MARCH to combat Zika virus infection – Nature

Advancing SDG 3: Cellular Mechanisms for Combating Viral Infections

Introduction to Protein Regulation and Global Health Security

Post-translational regulation of proteins via ubiquitination is a fundamental cellular process. This mechanism, crucial for maintaining cellular homeostasis, is primarily directed by E3 ubiquitin ligases. A specific family of these ligases, the membrane-associated RING-CH (MARCH) proteins, has emerged as a significant factor in immune regulation and antiviral defense. Understanding these molecular pathways is paramount to advancing the United Nations’ Sustainable Development Goal 3 (SDG 3), which aims to ensure good health and well-being for all, particularly through Target 3.3: ending the epidemics of communicable diseases like Zika, HIV, and Ebola.

The Role of MARCH Proteins in Antiviral Defense

The human genome encodes eleven MARCH proteins (MARCH1-11) that regulate protein trafficking and levels. Several members, notably MARCH1, MARCH2, and MARCH8, have demonstrated antiviral activity against a range of pathogens that pose significant global health threats. This research directly contributes to the scientific foundation needed to achieve SDG 3 by identifying host-directed targets to combat viral infections.

• Antiviral Mechanisms: MARCH proteins typically restrict viral propagation by downregulating the expression of viral or host proteins essential for the viral life cycle.
• Established Pathways: Common mechanisms include targeting viral glycoproteins for lysosomal degradation, retaining them within endosomes, or blocking their maturation.
• Novel Discovery: Recent findings have uncovered a new antiviral strategy where MARCH proteins downregulate host cell receptors required for viral entry, thereby preventing infection at the initial stage.

Report on MARCH2 and MARCH3 Ligases in Zika Virus Restriction

Identification and Mechanism of TIM-1 Receptor Downregulation

A pivotal study by Zhang et al. identified a specific mechanism contributing to host defense against Zika virus (ZIKV), a pathogen of global concern. The research demonstrated that MARCH2 and MARCH3 proteins are key negative regulators of the T-cell immunoglobulin and mucin domain-1 (TIM-1) receptor, which ZIKV utilizes for cellular entry. This discovery provides a molecular basis for developing new strategies to meet the targets of SDG 3.

1. Specificity: Experiments co-expressing all eleven human MARCH proteins with TIM-1 revealed that only MARCH2 and MARCH3 significantly reduced TIM-1 levels.
2. Interaction and Ubiquitination: Both MARCH2 and MARCH3 were found to interact with the TIM-1 receptor, promoting its K48-linked polyubiquitination at distinct lysine residues (K338 for MARCH2, K346 for MARCH3 in humans).
3. Degradation Pathway: This polyubiquitination marks the TIM-1 receptor for degradation by the proteasome, effectively reducing the number of available entry points for ZIKV on the cell surface.

Experimental Validation and Impact on Viral Infection

The antiviral function of MARCH2 and MARCH3 was rigorously validated through a series of in vitro and in vivo experiments, confirming their role in controlling viral infections and underscoring their relevance to public health goals outlined in SDG 3.

In Vitro Findings

• Increased Susceptibility: Knocking out either MARCH2 or MARCH3 in various human cell lines (hepatic, placental, neuronal) led to increased TIM-1 levels and a corresponding rise in ZIKV infection.
• Redundant Function: A double knockout of both MARCH2 and MARCH3 resulted in a much stronger increase in ZIKV susceptibility, highlighting their redundant but critical roles.
• Broad-Spectrum Potential: Infection by Dengue virus (DENV), another flavivirus that uses the TIM-1 receptor, was also increased in double-knockout cells, suggesting a broader antiviral application.

In Vivo Findings

• Animal Model Confirmation: Knockout mice lacking MARCH2 and/or MARCH3 exhibited elevated TIM-1 levels in their tissues.
• Disease Severity: Upon ZIKV infection, these knockout mice suffered from more significant weight loss and higher viral loads in the spleen, liver, and lungs compared to wild-type mice.
• Mechanism Conservation: The study confirmed that while the specific lysine residues targeted on TIM-1 differ between humans and mice, the overall mechanism of restriction is conserved.

Strategic Implications for Achieving Sustainable Development Goal 3

Potential for Novel Therapeutic Interventions

The identification of the MARCH2/3-TIM-1 axis as a natural host defense mechanism opens new avenues for developing therapeutic interventions against a host of viral diseases. By targeting this pathway, it may be possible to create broad-spectrum antivirals against pathogens that rely on TIM-1 for entry, including ZIKV, filoviruses (Ebola), dengue virus, and chikungunya virus. Such advancements are critical for building resilient health systems and achieving the targets of SDG 3.

Unresolved Questions and Future Research Priorities

While this research marks a significant step forward, several questions remain that must be addressed to translate these findings into clinical applications. Future research should focus on clarifying the complex biology of MARCH proteins to ensure that any therapeutic manipulation is both safe and effective.

