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A remarkable percentage of cows in industrialized dairy farms can be affected by uterine diseases including endometritis. Different viral and bacterial agents are causing endometritis in dairy cows including Trueperella pyogenes , and bovine alphaherpesvirus 1. Also, bovine gammaherpesvirus type 4 (BoGHV-4) is responsible for different reproductive disorders. The present study aimed to investigate the role of BoGHV-4 in histopathological and cytological changes of post-partum uterine diseases and its relation to bacterial co-infection. Forty-seven uteri were collected from Holstein dairy cows at least 35 days post-partum. Bacterial culture, cytological, and histopathological studies were conducted on the endometrial samples. The PCR reaction was conducted for the sequencing of the gB gene. PCR examination indicated that from 47 uteri obtained from a slaughterhouse, 13 uteri (27.7%) were positive for BoGHV-4. Statistical analysis revealed a significant relationship between virus presence, and histopathologic and cytologic endometritis ( P  < 0.05). Also, Escherichia coli and Fusobacterium necrophorum presence was significantly related to BoGHV-4 infection. Vast varieties of other bacterial species were isolated from different samples but the relation between these bacteria and BoGHV-4 was not significant ( P  > 0.05). Altogether, it can be concluded that BoGHV-4 can play some roles in establishing endometrial inflammation increasing leukocyte infiltration in endometrium, and enhancing bacterial infection in the uterus of dairy cows. This is the first study, which detected the BoGHV-4 in Iranian cows using molecular methods.

Background Bovine herpesvirus 4 (BoHV-4) is a gammaherpesvirus with a Worldwide distribution in cattle and is often isolated from the uterus of animals with postpartum metritis or pelvic inflammatory disease. Virus strain adaptation to an organ, tissue or cell type is an important issue for the pathogenesis of disease. To explore the mechanistic role of viral strain variation for uterine disease, the present study aimed to develop a tool enabling precise genetic discrimination between strains of BoHV-4 and to easily manipulate the viral genome. Methods A strain of BoHV-4 was isolated from the uterus of a persistently infected cow and designated BoHV-4-U. The authenticity of the isolate was confirmed by RFLP-PCR and sequencing using the TK and IE2 loci as genetic marker regions for the BoHV-4 genome. The isolated genome was cloned as a Bacterial Artificial Chromosome (BAC) and manipulated through recombineering technology Results The BoHV-4-U genome was successfully cloned as a BAC, and the stability of the pBAC-BoHV-4-U clone was confirmed over twenty passages, with viral growth similar to the wild type virus. The feasibility of using BoHV-4-U for mutagenesis was demonstrated using the BAC recombineering system. Conclusion The analysis of genome strain variation is a key method for investigating genes associated with disease. A resource for dissection of the interactions between BoHV-4 and host endometrial cells was generated by cloning the genome of BoHV-4 as a BAC.

Study Objective. To identify sensitive and specific histological criteria for endometritis in women with laparoscopically-confirmed acute salpingitis. Methods. Women, age 18–40 years of age presenting with complaints of lower abdominal pain ≤2 weeks and no antibiotics use in past two weeks, were enrolled. They underwent clinical examination, screening for HIV; other sexually transmitted infections plus endometrial biopsy sampling for histopathology. Diagnostic laparoscopy confirmed the diagnosis of acute salpingitis. Controls were women undergoing tubal ligation and HIV-1 infected women asymptomatic for genital tract infection. Results. Of 125 women with laparoscopically-confirmed salpingitis, 38% were HIV-1 seropositive. Nineteen HIV-1 negative controls were recruited. For the diagnosis of endometritis, ≥1 plasma cells (PC) and ≥3 polymorphonuclear lymphocytes (PMN) per HPF in the endometrium had a sensitivity of 74% for HIV-1-seropositive, 63% for HIV-1-seronegative women with a specificity of 75% and positive predictive value of 85% regardless of HIV-1-infection for predicting moderate to severe salpingitis. For HIV-1-seronegative women with mild salpingitis, ≥1 PC and ≥3 PMN had a sensitivity of 16% and a PPV of 57%. Conclusion. Endometrial histology, did not perform well as a surrogate marker for moderate to severe salpingitis, and failed as a surrogate marker for mild salpingitis.

