The role of iron in the course of bacterial infection of the testis
Final Report Abstract
Uropathogenic Escherichia coli (UPEC) is a pathogen that expresses various iron-acquiring systems to survive in an iron-deficient environment. UPEC are prevalent pathogens for bacterial infections of the male urogenital tract, manifesting as combined epididymo-orchitis in ascites. In 40% of men with epididymo-orchitis, there are long-term fertility restrictions due to reduced sperm counts. During an infection, the high iron requirement of spermatogenesis competes with the sequestration of iron by pathogen-activated immune cells and the bacteria themselves. On the host side, iron is tightly regulated by iron regulatory proteins (IRP) 1 and 2 and these factors have been reported to play a role in testicular and immune cell function, however, their precise role remains unclear. To investigate the influence of altered iron homeostasis on the course of UPEC-induced epididymo-orchitis, the disease was induced in mice with targeted deletions of iron regulatory proteins (IRP) 1 and 2. Infected WT and Irp2-/- testes showed remarkable immunopathologic alterations with spermatogenesis defects, whereas infected Irp1-/- testes showed largely normal spermatogenesis. Interestingly, the absence of IRP1 results in a reduced immune response and reduced testicular damage. Compared to infected wild-type (WT)-mice, testis of UPEC-infected Irp1-/- mice showed impaired ERK signaling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast to WT and Irp2-/- mice, no increase in monocytes and neutrophils was detected in testis of Irp1-/- mice upon UPEC-infection. Interestingly, in Irp1-/- UPEC-infected testis, we observed an increase in a subpopulation of macrophages (F4/80+ CD206+) associated with anti-inflammatory and wound-healing activities compared to WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signaling and dampening the immune response. The detailed mechanism remains elusive though why IRP1 and IRP2 that are established to similarly regulate iron homeostasis have opposing roles in regulating inflammation in UPEC-induced orchitis and therefore, it needs to be further investigated. In addition to investigating the influence of iron on the course of infection in UPEC-induced epididymo-orchitis, we discovered that the absence of IRP1 leads to impaired spermatogenesis under physiological conditions. Histological data and further analysis of testicular cross-sections revealed a hypospermatogenesis phenotype with a reduced number of germ cells, resulting in lower daily sperm production in Irp1-/- mice. Importantly, this impaired spermatogenesis is not due to the changes in iron homeostasis. Altogether, this study uncovers a novel role for IRP1 in maintaining germ cell survival and spermatogenesis, independent of iron regulation.
Publications
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BioIron (2023) Darwin, Australia (oral talk) Title: Impaired iron homeostais can modulate the course of uropathogenic E.coli (UPEC)-induced epididymo-orchitis in different directions
Niraj Ghatpande
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DVG joint conference (2023) Münster, Germany (oral short talk) Title: The infection course of uropathogenic Escherichia coli induced epididymoorchitis is affected by changes in iron homeostasis.
Aileen Harrer
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Iron regulatory proteins 1 and 2 have opposing roles in regulating inflammation in bacterial orchitis. JCI Insight.
Ghatpande, Niraj; Harrer, Aileen; Azoulay-Botzer, Bar; Guttmann-Raviv, Noga; Bhushan, Sudhanshu; Meinhardt, Andreas & Meyron-Holtz, Esther G.
