Murphy Lam Yim Wan, Ines Ambite, Thi Hien Tran, Shahram Ahmadi, Atefeh Nazari, Arunima Chaudhuri, Farhan Haq, Christian Krintel, Björn Wullt, Florian Wagenlehner and Catharina Svanborg. University of Lund, Sweden and University of Giessen, Germany.

A transformative shift in infectious disease management is now emerging, built on the discovery of molecules that target the disease response of the host rather than the pathogen. We have identified four examples of such molecules, studied their mechanisms of action and generated evidence of potent protective effects in models of bacterial infection. Clinical efficacy of this approach has recently been demonstrated in a Phase II trial of recurrent acute cystitis (Nature Microbiology, Feb 12, 2026).

 New treatments should preferably target the disease response to infection and facilitate bacterial clearance. Extensive studies have identified molecular determinants of disease severity, that can be targeted therapeutically, in animal models of bacterial infection. Importantly, since these therapies target the disease rather than the bacteria, they show similar efficacy against infections caused by antibiotic sensitive and resistant strains in murine models. 

Excessive innate immune responses to bacterial infection are silenced by treatment with IRF7 siRNA, which targets the type I IFN response, the Lon protease, which targets the MYC transcription factor, the NlpD protein, which inhibits RNA Polymerase II phosphorylation and pro-inflammatory gene expression and an IL-1 receptor antagonist that blocks excessive IL-1 activation, all reducing disease severity and accelerating bacterial clearance, with similar efficacy as antibiotics. This group of transcriptional regulators offer a precise, host-directed strategy to combat excessive, disease-causing innate immune responses during acute bacterial infections and a new alternative to antibiotics. 

IL-1β over-activation has been identified as a molecular basis of severe cystitis, in experimental models and associated with genetic dysfunctions enhancing IL-1β processing. The clinical Phase II study enrolled patients with a documented history of recurrent cystitis and a current acute cystitis episode were randomized in a 2:1 ratio to treatment with anakinra or the antibiotic nitrofurantoin for five days. The results show non-inferiority of IL-1RA compared to nitrofurantoin defined by significant effects of on symptom scores, recurrence rates and quality of life. Gene expression analysis detected more extensive inhibition of the innate immune response by anakinra treatment, as well as key regulators of innate immunity. 

Publications, examples

1. Ambite I, Puthia M, Nagy K, Cafaro C, Nadeem A, Rydström G, Butler D, Zheng Y, Wullt B, Miethke T and Svanborg C. The molecular basis of acute cystitis; susceptibility genes and immunotherapeutic targets. PloS Pathogens 12(10): e1005848 (2016).

2. Puthia M, Ambite I, Cafaro C, Butler D, Huang Y, Lutay N, Rydström G, Gullstrand B, Swaminathan B, Nadeem A, Nilsson B and Svanborg C. IRF7 inhibition prevents destructive innate immunity - a target for non-antibiotic therapy of bacterial infections. Science Translational Medicine 8(336):336ra59 (2016).

3. Butler DSC, Cafaro C, Putze J, Wan MLY, Tran TH, Ambite I, Ahmadi S, Kjellström S, Welinder C, Chao SM, Dobrindt U and Svanborg C. A bacterial protease depletes c-MYC and increases survival in mouse models of bladder and colon cancer. Nature Biotechnology 39, 754–764 (2021).

4. Ambite I, Pilatz A, Buch-Heberling M, Ahmadi S, Godaly G, Wagenlehner F, Svanborg C. Targeted innate immune inhibition therapy compared with antibiotics for recurrent acute cystitis: a randomized, open-label phase 2 trial. Nature Microbiology (2026), doi: 10.1038/s41564-026-02262-1.