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Clostridial dermatitis (CD), caused by the anaerobic spore-forming Clostridium septicum bacteria, is an important emerging disease of turkeys. Despite its economic burden on the poultry industry, there are no efficacious vaccines currently available for CD control in turkeys. We recently identified two non-toxic domains of C. septicum alpha toxin (ntATX), namely ntATX-D1 and ntATX-D2, and showed that subcutaneous immunization of turkeys with purified recombinant subunit ntATX proteins can offer protection against CD. In the present study, we used the pNZ8124-NICE vector®-based Lactococcus lactis (Str. NZ9000) cloning system to express ntATX-D1 and ntATX-D2 proteins, and immunized turkeys orally at 7, 8 and 9 weeks of age followed by a virulent C. septicum challenge at one-week post-last immunization. Results showed that while both ntATX-D1 and ntATX-D2 vectored-L. lactis vaccines could effectively prevent mortality, the ntATX-D2 carrying vaccine conferred significantly stronger protective immunity, as determined by the gross and histopathological evaluations. Additionally, the immunized birds were found to have antigen-specific serum IgY antibodies. Furthermore, the L. lactis-ntATX-D2 vaccinated turkeys had significantly reduced expression of pro-inflammatory cytokine (Interleukin-1β, IL-6 or Interferon-γ) genes in the skin, muscle, spleen and cecal tonsil tissues when compared to unvaccinated and C. septicum-challenged control group. Our findings show that a L. lactis-based oral recombinant vaccine expressing ntATX-D2 of C. septicum alpha-toxin can provide protective immunity against CD in turkeys, and thus providing a novel scope for devising probiotic-based oral vaccines against important Clostridial diseases in poultry.

Background Clostridium septicum is an opportunistic pathogen residing in the human gut flora. Due to its aerotolerance and production of exotoxins, dissemination is an uncommon but potentially lethal condition, often associated with underlying malignancy. This report represents the first described case of a patient with aortic, musculoskeletal and epidural infection caused by C. septicum. It illustrates an example of successful treatment and discusses specific treatment options in relation to current antibiotic and surgical recommendations. Case presentation We report a rare case of a 76-year-old man presenting with mild symptoms, who developed life-threatening complications caused by C. septicum including an aortic aneurysm as well as an epidural abscess and spondylodiscitis. The patient was successfully treated with endovascular stents in conjunction with a six-week course of intravenous antibiotics and was discharged from the hospital with oral clindamycin. After more than a year on oral antibiotics the treatment was terminated, which promptly led to a relapse of C. septicum bacteremia and spondylodiscitis. Following a second hospitalization with IV therapy, lifelong suppressive antibiotic therapy was deemed necessary. Conclusion C. septicum bacteremia is a severe condition that may cause multifocal infection although presenting with few clinical signs. This unique case reflects the aggressiveness of the bacteria and how antibiotic and surgical treatment should be thoughtfully considered in the presence of aortitis, epidural abscesses and spondylodiscitis.

Background The pathogenic Clostridia cause neurotoxic, histotoxic and enterotoxic infections in humans and animals. Several Clostridium species have been associated with abomasitis in ruminants. The present study aimed to investigate the frequency, and the presence of virulence genes, of Clostridium perfringens, Paeniclostridium sordellii and Clostridium septicum in lambs and goat kids with hemorrhagic abomasitis. Results A total of 38 abomasum samples, collected from lambs and goat kids of 1 week to 1 month of age in different farms located in eastern Turkey between 2021 and 2022, were evaluated by histopathology, culture and PCR. At necropsy, the abomasum of the animals was excessively filled with caseinized content and gas, and the abomasum mucosa was hemorrhagic in varying degrees. In histopathological evaluation, acute necrotizing hemorrhagic inflammation was noted in abomasum samples. The examination of swab samples by culture and PCR revealed that C. perfringens type A was the most frequently detected species (86.84%) either alone or in combination with other Clostridium species. P. sordellii , C. perfringens type F and C. septicum were also harboured in the samples, albeit at low rates. Beta2 toxin gene ( cpb2 ) was found in three of C. perfringens type A positive samples. Conclusion It was suggested that vaccination of pregnant animals with toxoid vaccines would be beneficial in terms of protecting newborn animals against Clostridial infections. This study investigated the presence of clostridial toxin genes in abomasal samples for the first time in Turkey.