Background Uterine infections, primarily caused by bacterial pathogens, pose a significant problem for dairy farmers worldwide, leading to poor reproductive performance and economic losses. However, the bacteria responsible for uterine infections have not been adequately studied, nor has the antibiotic susceptibility of the causative bacteria been frequently tested in Ethiopia. This study aims to estimate the cumulative incidence of uterine infections in postpartum dairy cows, identify bacterial causes and determine antimicrobial susceptibility profile of the isolated bacteria. Methods A prospective cohort study was conducted in which 236 cows from 74 dairy farms were monitored biweekly from calving to 90 days postpartum for metritis, endometritis and other disorders. Aseptic uterine swab samples were collected from 40 cows with uterine infections. The samples were cultured, and the isolated bacteria were tested for antimicrobial susceptibility using the disk diffusion method. Results Out of 236 cows monitored during the postpartum phase, 45 (19.1%) were found to have contracted uterine infection. The cumulative incidence of metritis was 11.4% ( n  = 27), while the cumulative incidence of endometritis was 7.6% ( n  = 18). Of the 40 cultured swab samples, 29 (72.5%) had one or more bacteria isolated. The most commonly isolated bacteria were Escherichia coli (45%), coagulase-positive staphylococci (30%), and Klebsiella spp. (22.5%). Other bacterial spp, including Arcanobacterium pyogenes (12.5%), Fusobacterium spp. (12.5%), Enterobacter aerogenes (12.5%), coagulase-negative staphylococci (12.5%), Streptococcus spp. (7.5%), Salmonella spp, (5%) Proteus spp (5%) and Pasteurella spp (2.5%) were also isolated. All of the isolated bacteria demonstrated resistance to at least one of the antimicrobials tested. Multidrug resistance was observed in E. coli , Klebsiella spp., A. pyogenes , and Fusobacterium spp. Gentamicin was found to be the most effective antimicrobial against all bacteria tested, while tetracycline was the least effective of all. Conclusion The study found that a significant proportion of cows in the population were affected by uterine infections and the isolated bacteria developed resistance to several antimicrobials. The study emphasizes the need for responsible use of antimicrobials to prevent the emergence of antimicrobial resistance. It also highlights the importance of raising awareness among dairy farmers to avoid the indiscriminate use of antibiotics and its consequences.

Sow endometritis is usually caused by multiple species of pathogenic bacteria. Numerous isolates from endometritis patients have developed antimicrobial resistance. Thus, novel antibacterial agents and strategies to combat endometritis are needed. A total of 526 bacteria, including Staphylococcus spp. (26.3%), Streptococcus spp. (12.3%), E. coli (28.9%), Enterococcus spp. (20.1%), Proteus spp. (9.5%), and Corynebacterium spp. (2.8%), were isolated from sows with endometritis. We constructed a novel chimeric lysin, ClyL, which is composed of a cysteine- and histidine-dependent amidohydrolase/peptidase (CHAP) catalytic domain from the phage lysin LysGH15 and a cell wall-binding domain (CBD) from the prophage lysin Lys0859. The activities of ClyL and Lys0859 were most pronounced for the Staphylococcus and Streptococcus strains isolated from sow endometritis and bovine mastitis, respectively. ClyL and Lys0859 were combined to create a phage lysin cocktail, which demonstrated a synergistic effect against the coinfection of Staphylococcus and Streptococcus in vitro and in vivo. Furthermore, the combination of phage lysin cocktail and cefquinome had a synergistic bactericidal effect on boar semen that did not influence the activity of sperm. Remarkably, the incidence rate of sow endometritis was 0% (0/7) when the combination of phage lysin cocktail and cefquinome was used in semen via artificial insemination compared with 50% (3/6) when PBS was administered. Overall, the administration of a phage lysin cocktail and cefquinome in semen via artificial insemination is a promising novel strategy to prevent sow endometritis after artificial insemination.

