Iron regulatory proteins 1 and 2 have opposing roles in regulating inflammation in bacterial orchitis.

Acute bacterial orchitis (AO) is a prevalent cause of intrascrotal inflammation, often resulting in sub- or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in a low-iron environment. On the host side, iron is tightly regulated by iron regulatory proteins 1 and 2 (IRP1 and -2) and these factors are reported to play a role in testicular and immune cell function; however, their precise role remains unclear. Here, we showed in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in less testicular damage and a reduced immune response. Compared with infected wild-type (WT) mice, testes 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 with WT and Irp2-/- mice, no increase in monocytes and neutrophils was detected in testes of Irp1-/- mice upon UPEC infection. Interestingly, in Irp1-/- UPEC-infected testes, we observed an increase in a subpopulation of macrophages (F4/80+CD206+) associated with antiinflammatory and wound-healing activities compared with WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signaling and dampening the immune response.

Gasdermin D in macrophages drives orchitis by regulating inflammation and antigen presentation processes.

Inflammation in the testes induced by infection and autoimmunity contributes significantly to male infertility, a public health issue. Current therapies using antibiotics and broad-spectrum anti-inflammatory drugs are ineffective against non-bacterial orchitis and induce side effects. This highlights the need to explore the pathogenesis of orchitis and develop alternative therapeutic strategies. In this study, we demonstrated that Gasdermin D (GSDMD) was activated in the testes during uropathogenic Escherichia coli (UPEC)-induced acute orchitis, and that GSDMD in macrophages induced inflammation and affected spermatogenesis during acute and chronic orchitis. In testicular macrophages, GSDMD promoted inflammation and antigen presentation, thereby enhancing the T-cell response after orchitis. Furthermore, the pharmacological inhibition of GSDMD alleviated the symptoms of UPEC-induced acute orchitis. Collectively, these findings provide the first demonstration of GSDMD's role in driving orchitis and suggest that GSDMD may be a potential therapeutic target for treating orchitis.

Uropathogenic Escherichia coli Infection Compromises the Blood-Testis Barrier by Disturbing mTORC1-mTORC2 Balance.

The structural and functional destruction of the blood-testis barrier (BTB) following uropathogenic E. coli (UPEC) infection may be a critical component of the pathologic progress of orchitis. Recent findings indicate that the mammalian target of the rapamycin (mTOR)-signaling pathway is implicated in the regulation of BTB assembly and restructuring. To explore the mechanisms underlying BTB damage induced by UPEC infection, we analyzed BTB integrity and the involvement of the mTOR-signaling pathway using in vivo and in vitro UPEC-infection models. We initially confirmed that soluble virulent factors secreted from UPEC trigger a stress response in Sertoli cells and disturb adjacent cell junctions via down-regulation of junctional proteins, including occludin, zonula occludens-1 (ZO-1), F-actin, connexin-43 (CX-43), ß-catenin, and N-cadherin. The BTB was ultimately disrupted in UPEC-infected rat testes, and blood samples from UPEC-induced orchitis in these animals were positive for anti-sperm antibodies. Furthermore, we herein also demonstrated that mTOR complex 1 (mTORC1) over-activation and mTORC2 suppression contributed to the disturbance in the balance between BTB "opening" and "closing." More importantly, rapamycin (a specific mTORC1 inhibitor) significantly restored the expression of cell-junction proteins and exerted a protective effect on the BTB during UPEC infection. We further confirmed that short-term treatment with rapamycin did not aggravate spermatogenic degeneration in infected rats. Collectively, this study showed an association between abnormal activation of the mTOR-signaling pathway and BTB impairment during UPEC-induced orchitis, which may provide new insights into a potential treatment strategy for testicular infection.

Differential tissue-specific damage caused by bacterial epididymo-orchitis in the mouse.