Gas gangrene is a rare presentation of a necrotizing fasciitis, caused by Clostridium perfringens , C. septicum and other clostridial species. With its rapid progression it is a potentially life-threatening infection, that poses as a challenge in the clinical management requiring an interdisciplinary approach. Here we present a 62-year-old woman, who developed neutropenic fever while undergoing chemotherapy for triple negative breast cancer. She presented with a high fever, reporting little pain in her left thigh accompanied by redness and induration locally. Subsequently the patient developed pain and redness of the back of the left hand. The initial findings suggested cellulitis and immediate empiric treatment with intravenous meropenem was started. Despite the antibiotic treatment the patient rapidly developed septic shock along with progression of the local infection. Emergency surgical debridement revealed extensive necrosis of the soft tissues including extensive myonecrosis of the thigh. On the left hand an extensive debridement was performed, the left lower limb could not be preserved and exarticulation of the left hip was required. Microbiologically C. septicum was isolated in different samples, confirming gas gangrene. As there was no local entry portal on the skin, hematogenous seeding from intestinal translocation in this neutropenic patient was suspected. The empiric antibiotic treatment was tailored to intravenous penicillin and complemented with clindamycin for toxin inhibition. Following radical debridement and antibiotic treatment, the patient could be stabilized. After repetitive debridement wound closure was achieved and the patient was discharged for rehabilitation. Antibiotic treatment was continued for four weeks. This rare case of gas gangrene in a neutropenic patient shows the complexity in the diagnostic and therapeutic management of necrotizing soft tissue infections in immunocompromised patients. It particularly highlights the importance of an interdisciplinary management with fast recognition of the disease and rapid, if needed radical, surgical debridement as well as tailored antibiotic treatment for a successful outcome.

Background Cellulitis due to infection with clostridia has not been documented in horses in Iceland. However, clostridia are well-known pathogens in Icelandic sheep, which have traditionally shared grazing land with horses. Clostridial infections of equine muscle or subcutis following injection with medicinal products have been described in other countries but have never been reported in Iceland. In this case report, we present the first documented outbreak of subcutaneous clostridial infection in horses in Iceland following subcutaneous injection. Case presentation In November 2022, 16 out of 32 horses, that some days earlier had received a subcutaneous injection of Noromectin ® 1% injectable solution, developed clinical signs indicating malignant oedema. The clinical signs included pyrexia, depression, swollen limbs, chest and neck, reluctance to move and dyspnoea, leading to the death or euthanasia of five horses. In addition, one horse was found dead with no previously noted clinical signs. Necropsy of one of the five horses revealed severe, acute cellulitis in the neck region, as well as lymphadenitis in regional lymph nodes. Abscesses, some with subsequent spontaneous drainage of seropurulent material, were observed at the presumed injection site on eight surviving horses approximately 2 weeks post-injection. Bacterial culture of samples from the necropsied horse and from abscesses from three surviving horses yielded the growth of C. septicum . Analysis of water samples from the pasture where the herd was kept also revealed the presence of C. septicum . Whole genome sequencing suggested that the isolates from the diseased horses contained the same C. septicum strain, whereas the strain isolated from the water samples differed from the disease-causing isolates. Conclusions Clinical signs compatible with serious subcutaneous C.   septicum infection were seen in over half of 32 horses injected with an ivermectin product, with the subsequent death of six of the horses. In the absence of other obvious sources, the outbreak suggests that C. septicum spores on the skin of these horses were introduced under the skin when they were injected. Such infections have not been reported in Iceland, although ivermectin products formulated for subcutaneous injection have been widely used for more than 30 years. The outbreak warrants further investigation into C. septicum in the environment of grazing horses in Iceland.