Background Bovine endometritis is a prevalent uterine disease that directly curtails reproductive performance and indirectly reduces milk production by increasing calving intervals. Postpartum uterine bacterial infection is the primary cause of bovine endometritis, which is typically treated with prostaglandin F2α and antimicrobials. However, abuse of antimicrobials has led to the emergence of multidrug-resistant bacteria, threatening both human and animal health. To explore alternatives to antimicrobial therapy for bovine endometritis, we integrated uterine metagenomic and metabolomic analyses and identified a novel bioactive metabolite with therapeutic potential. The potential antibacterial and anti-inflammatory effects of this metabolite against bovine endometritis were evaluated by assessing its inhibitory effect on the growth of F. necrophorum in vitro, and by quantifying histopathological scores and inflammatory cytokine expression levels in an in vivo mouse model of endometritis, respectively. Results A total of 40 Holstein dairy cows at 21 days to 30 days postpartum were assigned into heathy cows ( n  = 15), subclinical endometritis cows ( n  = 12) and clinical endometritis cows ( n  = 13) according to clinical signs and laboratory tests for bovine endometritis. The uterine fluid was collected aseptically for metagenomics and metabolomics sequencing to identify bacterial species associated with bovine endometritis and metabolites that could potentially be used for treatment of bovine endometritis. A total of 17 bacterial species were significantly associated with bovine endometritis, with Fusobacterium necrophorum as the most significantly enriched in cows with clinical endometritis compared to healthy counterparts. In total, 391 metabolites were significantly differentially abundant between healthy and clinical endometritis cows. Among these, a plant-derived compound, tenacissoside G was significantly enriched in healthy cows. Notably, the abundance of F. necrophorum was significantly negatively associated with the concentration of tenacissoside G in clinical endometritis cows. Moreover, tenacissoside G significantly inhibited the growth of F. necrophorum in vitro and ameliorated inflammation in endometritis caused by F. necrophorum in a mice model. Conclusion This study provides new insights into the relationship between uterine microbiome and metabolites in bovine endometritis, potentially leading to novel strategies for treating bovine endometritis. Furthermore, tenacissoside G exhibits therapeutic effects against endometritis induced by F. necrophorum , and could serve as a potential alternative to antimicrobials for treating endometritis. 4zsjb51vT84em7kwK_qkxk Video Abstract

Endometritis is a common reproductive disorder in dairy cows, with antibiotics being the primary treatment option. However, the overuse of antibiotics has contributed to the growing problem of antimicrobial resistance. Antimicrobial peptides (AMPs) have been widely studied for their ability to kill bacteria and modulate immune responses. Previous research has focused on modifying natural AMPs extracted from Zophabas atratus haemolymph; however, these peptides have displayed limited effectiveness against bacteria. To overcome this limitation, researchers engineered a modified AMP, Z-FV7, by incorporating the sequence of the human-derived AMP LL-37. The resulting peptide demonstrated a favourable safety profile, with a minimum inhibitory concentration (MIC) reduced to 32 μg/mL and improved antibacterial activity against pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa . Z-FV7 was tested in a bovine uterine epithelial cell model infected with Escherichia coli and in a murine model of endometritis. The findings showed that Z-FV7 alleviated clinical symptoms, inhibited the activation of the NF-κB signalling pathway induced by drug-resistant E. coli , reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and promoted the expression of tight junction proteins (Claudin-1 and ZO-1). These results indicated that Z-FV7 can help reduce uterine inflammation and provide therapeutic outcomes similar to those of antibiotics during E. coli infection. Overall, Z-FV7 holds promise as a potential alternative to antibiotics for treating endometriosis in the future.

The infection of the bovine endometrium by Escherichia coli often results in endometrial injury with lower fertility in the bovine industry. However, what functions does ferroptosis play during endometritis? This is not completely explained. Therefore, this study aimed to elucidate the potential mechanism of ferroptosis during endometrial injury induced by E. coli . The endometrial tissues from sixteen Holstein cows with E. coli infection were harvested for pathological examination and RNA-seq. Primary bovine endometrial epithelial cells (BEECs) were used to establish an E. coli infection model in vitro. The mechanism by which ferroptosis is involved in endometritis was explored by western blot, flow cytometry, and immunofluorescence methods. The results revealed that the injury of endometrial tissues and BEECs induced by E. coli was associated with ferroptosis via Fe 2+ accumulation, increased lipid peroxidation, decreased glutathione concentration, and inhibited expression of solute carrier family 7-member 11, glutathione peroxidase 4, and ferritin heavy chain 1. Ferroptosis inhibition alleviated BEEC damage induced by E. coli . Further analysis revealed that the E. coli -induced ferroptosis was associated with impaired nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant defense, which is characterized by mitigated NRF2 degradation and blunted induction of target antioxidant enzymes, such as NAD(P)H quinone oxidoreductase 1. In contrast, promoting the expression of NRF2 mitigated the cellular damage and ferroptosis induced by E. coli . In particular, glycogen synthase kinase (GSK)-3β exhibited sustained expression and hyperactivity in endometrial tissue and BEECs infected with E. coli , which confirmed that the suppression of GSK-3β could significantly inhibit NRF2 degradation and attenuate ferroptosis. This study demonstrated that E. coli can trigger ferroptosis in endometrial tissues and BEECs through GSK-3β-mediated NRF2 degradation. Modulating GSK-3β/NRF2 holds promise as a potential therapeutic strategy for alleviating endometritis induced by E. coli .