• Substrate Specificity: What determines why only MARCH2 and MARCH3, among the eleven family members, target the TIM-1 receptor?
• Viral Evasion: Do ZIKV and other TIM-1-dependent viruses possess mechanisms to counteract this MARCH-mediated downregulation?
• Regulation of MARCH Proteins: How are the expression and activity of MARCH2 and MARCH3 regulated during a viral infection?
• Duality of Function: How can the antiviral properties of some MARCH proteins be harnessed therapeutically while avoiding the proviral activities exhibited by others, such as MARCH8 in certain contexts?

Conclusion: Integrating Molecular Biology with Global Health Goals

The detailed elucidation of the antiviral mechanism of MARCH2 and MARCH3 against Zika virus provides a powerful example of how fundamental molecular biology research directly supports global health initiatives. This knowledge contributes fundamentally to the strategic objectives of SDG 3: Good Health and Well-being by identifying novel targets for antiviral drug development. Continued investigation into these host-pathogen interactions is essential for enhancing global preparedness and response capabilities against emerging and re-emerging infectious diseases.

1. Relevant Sustainable Development Goals (SDGs)

• SDG 3: Good Health and Well-being

  The article is fundamentally centered on biomedical research aimed at understanding and combating infectious diseases. It explores the molecular mechanisms of how human cells defend against viruses like Zika, HIV, Ebola, and SARS-CoV-2. The research’s stated goal is to open “new avenues for potential targets against many human pathogens,” which directly contributes to the overarching goal of ensuring healthy lives and promoting well-being for all at all ages by fighting communicable diseases.

• SDG 9: Industry, Innovation, and Infrastructure

  This goal is relevant as the article represents cutting-edge scientific research and innovation. The study describes a “novel way” and a “new mechanism” by which host proteins can inhibit viral infection. This type of fundamental research, supported by institutions like the “United States National Institutes of Health,” is a critical component of enhancing scientific research and fostering innovation (Target 9.5), which can lead to new therapeutic technologies and industries.

2. Specific SDG Targets

SDG 3: Good Health and Well-being

1. Target 3.3: By 2030, end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases.

   The article directly addresses this target by focusing on a wide range of communicable diseases. It explicitly mentions research on “human immunodeficiency virus (HIV-1), influenza virus, Ebola virus, SARS-CoV-2,” and the primary focus is on “Zika virus (ZIKV),” which is considered a neglected tropical disease. The research aims to “limit Zika virus infection” and could potentially be applied to “dengue virus, and chikungunya virus,” all of which are major global health threats covered by this target.

2. Target 3.b: Support the research and development of vaccines and medicines for the communicable and non-communicable diseases that primarily affect developing countries…

   The entire article is a testament to the importance of supporting research and development. The study’s conclusion that this research “undoubtedly opens new avenues for potential targets against many human pathogens” highlights its role in the pre-clinical phase of developing new medicines. The acknowledgement of funding from the “United States National Institutes of Health” demonstrates the support mechanism for such foundational scientific work, which is essential for creating future “medical interventions” and “therapeutic application[s].”

SDG 9: Industry, Innovation, and Infrastructure

1. Target 9.5: Enhance scientific research, upgrade the technological capabilities of industrial sectors in all countries… including… encouraging innovation and substantially increasing… public and private research and development spending.

   The article is a direct output of the activities described in this target. It is an example of enhanced scientific research that has produced innovative findings (a “new mechanism by which MARCH2/3 proteins restrict Zika virus”). The mention of funding from the NIH (“supported by the United States National Institutes of Health (P20 GM134974 to RKJ)”) is a specific instance of public R&D spending that fuels such scientific progress and innovation.

3. Mentioned or Implied Indicators

While the article does not mention official SDG indicators, it contains data and information that serve as proxies for measuring progress towards the identified targets.

• Indicator for Target 3.3 (Combat communicable diseases): The article provides experimental data that can be used as a proxy for measuring the effectiveness of potential antiviral strategies. Specifically, it measures “viral loads in the spleen, liver, and lung tissues” and “ZIKV infectivity” in cell cultures. A reduction in these metrics within the experimental model implies progress towards developing an intervention that could eventually reduce the incidence of the disease in human populations.

• Indicator for Target 3.b and 9.5 (Support and enhance R&D): The article itself, as a scientific publication, is an indicator of research output. Furthermore, the explicit acknowledgement of the funding source, “United States National Institutes of Health (P20 GM134974 to RKJ),” serves as a direct indicator of public investment in scientific research. The identification of “potential targets against many human pathogens” is a qualitative indicator of progress in the R&D pipeline for new medicines.

4. Summary Table of SDGs, Targets, and Indicators

Source: nature.com