Altered IFN-γ-mediated immunity and transcriptional expression patterns in N-Ethyl-N-nitrosourea-induced STAT4 mutants confer susceptibility to acute typhoid-like disease.

Abstract

Salmonella enterica is a ubiquitous Gram-negative intracellular bacterium that continues to pose a global challenge to human health. The etiology of Salmonella pathogenesis is complex and controlled by pathogen, environmental, and host genetic factors. In fact, patients immunodeficient in genes in the IL-12, IL-23/IFN-γ pathway are predisposed to invasive nontyphoidal Salmonella infection. Using a forward genomics approach by N-ethyl-N-nitrosourea (ENU) germline mutagenesis in mice, we identified the Ity14 (Immunity to Typhimurium locus 14) pedigree exhibiting increased susceptibility following in vivo Salmonella challenge. A DNA-binding domain mutation (p.G418_E445) in Stat4 (Signal Transducer and Activator of Transcription Factor 4) was the causative mutation. STAT4 signals downstream of IL-12 to mediate transcriptional regulation of inflammatory immune responses. In mutant Ity14 mice, the increased splenic and hepatic bacterial load resulted from an intrinsic defect in innate cell function, IFN-γ-mediated immunity, and disorganized granuloma formation. We further show that NK and NKT cells play an important role in mediating control of Salmonella in Stat4(Ity14/Ity14) mice. Stat4(Ity14/Ity14) mice had increased expression of genes involved in cell-cell interactions and communication, as well as increased CD11b expression on a subset of splenic myeloid dendritic cells, resulting in compromised recruitment of inflammatory cells to the spleen during Salmonella infection. Stat4(Ity14/Ity14) presented upregulated compensatory mechanisms, although inefficient and ultimately Stat4(Ity14/Ity14) mice develop fatal bacteremia. The following study further elucidates the pathophysiological impact of STAT4 during Salmonella infection.

• Authors: Megan M Eva, Kyoko E Yuki, Shauna M Dauphinee, Jeremy A Schwartzentruber, Michal Pyzik, Marilène Paquet, Mark Lathrop, Jacek Majewski, Silvia M Vidal, Danielle Malo
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 1 Pg. 259-70 (Jan 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24285835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD11b Antigen
• Cation Transport Proteins
• Nitrosourea Compounds
• STAT4 Transcription Factor
• natural resistance-associated macrophage protein 1
• Interferon-gamma

Topics

• Animals
• Bacterial Load
• CD11b Antigen (genetics, metabolism)
• Cation Transport Proteins (genetics)
• Cluster Analysis
• DNA Mutational Analysis
• Dendritic Cells (immunology, metabolism)
• Gene Expression Regulation
• Genetic Loci
• Genetic Predisposition to Disease
• Immunity, Innate (genetics)
• Interferon-gamma (immunology, metabolism)
• Killer Cells, Natural (immunology, metabolism)
• Liver (immunology, metabolism, microbiology)
• Mice
• Mutation (drug effects)
• Natural Killer T-Cells (immunology, metabolism)
• Nitrosourea Compounds (toxicity)
• Pedigree
• STAT4 Transcription Factor (genetics)
• Salmonella Infections, Animal (genetics, immunology, microbiology, mortality)
• Salmonella typhimurium (immunology)
• Spleen (immunology, metabolism, microbiology)
• Transcription, Genetic
• Transcriptome