Characterization of the Two-Component Abortive Phage Infection Mechanism AbiT from Lactococcus lactis

Abstract

Objectives: To determine the association between risk of rheumatoid arthritis (RA) and alcohol consumption in combination with smoking and HLA-DRB1 shared epitope (SE). Methods: Data from two independent case-control studies of RA, the Swedish EIRA (1204 cases and 871 controls) and the Danish CACORA (444 cases and 533 controls), were used to estimate ORs of developing RA for different amounts of alcohol consumed. Results: Alcohol consumption was significantly more common in controls (p,0.05) and dose-dependently associated with reduced risk of RA (p for trend ,0.001) in both studies. Among alcohol consumers, the quarter with the highest consumption had a decreased risk of RA of the order of 40-50% compared with the half with the lowest consumption (EIRA, OR = 0.5 (95% CI 0.4 to 0.6); CACORA, OR = 0.6 (95% CI 0.4 to 0.9)). For the subset of RA that is seropositive for antibodies to citrullinated peptide antigens, alcohol consumption reduced the risk most in smokers carrying HLA-DRB1 SE alleles. Conclusions: The observed inverse association between alcohol intake and risk of RA and the recent demonstration of a preventive effect of alcohol in experimental arthritis indicate that alcohol may protect against RA. This highlights the potential role of lifestyle in determining the risk of developing RA, and emphasises the advice to stop smoking, but not necessarily to abstain from alcohol in order to diminish risk of RA. The evidence of potential RA prevention should prompt additional studies on how this can be achieved.Rheumatoid arthritis (RA) is a common, complex disease which seems to develop as a result of an interplay between inducing and protective environmental and genetic factors. [1][2][3][4][5] Recently, evidence for a possible interaction between lifestyle factors and genetic factors was provided by studies showing how smoking interacts with the shared epitope (SE) alleles of the HLA-DRB1 gene in providing a very high risk of developing RA. Furthermore, the effect of both these risk factors was confined to one subset of RA, characterised by the presence of antibodies to citrullinated peptide antigens (ACPAs).2-4 6 These findings are of interest not only for public health, but also from a biological perspective, as they provide leads to a possible aetiology of RA.2 In a more general sense, they illustrate how investigations of lifestyle factors can benefit from being performed in the context of genetics, after appropriate subdivision of the disease into subsets.Our interest in the role of alcohol consumption was triggered by several reports suggesting that alcohol influences inflammation in general and arthritis in particular; alcohol has been shown to diminish the response to immunogens in animals as well as in humans.7-10 Alcohol can downregulate the production of proinflammatory molecules through its influence on innate immunity. 11Notably, addition of alcohol to the drinking water of mice was recently shown to reduce clinical signs of arthritis as well as joint destruction.12 An indication that ...

Involvement of the LlaKR2I Methylase in Expression of the AbiR Bacteriophage Defense System in Lactococcus lactis subsp. lactis biovar diacetylactis KR2

“…A single gene encodes the majority of Abi systems. However, five systems, AbiE, AbiG, AbiL, AbiT, and AbiU, are encoded by two genes (4,10,11,16,26), and AbiR was found to be encoded by at least three genes (38). A distinctive feature shared by most abi genes to date is their atypical GϩC content (less than 30%), which is significantly lower than the average GϩC content over the L. lactis genome (35.4%).…”

The Lactococcal Abortive Phage Infection System AbiP Prevents both Phage DNA Replication and Temporal Transcription Switch

“…Twenty-two lactococcal Abi genes, designated abiA to abiT, have been described (7,9,43; for a review, see reference 20). Three of these (abiD, abiD1, and abiF) code for proteins sharing 28 to 46% identity throughout the protein sequence.…”

“…It has been proposed that AbiB either induces the synthesis of an RNase or stimulates its activity (34). AbiT, which has no effect on either DNA replication or transcription, has been proposed to be activated by one of the late phage mRNAs or proteins and to rapidly cause premature cell death (7). AbiD1 has been proposed to decrease an essential RuvClike endonucleolytic activity (4,5), resolving branched DNA structures, and thus conceivably to be involved in phage DNA replication and/or packaging.…”

A Phage Protein Confers Resistance to the Lactococcal Abortive Infection Mechanism AbiP

“…In particular, they frequently possess bacteriophage abortive infection mechanisms (Abi) (4,6,15,28) that interrupt an intracellular step of phage multiplication, leading to death of the infected cell and survival of the bacterial population (23,27). Functional studies of these mechanisms have revealed a great diversity in their modes of action (14).…”

“…In some instances, sensitive phages have been reported to give rise to resistant variants. P335 phages have been shown to acquire resistance to Abi by either exchange of a DNA segment with a resident prophage or point mutations (4,5,12,13,22). By contrast, virulent phages of the 936 group, which have no homologous prophage on the host chromosome, evolved resistance to Abi only by point mutations (2-4, 13, 15).…”