes. But serum measurements do not explain how zinc availability is translated inside cells into immune behavior. That gap has fueled interest in an “intracellular targetome”—the zinc-buffering and redox-responsive systems that activate under inflammatory stress. Metallothioneins, particularly MT2A, are cysteine-rich proteins that bind zinc tightly and help buffer oxidative stress. If this buffering system is overactivated or poorly controlled, it could reshape zinc-dependent signaling and immune balance during infection.

A study (DOI:10.48130/targetome-0026-0006) published in Targetome on 13 February 2026 by Jiahuang Li’s & Bo Zhu’s team, China Pharmaceutical University, links zinc’s clinical survival benefit in COVID-19 to a reproducible, cross-compartment immune stress marker (MT2A), offering a biomarker-guided path to more precise host-directed interventions and timing.

Using a two-tier strategy that combined clinical synthesis with multi-compartment transcriptomics, the researchers first conducted a PRISMA-guided fixed-effects meta-analysis of seven studies totaling 1,972 hospitalized COVID-19 patients (infants to adults). After standard quality assessment, sensitivity testing, and publication-bias evaluation, zinc supplementation was associated with a markedly lower risk of death (OR = 0.48, 95% CI 0.36–0.64), with low heterogeneity, a stable pooled estimate in sensitivity analyses (OR remained 0.48), and no evidence of publication bias (Egger’s p = 0.43). They then profiled peripheral blood mononuclear cells (PBMCs) using single-cell RNA-seq across disease stages and severity, prioritizing zinc-homeostasis genes and testing associations via correlation and median-based stratification. This revealed severity-linked immune remodeling—higher proportions of monocytes, megakaryocytes, B cells, and plasma cells, alongside reduced CD4+ and CD8+ T cells, DCs, and NK cells—and identified MT2A as the most highly expressed metallothionein in monocytes/macrophages. MT2A decreased in mild/moderate progression and convalescence but increased in severe/critical progression, and patient-level analyses linked MT2A to many SARS-CoV-2–related genes. In monocytes, MT2A-high patients in both moderate and severe groups showed higher CTSB and IFIH1; CTSL and TLR7 were additionally elevated in moderate disease, while severe disease showed divergence (higher IL1B/CCL3 in MT2A-low but higher TLR8 in MT2A-high). To validate across tissues, single-cell analyses of bronchoalveolar lavage fluid (BALF) and sputum showed severe-state shifts toward myeloid cells and MT2A coupling with SARS-CoV-2 programs: in severe BALF, MT2A correlated positively with CTSB, CTSL, IFIH1, CCL2, and CXCL10, and MT2A-high monocytes/macrophages expressed more CTSL/CCL2 (and more CTSB in macrophages). Sputum displayed cell-type–specific MT2A patterns and severity-dependent correlations (e.g., CTSB/IFIH1/IL18 in severe disease). Bulk RNA-seq from postmortem lungs showed higher MT2A in deceased patients and links to TMPRSS2/CTSL and inflammatory cytokines. Finally, longitudinal blood data indicated MT2A peaks at day 1 post-infection and then declines, supporting MT2A as an early, stage-dependent marker of metal/redox immune stress.

These results position MT2A as a candidate biomarker of “metal/redox immune stress” that could help reduce heterogeneity in future zinc trials—by identifying who is most likely to benefit and when. Rather than treating zinc as a one-size-fits-all supplement, biomarker-guided stratification could support more precise host-directed strategies, including optimized intervention timing and monitoring of response. The findings also nominate MT2A as a testable host node that links micronutrient handling to immune dysregulation across tissues.

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References

DOI

10.48130/targetome-0026-0006

Original Source URL

https://doi.org/10.48130/targetome-0026-0006

About Targetome

Targetome refers to the complete collection of molecular targets (e.g., proteins, RNA or DNA) that interact with and mediate the effect of a specific biomolecule, such as a drug, toxin, metabolites, transcription factor or microRNA, within a biological system. Targetome is an open access journal publishing rigorously peer-reviewed original research articles, reviews, break-through methods, and perspectives that advance our understanding, identification and validation of molecular targets for new drug development.