Ascending bacterial urinary tract infections can cause epididymo-orchitis. In the cauda epididymidis, this frequently leads to persistent tissue damage. Less coherent data is available concerning the functional consequences of epididymo-orchitis on testis and caput epididymidis. This in vivo study addresses the functional and spatial differences in responsiveness of murine epididymis and testis to infection with uropathogenic Escherichia coli (UPEC). Whole transcriptome analysis (WTA) was performed on testis, caput, corpus and cauda epididymidis of adult C57BL/6 J wildtype mice. Following UPEC-induced epididymo-orchitis in these mice, epididymal and testicular tissue damage was evaluated histologically and semi-quantitatively at 10 days and 31 days post-inoculation. Expression of inflammatory markers and candidate antimicrobial genes were analysed by RT-qPCR. WTA revealed distinct differences in gene signatures between caput and cauda epididymidis, particularly amonst immunity-related genes. Cellular and molecular signs of testicular inflammation and disruption of spermatogenesis were noticed at day 10, but recovery was observed by day 31. In contrast to the cauda, the caput epididymidis did not reveal any signs of gross morphological damage or presence of pro-inflammatory processes despite confirmed infection. In contrast to beta-defensins, known UPEC-associated antimicrobial peptides (AMP), like Lcn2, Camp and Lypd8, were inherently highly expressed or upregulated in the caput following infection, potentially allowing an early luminal protection from UPEC. At the time points investigated, the caput epididymidis was protected from any obvious infection/inflammation-derived tissue damage. Studies addressing earlier time-points will conclude whether in the caput epididymidis a pro-inflammatory response is indeed not essential for effective protection from UPEC.

Brucellar epididymo-orchitis: a retrospective study of 25 cases.

Objective: Brucellosis is a multisystemic disease which may affect all organs. Epididymo-orchitis is the most common form of genitourinary involvement. The aim of this study was to present our eight-year experience regarding the management of patients with brucellar epididymo-orchitis (BEO).Materials and method: The medical records of male brucellosis patients treated in two centers, between 2010 and 2018 were analyzed retrospectively. The diagnosis of epididymo-orchitis was made when the patients had scrotal pain, swelling, and enlarged tender testicles and/or epididymis on clinical examination. Brucellosis was diagnosed with a positive standard tube agglutination test or a positive blood culture.Results: Brucellosis was diagnosed in 996 male patients. Of these patients, 25 had a diagnosis of BEO (2.5%). All BEO patients suffered from enlarged painful testicles, however, testicular complaints were the only presentation symptoms in three of them. All patients received medical treatment alone except one patient with testicular abscess who underwent surgical drainage besides medical treatment. All patients recovered completely and no relapses have been detected during six-month follow-up.Conclusion: Patients with epididymo-orchitis should be investigated for brucellosis especially in endemic regions. To our knowledge, BEO patients may present with isolated testicular symptoms that make a diagnostic challenge.

Case Report: Epididymo-Orchitis due to Mycobacterium tuberculosis.

Genitourinary tuberculosis (TB) is a rare but well-described form of extrapulmonary TB. We present a case of a 35-year-old man from Ethiopia with scrotal swelling and fever who was found to have epididymo-orchitis due to Mycobacterium tuberculosis. The patient presented to the hospital multiple times before undergoing operative debridement with fine needle aspiration and tissue biopsy to confirm the diagnosis. He improved with antituberculous therapy. Patients with TB risk factors presenting with epididymitis that is refractory to empiric antibiotic therapy warrant consideration of TB epididymitis. Our case demonstrates the high index of suspicion required to establish a diagnosis of genitourinary TB.

Brucella and non-Brucella epididymo-orchitis: comparison of ultrasound findings.

AIM: In brucellosis the male genitourinary system can be affected in a small number of patients. In this study we aimed to identify, discuss and compare the radiologic findings of 24 cases with Brucella epididymo-orchitis (BEO) and 285 cases with non-Brucella epididymis orchitis (NBEO). MATERIAL AND METHODS: The study had a retrospective design. The area of involvement, side of involvement (left, right or bilateral), presence of abscess, hydrocele and testicular involvement pattern were analyzed and compared between the BEO and NBEO cases. RESULTS: The median age of the included cases was 33 years, with a minimum of 0 and maximum of 89. Epididymo-orchitis and isolated orchitis were more frequent in BEO cases while isolated epididymis involvement was more common in patients with non-BEO (p=0.0117). Bilateral involvement was present in 20.8% and 4.6% cases in the BEO and non-BEO groups, respectively (p=0.008). The frequency of abscess was significantly higher in BEO cases (p=0.003). CONCLUSION: Although the radiological indications of BEO are similar to those of other types of epididymo-orchitis, abscess formation, bilateral involvement and testicular involvement contribute significantly to diagnosis.

