Host responses in Fas deficient autoimmune prone lpr mice upon Salmonella Typhimurium infection

Abstract

Autoimmune diseases can potentially pre-dispose an individual to infections. On the other hand, infections can trigger, exacerbate or ameliorate autoimmunity. Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare genetic disorder, often leading to a systemic autoimmune disease, and arises due to mutations in genes encoding the Fas-death pathway. lpr (lymphoproliferation) mice, widely used as autoimmune disease models for systemic autoimmune diseases like SLE, bear clinical and genotypic resemblance to ALPS. lpr mice are mutants for Fas and develop an age-dependent progressive systemic autoimmune disease that is associated with spontaneous lymphoproliferation. ALPS patients have been reported to exhibit a pre-disposition to post splenectomy related sepsis. The dynamics of other infections in ALPS remain widely unexplored. The lpr mouse model, on the other hand, has been used to study a wide range of infection outcomes, with an increased susceptibility observed for certain infections, but an increased clearance from others. At the same time, certain infections accelerate the autoimmune disease progression in lpr mice while a few reduce it. However, the role of Salmonella infection in this context remains largely unknown. Salmonella spp. are Gram-negative, intracellular pathogens and one of the most common causative agents of foodborne diseases globally. Salmonella Typhi, a human restricted pathogen, causes Typhoid (enteric fever). Salmonella Typhimurium, a zoonotic pathogen causes gastroenteritis in humans and a systemic typhoid-like disease in susceptible mice strains (mouse typhoid model). S. Typhimurium mutants of certain genes, such as rpoS, are compromised in virulence, exhibiting increased survival in mice. RpoS is an alternate sigma factor of bacterial RNA polymerase that plays an important role during stationary phase and regulation of various stress responses as well as virulence. The objective of the first part of the study was to confirm the rpoS gene deletion in Salmonella Typhimurium...