The interplay between copper metabolism and microbes: In perspective of host copper-dependent ATPases ATP7A/B Original paper

What was studied?

This review focuses on the interplay between copper metabolism and microbial infections, specifically through the lens of host copper-dependent ATPases ATP7A/B. These transporters are vital for regulating copper homeostasis in the body, as they facilitate the transport of copper ions across cell membranes. The study explores the role of ATP7A and ATP7B in copper distribution within the body, as well as their interactions with various microbial pathogens like Salmonella enterica, Mycobacterium tuberculosis, and viruses like Influenza A Virus (IAV) and Zika Virus (ZIKV). The review outlines how microbes either exploit or disrupt copper metabolism to enhance their survival in the host, highlighting the dual role of copper as both an antimicrobial agent and a pathogen-facilitating factor.

Who was studied?

The review examines ATP7A and ATP7B, two copper-dependent ATPases in humans, and their interaction with copper transport mechanisms. It discusses the regulation and trafficking of these transporters in response to copper levels, as well as their involvement in various copper-related diseases, such as Wilson’s disease and Menkes disease. The research also delves into microbial pathogens like Salmonella, Mycobacterium tuberculosis, Cryptococcus, and Influenza A Virus, which influence host copper metabolism either by manipulating the expression of these transporters or by adapting their own copper handling mechanisms to survive in the host. The review underscores the microbial-host interactions that influence copper balance and their implications for immune responses and disease outcomes.

Most important findings

The study revealed several key insights into the interaction between ATP7A/B and microbes. Copper is essential for both host defense and pathogen survival, and copper’s antimicrobial properties are well-established. The review highlighted that microbial pathogens like Salmonella and Mycobacterium tuberculosis manipulate host copper metabolism by upregulating copper transporters like ATP7A to sequester copper within host cells. This sequestration, however, may also increase host vulnerability to microbial survival, as pathogens use copper pumps to export copper and mitigate its toxic effects. Influenza A Virus and Zika Virus also interfere with copper regulation, which disrupts host copper homeostasis and contributes to oxidative stress, aiding viral replication. The review also pointed out the copper-resistance mechanisms of microbes, such as the use of copper pumps (e.g., CopA, GolT) and binding proteins to counteract copper toxicity within the host environment.

Key implications

This research has significant clinical implications for the treatment of microbial infections. Understanding the copper-dependent mechanisms in microbial survival provides a potential therapeutic target for copper-modulating treatments. Enhancing the host’s copper sequestration during infections or using copper-based treatments could potentially weaken the pathogens’ ability to thrive in the host. On the other hand, microbial resistance to copper presents a challenge, as many pathogens have evolved systems to evade copper toxicity. Clinicians could consider copper homeostasis when designing treatments for infections, especially those involving antibiotic-resistant pathogens. Furthermore, targeting ATP7A/B transporters could offer new therapeutic approaches for diseases like Wilson’s disease and other copper metabolism disorders, where dysfunction of these transporters leads to toxic copper accumulation. Additionally, copper supplementation or copper-related drugs could potentially be used to boost antimicrobial immune responses in patients with weakened defenses.