Activation of the NLRP3 Inflammasome Pathway by Prokineticin 2 in Testicular Macrophages of Uropathogenic Escherichia coli- Induced Orchitis.

Infections of the reproductive tract are known to contribute to testicular inflammatory impairment, leading to an increase of pro-inflammatory cytokines such as IL-1ß, and a decline in sperm quality. Prokineticin 2 (PK2), a secretory protein, is closely associated with the secretion of pro-inflammatory cytokines in inflamed tissue. It was reported that increased PK2 is related to the upregulation of IL-1ß, but the underlying mechanism remains elusive. Here, we illustrated that PK2 was upregulated in testicular macrophages (TM) in a rat model of uropathogenic Escherichia coli (UPEC) infection, which induced the activation of the NLRP3 inflammasome pathway to boost IL-1ß secretion. Administration of PK2 inhibitor alleviated the inflammatory damage and suppressed IL-1ß secretion. Moreover, PK2 promoted NLRP3 expression and the release of cleaved IL-1ß from TM to the supernatants after the challenge with UPEC in vitro. IL-1ß in the supernatants affected Leydig cells by suppressing the expression of genes encoding for the enzymes P450scc and P450c17, which are involved in testosterone production. Overall, we revealed that increased PK2 levels in TM in UPEC-induced orchitis may impair testosterone synthesis via the activation of the NLRP3 pathway. Our study provides a new insight into the mechanisms underlying inflammation-associated male infertility and suggests an anti-inflammatory therapeutic target for male infertility.

Hematogenous dissemination of Chlamydia muridarum from the urethra in macrophages causes testicular infection and sperm DNA damage†.

The incidence of Chlamydia infection, in both females and males, is increasing worldwide. Male infections have been associated clinically with urethritis, epididymitis, and orchitis, believed to be caused by ascending infection, although the impact of infection on male fertility remains controversial. Using a mouse model of male chlamydial infection, we show that all the major testicular cell populations, germ cells, Sertoli cells, Leydig cells, and testicular macrophages can be productively infected. Furthermore, sperm isolated from vas deferens of infected mice also had increased levels of DNA damage as early as 4 weeks post-infection. Bilateral vasectomy, prior to infection, did not affect the chlamydial load recovered from testes at 2, 4, and 8 weeks post-infection, and Chlamydia-infected macrophages were detectable in blood and the testes as soon as 3 days post-infection. Partial depletion of macrophages with clodronate liposomes significantly reduced the testicular chlamydial burden, consistent with a hematogenous route of infection, with Chlamydia transported to the testes in infected macrophages. These data suggest that macrophages serve as Trojan horses, transporting Chlamydia from the penile urethra to the testes within 3 days of infection, bypassing the entire male reproductive tract. In the testes, infected macrophages likely transfer infection to Leydig, Sertoli, and germ cells, causing sperm DNA damage and impaired spermatogenesis.

Acute epididymo-orchitis from brucellosis melitensis in Australia.

Brucellosis epididymo-orchitis (BEO) is extremely rare in non-endemic areas such as Australia. While epididymo-orchitis is relatively common in adolescent men, when presented with a significant travel history, consideration should be given to rare causes such as this. Here, we present a case of BEO in a young 18-year-old man who recently migrated from Greece, with symptoms of acute scrotal pain, swelling and persistent fever. Brucella melitensis was isolated in the blood culture and confirmed with PCR. We suspect transmission was related to ingestion of unpasteurised goat dairy products. He made a full recovery after 7 days of intravenous gentamicin and 6 weeks of oral doxycycline. BEO should be considered in those who present with acute scrotal pain and fever after a recent history of travel to or from a brucellosis- endemic area.

