characterizing-salmonella-typhimurium-induced-septic-peritonitis

Characterizing <em>Salmonella</em> Typhimurium-induced Septic Peritonitis in Mice

Sepsis is a dysregulated host immune response to microbial invasion or tissue damage, leading to organ injury at a site distant from that of the infection ...

Indian Institute of Science

The hallmarks of the adaptive immune response are specificity and memory. The cellular response is mediated by T cells which express cell surface T cell receptors (TCRs) that recognize peptide antigens in complex with major histocompatibility complex (MHC) molecules on antigen presenting cells (APCs). However, binding of cognate TCRs with MHC-peptide complexes alone (signal 1) does not trigger optimal T cell activation. In addition to signal 1, the binding of positive and negative costimulatory receptors to their ligands modulates T cell activation. This complex signaling network prevents aberrant activation of T cells. CD28 is the main positive costimulatory receptor on naı¨ve T cells; upon activation, CTLA4 is induced but reduces T cell activation. Further studies led to the identification of additional negative costimulatory receptors known as checkpoints, e.g. PD1. This review chronicles the basic studies in T cell costimulation that led to the discovery of checkpoint inhibitors, i.e. antibodies to negative costimulatory receptors (e.g. CTLA4 and PD1) which reduce tumor growth. This discovery has been recognized with the award of the 2018 Nobel prize in Physiology/Medicine. This review highlights the structural and functional roles of costimulatory receptors, the mechanisms by which checkpoint inhibitors work, the challenges encountered and future prospects.

T cell costimulation, checkpoint inhibitors and anti-tumor therapy.

Autoimmunity can potentially pre-dispose to, exacerbate or ameliorate pathogenic infections. The current study was designed to compare and understand the infection outcomes with Salmonella enterica serovar Typhimurium ATCC 14028s (S. Typhimurium) wild type (WT) and attenuated ΔrpoS strains, in autoimmune-prone lpr mice. C57BL/6 (B6) and B6/lpr (lpr) 6-8 weeks old mice were orally infected with S. Typhimurium WT and ΔrpoS strains. Disease outcomes were assessed with respect to survival, organ bacterial load, tissue damage and inflammation in infected mice. The acute infection stage (day 4) was examined and compared to the later stages (up to day 12) post ΔrpoS infection. S. Typhimurium WT exhibited an acute and lethal infection in both B6 and lpr mice. However, the ΔrpoS strain exhibited prolonged infection with reduced mortality in B6 mice but complete mortality in lpr mice. During late infection, bacterial load and serum IFNγ levels were higher in the ΔrpoS strain infected lpr mice compared to B6 mice. The ΔrpoS strain infected lpr mice also exhibited greater bacterial faecal shedding and greater tissue histopathological changes. Interestingly, ΔrpoS-infected B6 mice displayed minimal microbial load in the brain; however, sustained brain bacterial load was observed in ΔrpoS-infected lpr mice, corresponding to abnormal gait. Overall, S. Typhimurium ΔrpoS is competent in establishing infection but compromised in sustaining it. Nonetheless, lpr mice are less efficient in controlling this attenuated infection. The findings from the study demonstrate that genetic pre-disposition to autoimmunity is sufficient for greater host susceptibility to infection by attenuated S. Typhimurium strains.

Article	Year
T cell costimulation, checkpoint inhibitors and anti-tumor therapy. Journal of biosciences\| PubMed ID: 32345776	2020
Autoimmune-prone lpr mice exhibit a prolonged but lethal infection with an attenuated Salmonella Typhimurium strain. Microbial pathogenesis\| PubMed ID: 33301858	2021

Avik Chattopadhyay

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