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SummaryThe ESX-1 secretion system plays a critical role in the virulence of Mycobacterium tuberculosis and M. marinum. To date, three proteins are known to be secreted by ESX-1 and necessary for virulence, two of which are CFP-10 and ESAT-6. The ESX-1 secretion and the virulence mechanisms are not well understood. In this study, we have examined the M. marinum secretomes and identified four proteins specific to ESX-1. Two of those are CFP-10 and ESAT-6, and the other two are novel: MM1553 (homologous to Rv3483c) and Mh3881c (homologous to Rv3881c). We have shown that Mh3881c, CFP-10 and ESAT-6 are co-dependent for secretion. Mh3881c is being cleaved at close to the C-terminus during secretion, and the C-terminal portion is critical to the co-dependent secretion, the ESAT-6 cellular levels, and interaction with ESAT-6. The co-dependent secretion is required for M. marinum intracellular growth in macrophages, where the Mh3881c C-terminal portion plays a critical role. The role of the co-dependent secretion in intracellular growth correlates with its role in inhibiting phagosome maturation. Both the secretion and the virulence defects of the Mh3881c mutant are complemented by Mh3881c or its M. tuberculosis homologue Rv3881c, suggesting that in M. tuberculosis, Rv3881c has similar functions.

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Acute kidney injury (AKI) remains a predominant clinical expression of nephropathia epidemica (NE). Its pathogenesis is not yet fully understood. Here, we describe the tissue injury comprehensively and present new data aimed to characterize the injury and explain its pathophysiology. When compared to tubulointerstitial nephritis of a wide variety of other aetiologies, a high degree of proteinuria is a distinguished trait of NE, a finding that is also helpful in the clinical suspicion of the disease. Recently, novel biomarkers for the prediction of severe AKI, including neutrophil gelatinase-associated lipocalin (NGAL), have been identified and ultrastructural tissue changes have been more accurately described. A role for soluble urokinase-type plasminogen activator (suPAR) in the pathogenesis of NE has been suggested, and data on gene polymorphisms, in relation to the severity of AKI have been presented. Smoking is a risk factor for NE and smoking is also associated with aggravated AKI in NE. Although no specific treatment is in sight, recent case reports concerning therapy directed against vascular permeability and vasodilation are of interest. In fact, future work trying to explain the pathophysiology of AKI might need concentrated efforts towards the mechanisms of increased vascular permeability and vasodilatation, which irrespective of organ manifestation, are two major determinants of NE.