Mcclearykvist0216

Fourth, a portion of the ILC3s expressed IFN-γ, thus defined as ex-ILC3s, and the transfer of the ex-ILC3s conferred colon resistance to mutant Chlamydia muridarum colonization in IFN-γ-deficient mice. Finally, genetically labeled RORγt-positive (RORγt+) ILCs were able to inhibit mutant colonization. Thus, we have demonstrated that ILC3s are sufficient for regulating chlamydial colonization, laying a foundation for further revealing the mechanisms by which an obligate intracellular bacterium activates colonic ILC3s.The stringent response is an essential mechanism of metabolic reprogramming during environmental stress that is mediated by the nucleotide alarmones guanosine tetraphosphate and pentaphosphate [(p)ppGpp]. In addition to physiological adaptations, (p)ppGpp also regulates virulence programs in pathogenic bacteria, including Salmonella enterica serovar Typhimurium. S Typhimurium is a common cause of acute gastroenteritis, but it may also spread to systemic tissues, resulting in severe clinical outcomes. During infection, S Typhimurium encounters a broad repertoire of immune defenses that it must evade for successful host infection. Here, we examined the role of the stringent response in S Typhimurium resistance to complement-mediated killing and found that the (p)ppGpp synthetase-hydrolase, SpoT, is required for bacterial survival in human serum. We identified the nucleotide hydrolase, PpnN, as a target of the stringent response that is required to promote bacterial fitness in serum. Using chromatography and mass spectrometry, we show that PpnN hydrolyzes purine and pyrimidine monophosphates to generate free nucleobases and ribose 5'-phosphate, and that this metabolic activity is required for conferring resistance to complement killing. In addition to PpnN, we show that (p)ppGpp is required for the biosynthesis of the very long and long O-antigen in the outer membrane, known to be important for complement resistance. Our results provide new insights into the role of the stringent response in mediating evasion of the innate immune system by pathogenic bacteria.Previous studies have shown that sphingosine kills a variety of pathogenic bacteria, including Pseudomonas aeruginosa and Staphylococcus aureus Sphingosine concentrations are decreased in airway epithelial cells of cystic fibrosis (CF) mice, and this defect has been linked to the infection susceptibility of these mice. Here, we tested whether the genetic overexpression of acid ceramidase rescues cystic fibrosis mice from pulmonary infections with P. aeruginosa We demonstrate that the transgenic overexpression of acid ceramidase in CF mice corresponds to the overexpression of acid ceramidase in bronchial and tracheal epithelial cells and normalizes ceramide and sphingosine levels in bronchial and tracheal epithelial cells. In addition, the expression of β1-integrin, which is ectopically expressed on the luminal surface of airway epithelial cells in cystic fibrosis mice, an alteration that is very important for mediating pulmonary P. aeruginosa infections in cystic fibrosis, is normalized in cystic fibrosis airways upon the overexpression of acid ceramidase. Most importantly, the overexpression of acid ceramidase protects cystic fibrosis mice from pulmonary P. aeruginosa infections. Infection of CF mice or CF mice that inhaled sphingosine with P. aeruginosa or a P. aeruginosa mutant that is resistant to sphingosine indicates that sphingosine and not a metabolite kills P. aeruginosa upon pulmonary infection. These studies further support the use of acid ceramidase and its metabolite sphingosine as potential treatments of cystic fibrosis.Leishmania, the causative agent of leishmaniasis, is an intracellular pathogen that thrives in the insect gut and mammalian macrophages to complete its life cycle. Apart from temperature difference (26 to 37°C), it encounters several harsh conditions, including oxidative stress, inflammatory reactions, and low pH. Heat shock proteins (HSPs) play essential roles in cell survival by strategically reprogramming cellular processes and signaling pathways. HSPs assist cells in multiple functions, including differentiation, adaptation, virulence, and persistence in the host cell. Due to cyclical epidemiological patterns, limited chemotherapeutic options, drug resistance, and the absence of a vaccine, control of leishmaniasis remains a far-fetched dream. The essential roles of HSPs in parasitic differentiation and virulence and increased expression in drug-resistant strains highlight their importance in combating the disease. In this review, we highlighted the diverse physiological importance of HSPs present in Leishmania, emphasizing their significance in disease pathogenesis. Subsequently, we assessed the potential of HSPs as a chemotherapeutic target and underlined the challenges associated with it. Furthermore, we have summarized a few ongoing drug discovery initiatives that need to be explored further to develop clinically successful chemotherapeutic agents in the future.Chlamydia trachomatis is an obligate intracellular pathogen that causes sexually transmitted disease. In women, chlamydial infections may cause pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. The role of antibodies in protection against a primary Chlamydia infection is unclear and was a focus of this work. Using the C. muridarum mouse infection model, we show that intestinal mucosa is infected via intranasal (i.n.) or per-oral (p.o.) Chlamydia inoculation and that unlike the female reproductive tract (FRT) mucosa, it halts systemic Chlamydia dissemination. Moreover, p.o. immunization or infection with Chlamydia confers protection against per-vaginal (p.v.) challenge, resulting in significantly decreased bacterial burden in the FRT, accelerated Chlamydia clearance, and reduced hydrosalpinx pathology. In contrast, subcutaneous (s.c.) immunization conferred no protection against the p.v. challenge. Both p.o. and s.c. immunizations induced Chlamydia-specific serum IgA. However, IgA was found only in the vaginal washes and fecal extracts of p.o.