An atypical Bacillus anthracis infection in a bull-A potential occupational health hazard.

Bacillus anthracis infecting cattle is usually identified based on the typical symptom: sudden death. Bacillus anthracis causing atypical symptoms may remain undiagnosed and represent a potential occupational health hazard for, that is veterinarians and producers, butchers and tanners. In the year 2004, one case of sudden death in a dairy farm in southern Finland was diagnosed as bovine anthrax. Four years later 2008, an atypical case of anthrax was diagnosed in the same holding. The bull was taken to the Production Animal Hospital of the Faculty of Veterinary Medicine, University of Helsinki because of fever, loss of appetite and a symmetrically swollen scrotal sac. Penicillin treatment cured the fever but not the swollen scrotum. Before the intended therapeutic castration, a punctuate consisting of 10 ml fluid collected into a syringe from the scrotal sac was cultivated on blood agar at 37°C. After 24 hr, an almost pure culture of a completely non-hemolytic Bacillus cereus-like bacteria was obtained. The strain was identified as B. anthracis using Ba-specific primers by the Finnish Food Safety Authority (RUOKAVIRASTO). After the diagnosis, the bull was euthanized and destroyed, the personnel were treated with prophylactic antibiotics and the clinic was disinfected. In this particular case, treatment with water, Virkon S and lime seemed to be effective to eliminate endospores and vegetative cells since no relapses of anthrax have occurred in 10 years. This case is the last reported anthrax case in Finland.

Anaplasma phagocytophilum presenting with orchitis in a renal transplant recipient.

Human granulocytic anaplasmosis (HGA), caused by Anaplasma phagocytophilum, is an emerging tick-borne disease. It is spread by the black-legged deer tick Ixodes scapularis that serves as the vector for six human pathogens. HGA is still rarely reported in solid organ transplant recipients. In solid organ transplant recipients, orchitis has been reported secondary to chickenpox, tuberculosis and infections due to Listeria monocytogenes and Nocardia asteroides. Orchitis as a presenting feature of HGA infection has only been reported in animals. We present a unique case of a renal transplant recipient with HGA that presented as orchitis. We also compare the clinical presentation and laboratory findings of our patient with other cases of HGA in transplant recipients. To the best of our knowledge, our patient is one of the first cases of A phagocytophilum mono-infection causing a classical presentation of orchitis in a transplant patient.

Scrotal enlargement in rams and bucks in Qassim region, central of Saudi Arabia: clinical and ultrasonographic findings and seroprevalence of brucellosis.

The aim of this study was to clarify the causes of scrotal enlargement in rams and bucks in Qassim region of Saudi Arabia. Enlarged scrotal contents of rams and bucks (n = 153) were examined by visual inspection, palpation, and ultrasonography. Blood samples were obtained and tested for Brucella sp. infection. Clinical and ultrasonographic findings showed that scrotal enlargement was mainly associated with orchitis, peri-orchitis, and epididymitis. Miscellaneous findings were scrotal hernia, scrotal hematoma, and hydrocele. The frequencies of orchitis, peri-orchitis, and epididymitis were 47.4, 21.1, and 14.1% in Awassi rams; 54.5, 21.7, and 8.7% in Najdi rams; 52.3, 20.5, and 9.1% in Ardi bucks; and 50, 16.7, and 16.7% in Damascus bucks, respectively. Orchitis was associated with no-abscess formation (23%), single-abscess formation (15.4%), and multiple-abscesses formation (61.6%). Peri-orchitis was characterized by hard consistency, atrophy of the testes, and extensive connective tissue formation. Epididymitis was observed mainly at the tail of the epididymis (82.4%) but rarely at the head (17.6%). Epididymitis was associated in many cases with abscessation (70.6%). Males with orchitis, peri-orchitis, and epididymitis were positive for Brucella melitensis and Brucella ovis in the frequency of 21.3% and 48.8%, respectively. In conclusion, scrotal enlargement in rams and bucks in Qassim region is caused mainly by inflammation of the testis and/or epididymis and associated tremendously with brucellosis seropositivity.

Acute epididymo-orchitis due to Salmonella Typhi in a young man from Bangladesh.