Trueperella pyogenes is an opportunistic pathogen frequently associated with bovine endometritis, yet the mechanisms by which it induces uterine inflammation remain incompletely understood. In this study, we investigated the effects of T. pyogenes and its membrane vesicles (MVs) on bovine endometrial epithelial cells (BEECs) and explored the underlying inflammatory pathways involved. Bovine endometrial epithelial cells (BEECs) were treated with T. pyogenes (MOI = 100) or MVs at various concentrations (1 × 10 8 , 1 × 10 7 , or 1 × 10 6 particles/mL) for 6–24 h. Inflammatory cytokines (IL-1β, IL-6, IL-18, or TNF-α) and the activation of the NLRP3 and MyD88/NF-κB signalling pathways were analysed by ELISA, qRT‒PCR, and western blotting. Cell death mechanisms were assessed by flow cytometry and scanning electron microscopy. T. pyogenes significantly upregulated inflammatory cytokine mRNA expression at 6 and 12 h and protein expression at 12 and 24 h. Compared with bacterial stimulation at 12 h, MVs induced earlier activation of the NLRP3 inflammasome at 6 h. High-concentration MVs induced necrosis-like membrane disruption, whereas moderate concentrations promoted apoptosis and pyroptosis. Both T. pyogenes and its MVs activated the MyD88/NF-κB signalling pathway, with significantly increased phosphorylation of P65 at 12 h. Cytokine secretion exhibited time- and dose-dependent trends, aligning with transcriptional changes. Collectively, these findings demonstrate that T. pyogenes MVs contribute to endometrial inflammation through the NLRP3 and MyD88/NF-κB signalling pathways, with distinct forms of cell death determined by MV concentration. These findings highlight MVs as key virulence factors and potential therapeutic targets for bovine endometritis.

The heightened susceptibility to infectious diseases in postpartum dairy cows is often attributed to immune dysfunction associated with the transition period. However, the cell populations involved in this immune dysfunction and the dynamics between those populations are not well defined. Monocytes play a crucial role in governing initial immune response in bacterial infections. Bovine monocytes are subdivided in classical (CD14 + /CD16 − ), intermediate (CD14 + /CD16 + ) and non-classical monocytes (CD14 − /CD16 + ) with distinct phenotypic and functional differences. This study investigated the relationship of monocyte subsets counts in blood at 42 and 14 days prior to expected calving date to occurrence of metritis and mastitis within 2 weeks postpartum. In the enrolled prospective cohort of 27 German Holstein cows, housed at the Institute of Animal Nutrition of the Friedrich-Loeffler-Institute Braunschweig, Germany, n  = 13 developed metritis and/or mastitis postpartum. A multivariable logistic regression was used to analyze the relationship between prepartum cell counts of monocyte subsets and neutrophils with postpartum disease. Our model revealed that higher counts of the two CD14 + monocyte subsets were predictive of disease. In contrast, higher numbers of the CD14 −  monocyte subset were negatively associated with disease. Interestingly, the neutrophil count, a common hallmark for inflammatory response, was not associated with the outcome variable at either time point. The results indicate that the number and composition of monocyte subsets before calving are related to the susceptibility to infectious disease within 2 weeks postpartum. Furthermore the oppositional effect of CD14 + and CD14 − subsets strengthens the hypothesis that these subsets have different functional roles in the inflammatory response in dairy cows.