-immunized animals. Following a p.v. challenge, unimmunized control and s.c.-s.c.-immunized animals developed Chlamydia-specific intestinal IgA yet failed to develop IgA in the FRT, indicating that IgA response in the FRT relies on the FRT to gastrointestinal tract (GIT) antigen transport. Vaginal secretions of p.o.-immunized animals neutralize Chlamydia in vivo, resulting in significantly lower Chlamydia burden in the FRT and Chlamydia transport to the GIT. We also show that infection of the GIT is not necessary for induction of protective immunity in the FRT, a finding that is important for the development of p.o. CC-92480 cost subunit vaccines to target Chlamydia and possibly other sexually transmitted pathogens.A 61-year-old Caucasian woman presented to an outpatient otolaryngology clinic with increased bleeding from a dorsal tongue telangiectasia for 3 weeks. Her history was significant for hereditary haemorrhagic telangiectasia (HHT), a rare condition that causes vascular dysplasia, and recent symptomatic anaemia requiring blood transfusions. After failing medical management with topical haemostatic agents, she was offered and underwent surgical intervention to remove the tongue telangiectasia with duel therapy potassium titanyl phosphate (KTP) laser coblation and bevacizumab injections. A team of otolaryngologists removed the lesion without complications, and the patient denied bleeding, had minimal pain, and endorsed increased quality of life postoperatively. Tongue telangiectasias can cause life-threatening bleeding in some patients with HHT, and no surgical management guidelines exist to treat them. This case demonstrates the efficacy of KTP laser followed by bevacizumab injections in treating tongue telangiectasias in a patient with HHT.A 27-year-old patient presented with acral chilblain-like lesions atypical of dermatological presentations appearing in current reports of COVID-19. Prominent bullae had formed on the dorsa of her toes and became haemorrhagic 2 days after the initial presentation. The patient had no underlying medical conditions, including any history of collagen vascular disease, Raynaud's phenomenon, chilblains or cold exposure, and was not taking any medications. The patient reported 10 days of ageusia and anosmia 6 weeks prior to the manifestation of her toe lesions, with no other symptoms. A nasopharyngeal swab test for SARS-CoV-2 RNA was positive. It is important that physicians recognise the myriad of cutaneous lesions associated with COVID-19 in this ongoing pandemic.We report a case of a 76-year-old British man living in Malta who presented with a 7-month history of recurrent epistaxis and an enlarging right nasal vestibular lesion. Of note, his medical history included rheumatoid arthritis for which he was on long-term methotrexate. Blood results were unremarkable other than a mild lymphopaenia. Despite the use of various antibiotics and intranasal steroids, the lesion failed to resolve. This was eventually biopsied, and the histological picture was that of mucosal leishmaniasis. Leishmania donovani complex was detected by PCR. The patient was treated with liposomal amphotericin B on alternate days for a total of 20 doses. The lesion was found to have healed well at follow-up and the patient denied any further episodes of epistaxis.An elderly African American woman presented to our clinic following 9 months of right-sided unilateral headache, otorrhoea and progressive hearing loss. Despite treatment with topical and oral antibiotics, her clinical condition worsened, and imaging showed mastoid coalescence with an associated subgaleal abscess. She underwent right mastoidectomy and was discharged 3 days later on broad-spectrum intravenous antibiotics despite negative operative cultures. Six weeks later, she was hospitalised with diplopia secondary to a right lateral rectus palsy. Imaging showed abscess resolution but progressive bony remodelling and enhancement of the lateral extending into anterior skull base. Chest CT demonstrated upper lobe predominant pulmonary micronodules, and mastoid biopsy on revision surgery was notable for non-caseating granulomas. Further extensive work-up could not identify an alternative cause, and a presumptive diagnosis of neurosarcoidosis was made. The patient was initiated on intravenous steroids, experienced symptomatic improvement and was thereafter transitioned to oral steroid taper on discharge.Heterotopic salivary tissue (HST) is a normal salivary tissue located outsides the major and minor salivary glands. Multiple sites of localisation of heterotopias have been described, the occurrence of HST in the neck is rare and it may have several clinical manifestation. We report the case of 72-year-old Caucasian man presenting a suspect mass on the left-sided supraclavicular region. He is known for melanoma of the right elbow, surgically treated 11 years ago. The final diagnosis of pleomorphic adenoma of HST was retained. Methods of diagnosis and management are documented. Neoplasms arising from HST are uncommon with approximately 80% of benign tumours. Warthin's tumour is the most frequent. The localisation of these neoplasms in the lower neck is very rare and often causes a diagnostic pitfall. Histological analysis provides certainty of diagnosis, defines management and follow-up.