Clostridium septicum and its associated cytolytic α toxin, along with several other clostridial species, has been implicated as the causative agent of gangrenous dermatitis. A recombinant noncytolytic C. septicum α toxin (NCAT) peptide was developed for use as a vaccine and demonstrated to be safe at concentrations as high as 1 mg/ml. NCAT, used as a purified antigen, partially purified antigen, or in combination with native antigens, was compared to salt-fractionated α toxin combined with denatured C. septicum bacteria (native) in a vaccination trial. Three-day-old poults were placed into one of five groups and received two, 0.2-ml vaccinations 5 wk apart. Subcutaneous challenge with 3.2 × 107 log phase C. septicum resulted in 78% to 95% of the vaccinated birds surviving challenge compared to 48% of sham-injected controls. By ELISA analysis on NCAT-coated plates, birds receiving vaccines containing the recombinant NCAT peptide showed significantly higher blood serum antibody concentrations than did birds receiving vaccines containing native antigens or alum controls. Additionally, high levels of maternally transferred antibodies reactive to NCAT-purified antigens found in the pre-immune sera from naïve 3-day-old poults suggest that the tertiary structure of the NCAT peptide has a high homology to the native protein structure. In conclusion, our study showed that the use of a vaccine comprised of a noncytolytic recombinant α toxin peptide antigen provided clinical protection equal to the use of vaccines formulated with inactivated native proteins at a reduced overall cost. Una proteína recombinante de la toxina α no citolítica induce protección en pavos contra el desafío con Clostridium septicum. Clostridium septicum y su toxina α asociada, junto con varias otras especies clostridiales, ha sido implicado como el agente causal de la dermatitis gangrenosa. Se desarrolló un péptido de una toxina α recombinante no citolítica de C. septicum (NCAT) para su uso como una vacuna y demostró ser seguro en concentraciones tan altas como 1 mg/ml. El péptido NCAT, usado como un antígeno purificado, como antígeno parcialmente purificado, o en combinación con antígenos nativos, se comparó en un ensayo de vacunación con la toxina α fraccionada con sal, combinada con bacterias desnaturalizadas de C. septicum (nativas). Se colocaron pavipollos de tres días de edad en cinco grupos y recibieron dos vacunaciones con un volumen de 0.2 ml con cinco semanas de diferencia. El desafío por vía subcutánea con 3.2 × 107 de C. septicum en fase logarítmica produjo una supervivencia del 78% a 95% de las aves vacunadas y desafiadas en comparación con el 48% observado con los controles inyectados con el tratamiento placebo. Mediante el análisis de ELISA con placas recubiertas con el péptido NCAT, las aves que recibieron vacunas que contenían el péptido NCAT recombinante mostraron concentraciones de anticuerpos en suero significativamente más altas en comparación con las aves que recibieron vacunas que contenían antígenos nativos o controles con alumbre. Además, los altos niveles de anticuerpos maternos transferidos reactivos contra los antígenos NCAT purificados encontrados en los sueros pre-inmunes de pavipollos no inoculados, de tres días de edad, sugieren que la estructura terciaria del péptido NCAT tiene una alta homología con la estructura de la proteína nativa. En conclusión, nuestro estudio mostró que el uso de una vacuna compuesta de un antígeno de péptido toxina α recombinante no citolítica proporcionó protección clínica similar a la observada con las vacunas formuladas con proteínas nativas inactivadas pero a un costo reducido.

Nontraumatic clostridial myonecrosis infections are predominantly caused by Clostridium septicum. Most patients have an underlying gastrointestinal malignancy. This case presents a rare association of spontaneous clostridial myonecrosis preceding cerebral septic emboli with underlying invasive colorectal adenocarcinoma. A 60-year-old male with a history of hypertension, diabetes, and a family history of colon cancer presented to the emergency room with worsening left-sided chest pain radiating to his left shoulder. Extensive workup revealed elevated D-dimer, troponin, C-reactive protein, white blood cell count, and creatinine phosphokinase. Due to his clinical signs, symptoms, elevated white count, and further decompensation, he was started on antibiotics for sepsis. Physical exam revealed left upper extremity (LUE) crepitus consistent with imaging of innumerable soft tissue gas collections along the LUE. Incision, drainage, and myomectomy were performed due to concerns of myositis and necrotizing infection. Muscle biopsy revealed myonecrosis, and subsequent samples were positive for C. septicum. Postoperative pressor support and several sessions of surgical debridement were required. He continued to deteriorate and developed left-sided paralysis. Computed tomography head revealed several white matter infarcts indicative of septic emboli. The patient slowly recovered neurologically after switching to central nervous system-penetrating antibiotics. Months later, a colonoscopy revealed cecal adenocarcinoma. This case features a unique course of spontaneous C. septicum infection. There are high mortality rates, and previous studies report an association with colorectal malignancies. Therefore, preventative and diagnostic evaluations are imperative with a confirmed C. septicum infection. To our knowledge, this is the first case reported of cerebral septic emboli secondary to spontaneous myonecrosis with C. septicum, highlighting a unique burden of emboli-induced neurological deficits.

Reduced tissue perfusion leading to tissue ischemia is a central component of the pathogenesis of myonecrosis caused by Clostridium perfringens. The C. perfringens alpha-toxin has been shown capable of inducing these changes, but its potential synergy with perfringolysin O (theta-toxin) is less well understood. Similarly, Clostridium septicum is a highly virulent causative agent of spontaneous gas gangrene, but its effect on the microcirculation has not been examined. Therefore, the aim of this study was to use intravital microscopy to examine the effects of C. perfringens and C. septicum on the functional microcirculation, coupled with the use of isogenic toxin mutants to elucidate the role of particular toxins in the resultant microvascular perfusion deficits. This study represents the first time this integrated approach has been used in the analysis of the pathological response to clostridial toxins. Culture supernatants from wild-type C. perfringens induced extensive cell death within 30 min, as assessed by in vivo uptake of propidium iodide. Furthermore, significant reductions in capillary perfusion were observed within 60 min. Depletion of either platelets or neutrophils reduced the alteration in perfusion, consistent with a role for these blood-borne cells in obstructing perfusion. In addition, mutation of either the alpha-toxin or perfringolysin O structural genes attenuated the reduction in perfusion, a process that was reversed by genetic complementation. C. septicum also induced a marked reduction in perfusion, with the degree of microvascular compromise correlating with the level of the C. septicum alpha-toxin. Together, these data indicate that as a result of its ability to produce alpha-toxin and perfringolysin O, C. perfringens rapidly induces irreversible cellular injury and a marked reduction in microvascular perfusion. Since C. septicum induces a similar reduction in microvascular perfusion, it is postulated that this function is central to the pathogenesis of clostridial myonecrosis, irrespective of the causative bacterium.