S. typhi infection rarely involves the genitourinary system. We report the first described case of acute epididymo-orchitis due to S. typhi in a 14-year-old boy from Bangladesh. A high index of suspicion should be maintained when evaluating patients coming from endemic countries also in case of unusual sites of infection.

Brucella canis infection in a young dog with epididymitis and orchitis.

INTRODUCTION: The following case report describes the clinical and diagnostic procedure for suspected brucellosis infection in a dog. A 21 month old intact male Border Collie was presented with an enlarged right testicle and epididymis. The dog was imported to Switzerland from Germany at the age of three months, but was never abroad since then. Clinical and laboratory diagnostic investigation included bacteriology and histology. An initial serological evaluation by means of rapid slide agglutination test (RSAT) was negative. Repeated examination of the same serum by a chromatographic immunoassay (ICT) revealed a positive result. Brucella canis infection was confirmed by culture. The present case is intended to underline the importance of the suspected diagnosis of 'brucellosis' in the presence of reproductive tract problems in dogs. In addition, Brucella canis has zoonotic potential and it is imperative to comply with strict hygiene management.

INTRODUCTION: Le rapport de cas suivant décrit la procédure clinique et diagnostique en cas de suspicion d'infection par la brucellose chez un chien. Un Border Collie mâle intact de 21 mois a été présenté avec un grossissement du testicule et de l'épididyme droits. Le chien avait été importé d'Allemagne en Suisse à l'âge de trois mois, mais n'avait si non jamais été à l'étranger depuis lors. Des examens diagnostiques cliniques et de laboratoire, notamment bactériologie et histologie ont été effectués. Une première évaluation sérologique au moyen du test d'agglutination rapide sur lame (RSAT) était négative. Un examen ultérieur du même sérum par une immunoanalyse chromatographique (ICT) a révélé un résultat positif. L'infection à Brucella canis a été confirmée par culture. Le présent cas souligne l'importance du diagnostic présumé de «brucellose¼ en présence de problèmes de l>appareil reproducteur chez le chien. De plus, Brucella canis a un potentiel zoonotique et il est impératif d'appliquer des mesures d'hygiène strictes.

Neonatal epididymo-orchitis with pyocele caused by Escherichia coli: Successful treatment with antimicrobial therapy alone / Orquiepididimitis neonatal asociada a piocele por Escherichia coli: tratamiento efectivo con antibioterapia exclusiva

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Comparison of inflammatory markers between brucella and non-brucella epididymo-orchitis

ABSTRACT Objectives: Brucellosis is a multi-system infectious disease that is associated with inflammation, which causes an increase in acute phase reactants. Hematological inflammatory markers of brucellosis include mean platelet volume (MPV), red cell distribution width (RDW), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR). In this study, we aimed to evaluate the diagnostic value of hematological inflammatory markers in Brucella epididymo-orchitis (BEO), and to investigate the utility of these markers for differential diagnosis from non-Brucella epididymo-orchitis (non-BEO). Materials and Methods: We retrospectively reviewed the records of 22 BEO and 50 non-BEO patients. Hematological parameters were recorded and compared between the two groups. The main diagnostic criteria for BEO were positive clinical findings (i.e., testicular pain, tenderness and scrotal swelling), a positive Rose Bengal test result, standard tube agglutination (STA) titer ≥ 1/160, and/or a positive blood culture. Results: The most decisive factors in discriminating between BEO and non-BEO were NLR, RDW, and MPV, in decreasing order of their strength. Regardless of other factors, NLR values < 2.3 significantly increased the odds of BEO (OR=8.080, 95% CI: 1.929-33.843, p=0.004). After adjusting for other factors, RDW values >14.45% significantly increased the odds of BEO (OR=7.020, 95% CI: 1.749-28.176, p=0.006). Independent of the other factors, patients with MPV < 7.65 fL had a 6.336 times higher risk for BEO (95% CI: 1.393 - 28.822, p=0.017). Conclusion: Hematological inflammatory markers such as NLR, RDW, and MPV can aid in the differential diagnosis of BEO and non-BEO.