Unknown,Transcriptomics,Genomics,Proteomics

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Differences in the transcriptomic response of human adult, neonatal, and older adult monocytes to Listeria monocytogenes infection

ABSTRACT: Listeria monocytogenes (Lm) kills up to 60% of infected newborns and adults >60 years of age but is asymptomic is most young adults. Monocytes are central to effective host defense against Lm. We hypothesize that age-dependent, pathway-specific differences in the ability of the monocyte to respond to Lm explain the increased risk of the newborn and older adult to severely suffer or die from Lm infection. To delineate age-dependent differences in innate responses that lead to differential infectious outcome, monocytes were isolated from cord blood (newborn) and peripheral blood (young and older adults) and infected with Lm. RNA was collected to determine age-dependent transcriptomic changes upon infection. Total RNA was isolated from purified human monocytes from 6 adult, 6 cord , 6 older adult blood donors that were infected with wild-type Listeria monocytogenes at a multiplicity of infected (MOI)=5 for 2 and 6 hr.

ORGANISM(S): Homo sapiens

SUBMITTER: Kathleen Wee

PROVIDER: E-GEOD-67983 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Cerebral listeriosis is characterized by neuronal apoptosis and microglial cell activation, but little is known about the bacterial virulence factors involved in this process and how bacterial dissemination is controlled. Here, we show that the cellular target of Listeria monocytogenes (LM) in murine hippocampal cultures is microglia rather than neurons or other glial cells, which are rarely infected. This in vitro model served to demonstrate that infected microglial cells release a soluble factor to the medium responsible for neuronal apoptosis. We investigated the production of this factor in a well-established murine microglia cell model BV2 cells, and compared with J-774 macrophage cells after infection with different LM bacterial mutants. Our purpose was to study in both cell types parameters such as the listericidal capacities, pro-inflammatory cytokines released, and bacterial factors involved in the intracellular cycle. Our data reveal that microglia shows unique features to handle a LM infection. Microglia is three times more permissive for LM intracellular growth than murine macrophages; while producing five times higher levels of pro-inflammatory cytokines IL-6, MCP-1 and TNF-α than macrophages. Using different LM mutants (i.e., LMWT, LM∆LLO, LM∆ActA or LM∆plcB) we conclude that LLO and ActA are not involved in LM proliferation within microglia cells, while they are required for survival within macrophages. Moreover, ActA controls TNF-α production, a cytokine involved in neural apoptosis. Transcriptional differential response of microglia infected with different LM mutants reflected ActA controls the TNF-a signaling pathway through out molecules and chemokines involved in this pathway such as NFkβ, MAPK-1, Ccl2, Ccl3, Ccl4 and CxCl10. The project implies the analysis of two replicates from three different conditions, in total 6 samples: microglia cells non-infected, microglia cells infected with Listeria monocytogenes (LM) wild type (LLO+), microglia cells infected with LM deficient in listeriolysin O (LLO-) and microglia cells infected with LM deficient in ActA (1942). References samples were microglia cells non-infected (NT). Infection with LM was performed for 1 hour, followed by 24 hours in medium with antibiotics to avoid bacterial extracellular growth. Gene expression analysis was performed using Partek Genomics Suite software (version 6.11.0801; Partek). GeneChip data were filtered to remove those probe sets with an intensity raw value close to background levels. Probe sets for each array are pre-processed using RMA. Also, probe sets whose expression change under all experimental conditions was below a threshold, based on the standard desviation of the normalised intensity values, were filtered.

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Differences in the transcriptomic response of human adult, neonatal, and older adult monocytes to Listeria monocytogenes infection

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