Cystatin 9 and C: A novel immunotherapy that protects against multi-drug resistant New Delhi metallo-beta-lactamase-1 producing Klebsiella pneumoniae [PublishAheadOfPrint]

Multidrug-resistant (MDR) bacterial pneumonia can induce dysregulated pulmonary and systemic inflammation leading to morbidity and mortality. Antibiotics to treat MDR pathogens do not function to modulate the extent and intensity of inflammation and can have serious side effects. Herein, we evaluate the efficacy of two human cysteine proteinase inhibitors, cystatin 9 and cystatin C, as a novel immunotherapeutic treatment to combat MDR New Delhi metallo-beta-lactamase-1 (NDM-1) producing Klebsiella pneumoniae (Kp). Our results showed mice intranasally (i.n.) infected with an LD90 challenge of NDM-1 Kp then treated with the combination of human recombinant (r) rCST9 and rCSTC (rCSTs; 50 pg of each i.n. 1h post-infection (PI) and/or 500 pg of each intraperitoneal [i.p.] 3d PI) significantly improved survival compared to infected mice alone or infected mice treated with individual rCSTs (p<0.05). Results showed that both of our optimal rCST treatment regimens modulated pulmonary and systemic pro-inflammatory cytokine secretion in the serum, lungs, livers and spleens of infected mice (p<0.05). Treatment also significantly decreased bacterial burden (p<0.05), while preserving lung integrity with reduced inflammatory cell accumulation compared to infected mice. Further, rCST treatment regimens reduced lipid peroxidation and cell apoptosis in the lungs of infected mice. Additionally, in vitro studies showed that rCSTs (50 or 500 pg of each) directly decreased the viability of NDM-1 Kp. In conclusion, these data showed that rCST9/rCSTC worked synergistically to modulate host inflammation against MDR NDM-1 Kp pneumonia, which significantly improved survival. Therefore, rCST9/rCSTC are a promising therapeutic candidate for the treatment of bacterial pneumonia.

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