Salmonella enterica serovar Typhimurium inhibits the innate immune response and promotes apoptosis in a ribosomal/TRP53-dependent manner in swine neutrophils

Abstract

Neutrophils are the first barriers for resisting the invasion, proliferation, and damage caused by Salmonella Typhimurium. However, the mechanisms that control this resistance are not completely understood. In this study, we established an in vitro Salmonella infection model in porcine neutrophils, and analyzed the cellular transcriptome by deep sequencing and flow cytometry. The results showed that ribosomal gene transcription was inhibited, and two of these genes, RPL39 and RPL9, were related to TRP53 activation. Furthermore, several important innate immunity genes were also inhibited. Knock-down of RPL39 and RPL9 by siRNA caused an approximate fourfold up-regulation of TRP53. Knock-down of RPL39 and RPL9 also resulted in a significant down-regulation of IFNG and TNF, indicating an inhibition of the innate immune response. Silencing of RPL39 and RPL9 also resulted in the up-regulation of FAS, RB1, CASP6, and GADD45A, which play roles in cell cycle arrest and apoptosis. Neutrophils were either first treated with RPL39 siRNA, RPL9 siRNA, TRP53 activator, or TRP53 inhibitor, and then infected with Salmonella. Knock-down of RPL39 and RPL9, or treatment with TRP53 activator, can increase the intracellular proliferation of Salmonella in neutrophils. We speculate that much of the Salmonella virulence can be attributed to the enhancement of cell cycle arrest and the inhibition of the innate immune response, which allows the bacteria to successfully proliferate intracellularly.

Antimicrobial and immunomodulatory effects of tannic acid supplementation in broilers infected with Salmonella Typhimurium

“…The mRNA expression of TLR2 (an activator of the innate immune system) and NFκB (proinflammatory transcription factor related to inflammation, immune response, and cell apoptosis) were reduced due to ST NR infection D 7 ( Jin et al, 2020 ). While a statistical significance was not achieved ( P = 0.123), supplementation of TA linearly reduced mRNA expression of NFκB in the ileum, which supports that TA has an anti-inflammatory function ( Huang et al, 2020 ). However, this did not lead to enhancement in ileal morphology on D 7.…”

Proteomics profiling reveals regulation of immune response to Salmonella Typhimurium infection in mice

“…The expression of RPL37A (60S ribosomal protein L37a) protein showed a significant difference between B6 and D2 after high-dose infection (Fig 5C). Intriguingly, although RPL37A was typically considered as a classic housekeeping gene 11/35 for normalizing protein expression, studies have shown that ribosomal proteins play crucial roles in immune response to pathogen infections [27,28]. Our results indicated that RPL37A could be a plausible candidate gene for this QTL.…”

“…Contradictory to our result showing the increased expression of RPL37A protein in B6 mice after high dose S . Typhimurium infection ( Fig 5C ), a previous study demonstrated that in porcine neutrophil, RPL37 was downregulated after Salmonella infection, which resulted in the inhibition of TNF pathway and therefore promoted Salmonella survival and replication[27]. We suspect that in B6 mice, the rising of RPL37A expression may server as a complementary mechanism in response to the relatively ineffective immune reaction to Salmonella invasion.…”

Systematic comparison of ranking aggregation methods for gene lists in experimental results

“…The virus data comes from a SARS-CoV-2 related meta-analysis study for prioritisation of host genes implicated in COVID-19 [21]. The dataset used in the evaluation to assess the result is selected from the lists collected by researchers later than the first published version (2020-07-9 to 2020- [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] and is not used as input for the ranking aggregation algorithms. 238 genes appearing more than once within the top 100 genes of new lists after the published lists (2020-07-9) are extracted as truth.…”

“…Two of the lists are provided by the SHIELD Consortium (SHIELD AMR Research Consortium: https:// shieldamrresearch.org/) including a ranked list from an infection-associated apoptosis CRISPR screen in human iPSC-derived macrophages and another ranked list of human orthologues of upregulated genes in murine bronchoalveolar lavage alveolar macrophages (BAL AM) 16 hours after infection with Streptococcus pneumoniae [22]. Whereas the other lists for this macrophage apoptosis data set are collected from published papers including [23][24][25][26][27][28][29][30].…”