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Microbes & Immunity Copper and cuproptosis in immunity

expression levels of FDX1 have been correlated with tumor to its sophisticated copper homeostasis system. Following
malignancy, suggesting that it may function as a potential the phagocytosis of M. tuberculosis by macrophages, the
therapeutic target. Notably, FDX1 appears to enhance host’s immune response actively deploys copper ions as
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antitumor immune responses, indicating its dual role in a means to limit bacterial growth. Despite this hostile
both cancer progression and immune modulation. The environment, M. tuberculosis has evolved complex
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differential expression and mutation of cuproptosis-related regulatory mechanisms to manage copper levels effectively,
genes across various cancers underscore their potential role which enhances its survival and pathogenicity.
in tumor prognosis, immune evasion, and the dynamics of A key component of the bacterial response to copper
the tumor microenvironment, suggesting that cuproptosis stress is the global regulator sigma factor C (SigC). Acting
may be instrumental in cancer initiation and progression. 57 as a transcriptional activator, SigC facilitates copper
Several cuproptosis-related proteins, such as DBT and acquisition and helps M. tuberculosis adapt to conditions
SLC31A1, have been shown to correlate significantly with of copper scarcity, thus underscoring its vital role in the
immune cell functions, including those of macrophages, bacterium’s pathogenic strategies during episodes of copper
neutrophils, and regulatory T cells. This relationship indicates deficiency. This regulatory pathway encapsulates the dual
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that cuproptosis may play a dual role in modulating immune nature of copper, which serves as an essential nutrient
responses and influencing the pathological mechanisms for bacterial growth but can also act as a toxin under
underlying diverse conditions, including metabolic disorders conditions of excess, particularly through the generation
such as diabetes. Furthermore, copper exposure has profound of harmful hydroxyl free radicals. Several copper-related
implications on mitochondrial function. Elevated copper proteins are integral to maintaining copper balance within
levels can result in the release of mitochondrial DNA into M. tuberculosis. Among these, copper efflux proteins
the cytoplasm, a phenomenon often triggered by deficiencies CptV (Rv0969) and MctB (Rv1698) play critical roles in
in transcription factor A. This release activates the conferring copper resistance by actively transporting
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cGAS-STING signaling pathway, which is a critical trigger for surplus copper ions out of the bacterial cytoplasm. In
innate immune responses, particularly in liver cells. addition, the copper-binding protein MymT (Rv0186A) is
Copper, while an essential trace element, can become involved in sequestering copper, thereby mitigating its toxic
toxic at elevated concentrations, necessitating the effects. The interplay among these proteins is particularly
development of sophisticated detoxification mechanisms crucial in the host environment, where elevated copper
to ensure bacterial stability. This is particularly significant concentrations arise during the immune response against
for M. tuberculosis, which exhibits a complex repertoire infection.
of copper resistance genes to mitigate the harmful The dynamics of copper metabolism are further
effects of excess copper (Figure 1). Key genes involved complicated by the action of interferon-gamma (IFN-γ),
in copper resistance include copA, copB, copC, and copD, a cytokine produced by CD4+ T cells, which enhances
which contribute directly to the bacteria’s ability to macrophage activation and boosts their capacity to contain
withstand copper-induced stress. The copper-inducible pathogens. IFN-γ upregulates various copper transport
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transcriptional regulatory factor CopR plays a vital role mechanisms, including the high-affinity copper uptake
in orchestrating the expression of these resistance genes, protein CTR1. This protein, along with partner proteins
ensuring a coordinated response to copper exposure. In such as ATOX1 and ATP7A, is instrumental in facilitating
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addition, the copper-resistance system comprises essential copper transport into phagosomes, thereby amplifying
components such as CopT, a copper-translocating the host’s antimicrobial strategies. Notably, the hypoxic
P-type ATPase critical for efficient copper transport, and conditions associated with granuloma formation during
CopZ, a copper-binding protein that sequesters free copper M. tuberculosis infection promote the expression of CTR1,
ions. Another key player is CopY, which functions as a highlighting the nuanced relationship between copper
copper tolerance protein, mitigating copper’s toxic effects. metabolism and immune responses.
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The interplay among these genes underlies a signaling While copper is essential for bacterial growth, the
pathway centered around the regulatory functions of high concentrations introduced by macrophages can
CopR, the transport capabilities of CopT, the binding be detrimental, catalyzing the production of reactive
affinities of CopZ, and the protective roles of CopY. hydroxyl radicals. In response, M. tuberculosis employs
5. The role of cuproptosis in M. tuberculosis various resistance mechanisms, such as the chelation of
immunoevasion copper by MymT and the efflux of copper ions mediated
by CptV and MctB. The cooperative action of CptV and
M. tuberculosis has developed intricate strategies to survive MctB is particularly significant, as MctB has been shown
and replicate within host macrophages, a feat closely linked to be essential for the virulence of M. tuberculosis. In the

Volume 2 Issue 1 (2025) 62 doi: 10.36922/mi.5657