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Disease Tolerance (DT) is a host response to infection that limits collateral damage to host tissues while having a neutral effect on pathogen fitness. Previously, we found that the pathogenic lactic acid bacterium Streptococcus pyogenes manipulates DT using its aerobic mixed-acid fermentation (ARMAF) pathway via the enzyme pyruvate dehydrogenase (PDH) to alter expression of the immunosuppressive cytokine IL-10. However, the microbe-derived molecules that mediate communication with the host's DT pathways remain elusive. Here, we show that ARMAF inhibits accumulation of IL-10-producing inflammatory cells including neutrophils and macrophages, leading to delayed bacterial clearance and wound healing. Expression of IL-10 is inhibited through streptococcal production of the short chain fermentation end-products acetate and formate, via manipulation of host acetyl-CoA metabolism, altering non-histone regulatory lysine acetylation. A bacterial-specific PDH inhibitor reduced tissue damage during murine infection, suggesting that reprogramming carbon flow provides a novel therapeutic strategy to mitigate tissue damage during infection., Competing Interests: Declaration of Interests The authors declare no competing interests. Additional Declarations: There is NO Competing Interest.

Pyrrole-imidazole polyamides bind DNA with affinities comparable to those of transcriptional regulatory proteins and inhibit the DNA binding activities of components of the transcription apparatus. If polyamides are to be useful for the regulation of gene expression in cell culture experiments, one pivotal issue is accessibility of specific sites in nuclear chromatin. We first determined the kinetics of uptake and subcellular distribution of polyamides in lymphoid and myeloid cells using fluorescent polyamide-bodipy conjugates and deconvolution microscopy. Then cells were incubated with a polyamide-chlorambucil conjugate, and the sites of specific DNA cleavage in the nuclear chromatin were assayed by ligation-mediated PCR. In addition, DNA microarray analysis revealed that two different polyamides generated distinct transcription profiles. Remarkably, the polyamides affected only a limited number of genes.

We previously reported that treatment of mice with a neutralizing mAb against listeriolysin O (LLO), the pore-forming toxin of Listeria monocytogenes, provided resistance to this intracellular bacterium. We evaluated whether anti-LLO mAb would affect Listeria handling by macrophages, essential cells in Listeria resistance. Macrophages infected in the presence of anti-LLO mAb showed a marked reduction in intracellular Listeria growth, with a concomitant block in LLO-dependent Listeria passage from phagosome to cytosol. Anti-LLO mAb did not opsonize Listeria but, rather, acted within macrophages to neutralize LLO. Importantly, anti-LLO mAb effects on Listeria growth were independent of Fcgamma receptor expression, IFNgamma signaling, and production of nitric oxide and superoxide. These results identify a novel mechanism for antibody control of bacteria within macrophages.

Infection with Listeria monocytogenes is a well studied model for understanding host resistance to intracellular bacteria. Recent advances in the study of Listeria have carefully quantitated the response of CD8(+) T cells to infection and analyzed the effector functions of these cells in vivo. A surprising role for antibody in mediating resistance to Listeria has also recently emerged, providing new insight into the mechanisms of host defense.

Listeriolysin O (LLO) is a secreted pore-forming toxin of the facultative intracellular bacterium Listeria monocytogenes. We assessed the ability of a murine anti-LLO mAb to affect the course of infection in mice challenged with Listeria. This mAb was previously shown to be capable of neutralizing LLO-mediated pore formation in vitro, and here we show that the passive administration of this Ab to mice before infection provides increased resistance. Mice treated with the mAb were protected from a lethal challenge with virulent Listeria and showed a significant reduction in Listeria burden during the first hours to days postinfection. These effects of the Ab were independent of host B or T cells, since treatment with the mAb provided enhanced resistance to SCID mice. The titer of anti-LLO Abs during the regular infection of mice with Listeria was found to be low to negative.

During the acute phase of growth of Listeria monocytogenes in spleen and lymph nodes, the infective foci consist of macrophages and neutrophils accompanied by extensive death of lymphocytes. Many of the lymphocytes die by apoptosis. The lesions are found by 48 hours after infection and can regress with time. Depending on the dose, the infected foci can be restricted to the thymus-dependent areas or can occupy the entire lymphoid tissue. The Listeria in the lesions are primarily found inside macrophages, but a few are extracellular amid cellular debris. Lymphocyte death appears to be an obligatory step in primary Listeria infection, the extent of which is controlled by the early restriction of Listeria growth by the innate cellular system.

The development of satellite communications over the past two decades has been very rapid. At the same time, space and electronics technologies have progressed sufficiently to allow satellite systems to keep pace with user requirements and to expand in several dimensions, including capacity, coverage, performance, reliability, and variety of services. The principal services provided by satellite systems have been long-distance trunks for telephone circuits and television program distribution. Recently, data transmission and network services have been added to meet emerging requirements for "office of the future" and other business applications. Data services are now expected to be the most rapidly expanding element of satellite communications.