Clostridia represents a group of anaerobic spore-forming bacteria ubiquitous in the poultry environment. They are widely distributed in soil and survive for many years as highly resistant, inactive spores. They enter the body through wounds and contaminated feed as active bacteria or spores. Multiplication of clostridial bacteria occurs only in the absence of oxygen or in environments with very low concentrations of oxygen. During active multiplication, the clostridial organisms produce several toxins that are responsible for most of the clinical signs seen in clostridial diseases. Immunosuppression is a problem for the poultry industry. In modern, intensive poultry-rearing conditions, stress due to high population densities pose a considerable challenge for the immune system, and infectious agents can exploit this situation to cause disease. Immunosuppression may predispose turkeys to clostridial infection, resulting in clostridial dermatitis and mortality. The purpose of this study was to determine whether immunosuppression predisposes turkeys to clostridial infection and causes clostridial dermatitis. We immunosuppressed 10-wk-old turkey poults with dexamethasone. The birds immunosuppressed and not immunosuppressed were then challenged with Clostridium perfringens, Clostridium septicum, or both and examined for the development of clostridial dermatitis. The dexamethasone-treated birds were found to be more susceptible to C. perfringens/C. septicum challenge and developed clostridial dermatitis than the no-dexamethasone-treated birds through the subcutaneous route. However, oral inoculation of the same agents did not cause any dermatitis lesions in either of the groups. Efectos de la inmunodepresión por dexametasona en la dermatitis clostridial de los pavos. Las bacterias del género Clostridium representan un grupo de bacterias anaerobias que forman esporas y que son ubicuas en los ambientes avícolas. Están ampliamente distribuidas en el suelo y sobreviven durante muchos años como esporas inactivas, altamente resistentes. Entran en el cuerpo a través de heridas y alimentos contaminados en forma de bacterias activas o esporas. La multiplicación de las bacterias clostridiales sólo se produce en ausencia de oxígeno o en ambientes con concentraciones muy bajas del mismo. Durante la multiplicación activa, los organismos clostridiales producen varias toxinas que son responsables de la mayoría de los signos clínicos observados en las enfermedades clostridiales. La inmunosupresión es un problema para la industria avícola. Bajo las condiciones de crianza intensiva modernas, el estrés debido a la alta densidad de población plantea un reto considerable para el sistema inmune y los agentes infecciosos pueden aprovechar esta situación para causar enfermedades. La inmunodepresión puede predisponer a los pavos a la infección por clostridios y causar dermatitis clostridial y mortalidad. El propósito de este estudio fue determinar si la inmunosupresión predispone a los pavos a la infección por clostridios y si es causa dermatitis por clostridios. Se inmunodeprimieron pavipollos de 10 semanas de edad con dexametasona. Posteriormente, aves inmunodeprimidas y normales fueron expuestas a Clostridium perfringens, a Clostridium septicum, o a ambos y se examinaron para el desarrollo de la dermatitis clostridial. Se encontró que las aves tratadas con dexametasona eran más susceptibles al desafío por C. perfringens/C. septicum y desarrollaron dermatitis clostridial a diferencia de las aves que no fueron tratadas con dexametasona por vía subcutánea. Sin embargo, la inoculación oral de los mismos agentes no causó lesiones de dermatitis en ninguno de los grupos.

Clostridium septicum is the causative agent of atraumatic gas gangrene, with α-toxin, an extracellular pore-forming toxin, essential for disease. How C. septicum modulates the host’s innate immune response is poorly defined, although α-toxin-intoxicated muscle cells undergo cellular oncosis, characterised by mitochondrial dysfunction and release of reactive oxygen species. Nonetheless, the signalling events that occur prior to the initiation of oncosis are poorly characterised. Our aims were to characterise the ability of α-toxin to activate the host mitogen activated protein kinase (MAPK) signalling pathway both in vitro and in vivo. Treatment of Vero cells with purified α-toxin activated the extracellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 arms of the MAPK pathway and stimulated the release of TNF-α in a dose-dependent manner. Studies using inhibitors of all three MAPK components suggested that activation of ERK occurred in a Ras-c-Raf dependent manner, whereas activation of JNK and p38 occurred by a Ras-independent mechanism. Toxin-mediated activation was dependent on efficient receptor binding and pore formation and on an influx of extracellular calcium ions. In the mouse myonecrosis model we showed that the MAPK pathway was activated in tissues of infected mice, implying that it has an important role in the disease process.