Typhoid fever is caused by the human-restricted pathogen Salmonella enterica sv. Typhi. Approximately 5% of people that resolve the disease become chronic carriers, with the gallbladder as the main reservoir of the bacteria. Of these, about 90% present with gallstones, on which Salmonella form biofilms. Because S. Typhi is a human-restricted pathogen, these carriers are the main source of dissemination of the disease; unfortunately, antibiotic treatment has shown to be an ineffective therapy. This is believed to be caused by the inherent antibiotic resistance conferred by Salmonella biofilms growing on gallstones. The gallstone mouse model with S. Typhimurium has proven to be an excellent surrogate for S. Typhi chronic infection. In this study, we test the hypothesis that the biofilm state confers Salmonella with the increased resistance to antibiotics observed in cases of chronic carriage. We found that, in the biofilm state, Salmonella is significantly more resistant to ciprofloxacin, a common antibiotic used for the treatment of Salmonella, both in vitro (p < 0.001 for both S. Typhi and S. Typhimurium with respect to planktonic cells) and in vivo (p = 0.0035 with respect to control mice).Typhoid fever is primarily caused by the human-restricted pathogen Salmonella enterica sv. Typhi (S. Typhi). This disease is a global problem that affects millions of people and causes over 600,000 deaths annually 1 . Typhoid fever is an acute illness with symptoms that include high fever, malaise, and abdominal pain. This disease is of special importance in developing nations where the lack of clean water and poor sanitation favor the capacity of the bacteria to spread. Although the incidence of Typhoid in developed countries is low, travelers are still at risk 2 .Typhoid has a mortality rate of 2-3% even with adequate antibiotic therapy. The emergence of multidrug-resistant (MDR) strains of S. Typhi is a significant problem as inexpensive and readily available antibiotics including ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole and streptomycin are frequently ineffective 3,4 . Although resistance to ciprofloxacin, a second-generation fluoroquinolone, is increasing, it is still recommended as first line therapy for children and adults [5][6][7] .In most cases, the infection is resolved and the patient recovers, but approximately 5% of people infected with S. Typhi fail to clear the bacteria within one year and become chronic carriers. Carriers are typically asymptomatic and can spread the disease through fecal shedding. The chronic carrier state is associated with Salmonella colonization of the biliary tract and is positively correlated with the presence of gallstones (GS); in fact, approximately 90% of chronically infected carriers have GS 8 . Antibiotic treatment is ineffective in the resolution of chronic S. Typhi colonization, making gallbladder removal the only effective therapy 2,9-11 .The presence of Salmonella biofilms on the gallstones of both typhoid carrier patients and mice (in a gallstone model of ch...
Solid tumors contain a mixture of malignant cells and non-malignant infiltrating cells that often create a chronic inflammatory and immunosuppressive microenvironment that restricts immunotherapeutic approaches. Although childhood and adult cancers share some similarities related to microenvironmental changes, pediatric cancers are unique, and adult cancer practices may not be wholly applicable to our pediatric patients. This review highlights the differences in tumorigenesis, viral infection, and immunologic response between children and adults that need to be considered when trying to apply experiences from experimental therapies in adult cancer patients to pediatric cancers.
A network of pattern recognition receptors (PRRs) is responsible for the detection of invading viruses and acts as the trigger for the host antiviral response. Central to this apparatus is stimulator of interferon genes (STING), which functions as a node and integrator of detection signals. Owing to its role in both intrinsic and adaptive immunity, STING has become a focus for researchers in the field of oncolytic virotherapy. In this review, we consider the function of the cGAS-STING axis and its regulation, both by cellular mechanisms and as a result of viral interference. HSV-I Infection as a Template for STING Signaling Activation In this review, we will consider the STING-mediated interferon (IFN) response to viral infection, cellular regulation of this response, and the viral mechanisms that directly counter it. We will also look briefly at related findings which predict the efficacy of oncolytic DNA viruses.
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