Regnase-1 Deficiency Restrains Klebsiella pneumoniae Infection by Regulation of a Type I Interferon Response

Excessive inflammation can lead to tissue damage and autoimmunity. While multiple negative feedback mechanisms exist to prevent uncontrolled inflammation, this system of immune checkpoints may come at the cost of less effective infection control. 

In a recent study published in mBio, UPMC Division of Rheumatology and Clinical Immunology researchers including Felix Aggor, PhD, Partha Biswas, BVSc, MVSc, PhD, and Sarah Gaffen, PhD, found that Regnase-1 (Reg1), a negative feedback regulator of IL-17 and LPS signaling, suppresses type I IFN signaling and thereby impairs resistance to Klebsiella pneumoniae (KP). These findings suggest that Reg1 could be therapeutically targeted in severe bacterial infections.

KP is the third most common cause of ventilator-associated pneumonia in the U.S. and presents a major infectious disease challenge due to antibiotic resistance and limited therapeutic options. These

UPMC authors hypothesized that Reg1-deficiency would be protective in the context of KP pneumonia given the role of Reg1 in restricting TLR-4 and IL-17-dependent signaling pathways. 

Their research shows the following:  

• Mice deficient in Reg1 are resistant to KP and that deficiency did not accelerate bacterial eradication
• Reg1-deficient alveolar macrophages had elevated Ifnb1 and enrichment of type I IFN genes
• Blockade of IFNR during KP infection reversed disease improvement
• Reg1 did not impact Ifnb1 stability directly, only affecting Irf7 expression

The immune system has evolved to successfully balance the effects of anti-microbial effector functions with the potential of collateral tissue damage, meaning that activation of every immune signaling pathway is accompanied by negative feedback signaling events that restrain inflammation.

However, in select conditions, it could be clinically beneficial to allow more inflammation to treat a life-threatening condition, similar to checkpoint inhibitor blockade for cancer therapy. This research suggests that Reg1 could be that target.

Read the full article here.

Reference

Trevejo-Nuñez G, Lin B, Fan L, Aggor FEY, Biswas PS, Chen K, Gaffen SL. Regnase-1 Deficiency Restrains Klebsiella pneumoniae Infection by Regulation of a Type I Interferon Response. mBio. 2022 Feb 1;13(1):e0379221. doi: 10.1128/mbio.03792-21. Epub ahead of print. PMID: 35100872; PMCID: PMC8805030.

The multidisciplinary team consists of members from the Division of Infectious Diseases, Division of Pulmonary, Allergy and Critical Care Medicine, and Division of Rheumatology and Clinical Immunology.