Highlights

In brief

A pro-inflammatory protein called calprotectin is naturally regulated by Dok3 but can also be lowered with clinically approved JAK2 inhibitor drugs, revealing a promising therapeutic approach for treating serious cases of COVID-19.

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Extinguishing the flames of inflammation

12 May 2023

Researchers unravel a complex inflammatory pathway involved in severe COVID-19 infection and identify a therapeutic mechanism to reverse it.

When it comes to fighting germs, the immune system is a frontline defence mechanism. White blood cells called neutrophils produce calprotectin, an antimicrobial protein with a curious mode of action. During an infection, calprotectin whisks away essential metal ions from the affected site, creating unfavourable conditions for bacteria and viruses.

However, uncontrolled calprotectin release can add fuel to the fires of inflammation. “Calprotectin was the most abundant biomarker present in the blood plasma of severe COVID-19 patients,” explained Jia Tong Loh, a Senior Research Fellow at A*STAR’s Singapore Immunology Network (SIgN).

Medicines that dial down excessive calprotectin may offer relief, added Loh, but first, scientists need to better understand the factors that control calprotectin production during infection. One promising clue was an immune signalling factor called Dok3; previous studies reported an uptick in Dok3 levels in hospitalised COVID-19 patients.

Alongside SIgN’s Executive Director, Kong-Peng Lam and Research Officer, Joey Teo, Loh connected the dots between Dok3, calprotectin and the uncontrolled immune response in COVID-19 infections.

A proposed mechanic for how Dok3 helps control excessive inflammation during SARS-CoV-2 infection. When TLR4, a surface protein on neutrophils, binds to the viral spike (S) protein, it triggers a signal relay across many intracellular proteins (MyD88, JAK2, STAT3 and others) to boost calprotectin production. Dok3 interrupts this relay by recruiting another protein, SHP-2, to deactivate MyD88, thus preventing further downstream activity.

The research team found that mice lacking Dok3 expression have an exaggerated calprotectin response after exposure to the Spike (S) protein of the SARS-CoV-2 virus. This means that under normal conditions, Dok3 is a stop signal for inflammation, explained Loh. The team suggests that high Dok3 levels in patients with severe COVID-19 could be an attempt by the immune system to blunt skyrocketing calprotectin levels.

Interestingly, the team found that certain commercially-available drugs can also do the same trick as Dok3 in this context—to reduce calprotectin levels. “We have demonstrated the efficacy of JAK2 inhibitors (Fedratinib and Momelotinib) in blocking calprotectin release in human immune cells, thus providing a rationale for repurposing these drugs for severe COVID-19,” commented Loh.

This strategy for controlling inflammation was also found to be effective for SARS-CoV-2 variants - Delta and Omicron – in lab-based studies since they are sensed by the same cell signalling pathway.

“Such immune-based treatments that suppress calprotectin production may be more effective in countering emergent SARS-CoV-2 variants as opposed to S protein-directed approaches,” said Loh, whose team is now testing these next-generation anti-inflammatory therapies in preclinical animal models.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).

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References

Loh, J.T., Teo, J.K.H. and Lam, K.-P. Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein. Frontiers in Immunology 13, 996637 (2022). | article

About the Researchers

Jia Tong Loh received her PhD from Nanyang Technological University under the A*STAR Graduate Scholarship. Currently, she is a Senior Research Fellow and SIgN Fellow at the Singapore Immunology Network (SIgN). Her research focuses on dissecting the immune mechanisms underlying health and disease for the discovery of novel drug targets. She was awarded the NMRC Young Individual Research Grant (Principal Investigator) in 2018 and 2022, and Individual Research Grant (Co-investigator) in 2019.
Kong-Peng Lam obtained his PhD in Immunology in 1994 from the College of Physicians & Surgeons at Columbia University, US. He then carried out postdoctoral research at the Institute for Genetics, University of Cologne, working to understand B cell biology and development. He is currently the Executive Director of A*STAR’s Singapore Immunology Network (SIgN), a Professor in the Departments of Microbiology and Immunology, Physiology, and Pediatrics at Yong Loo Lin School of Medicine, National University of Singapore (NUS), and an Adjunct Professor in the School of Biological Sciences at Nanyang Technological University (NTU).

This article was made for A*STAR Research by Wildtype Media Group