BackgroundWe have sought to explore the impact of dietary Pi intake on human age related health in the pSoBid cohort (n=666) to explain the disparity between health and deprivation status in this cohort. As hyperphosphataemia is a driver of accelerated ageing in rodent models of progeria we tested whether variation in Pi levels in man associate with measures of biological ageing and health.ResultsWe observed significant relationships between serum Pi levels and markers of biological age (telomere length (p=0.040) and DNA methylation content (p=0.028), gender and chronological age (p=0.032). When analyses were adjusted for socio-economic status and nutritional factors, associations were observed between accelerated biological ageing (telomere length, genomic methylation content) and dietary derived Pi levels among the most deprived males, directly related to the frequency of red meat consumption.ConclusionsAccelerated ageing is associated with high serum Pi levels and frequency of red meat consumption. Our data provide evidence for a mechanistic link between high intake of Pi and age-related morbidities tied to socio-economic status.

Coxiella burnetii is an intracellular pathogen and the cause of Q fever. Gamma interferon (IFN-␥) is critical for host protection from infection, but a role for type I IFN in C. burnetii infection has not been determined. Type I IFN supports host protection from a related pathogen, Legionella pneumophila, and we hypothesized that it would be similarly protective in C. burnetii infection. In contrast to our prediction, IFN-␣ receptor-deficient (IFNAR ؊/؊ ) mice were protected from C. burnetii-induced infection. Therefore, the role of type I IFN in C. burnetii infection was distinct from that in L. pneumophila. Mice treated with a double-stranded-RNA mimetic were protected from C. burnetii-induced weight loss through an IFNAR-independent pathway. We next treated mice with recombinant IFN-␣ (rIFN-␣). When rIFN-␣ was injected by the intraperitoneal route during infection, disease-induced weight loss was exacerbated. Mice that received rIFN-␣ by this route had dampened interleukin 1␤ (IL-1␤) expression in bronchoalveolar lavage fluids. However, when rIFN-␣ was delivered to the lung, bacterial replication was decreased in all tissues. Thus, the presence of type I IFN in the lung protected from infection, but when delivered to the periphery, type I IFN enhanced disease, potentially by dampening inflammatory cytokines. To better characterize the capacity for type I IFN induction by C. burnetii, we assessed expression of IFN-␤ transcripts by human macrophages following stimulation with lipopolysaccharide (LPS) from C. burnetii. Understanding innate responses in C. burnetii infection will support the discovery of novel therapies that may be alternative or complementary to the current antibiotic treatment.

Human TLR4 (hTLR4) and mouse TLR4 molecules respond differently to hypo-acylated LPS. The LPS of Coxiella burnetii is hypo-acylated and heavily glycosylated and causes a minimal response by human cells. Thus, we hypothesized that mice expressing hTLR4 molecules would be more susceptible to C. burnetii infection. Our results show that transgenic mice expressing hTLR4 and the human myeloid differentiation factor 2 (MD-2) adaptor protein (hTLR4/MD-2) respond similarly to wild type mice with respect to overall disease course. However, differences in bacterial burdens in tissues were noted, and lung pathology was increased in hTLR4/MD2 compared to wild type mice. Surprisingly, bone marrow chimera experiments indicated that hTLR4/MD-2 expression on non-hematopoietic cells, rather than the target cells for C. burnetii infection, accounted for increased bacterial burden. Early during infection, cytokines involved in myeloid cell recruitment were detected in the plasma of hTLR4/MD2 mice but not wild type mice. This restricted cytokine response was accompanied by neutrophil recruitment to the lung in hTLR4/MD2 mice. These data suggest that hTLR4/MD-2 alters early responses during C. burnetii infection. These early responses are precursors to later increased bacterial burdens and exacerbated pathology in the lung. Our data suggest an unexpected role for hTLR4/MD-2 in non-hematopoietic cells during C. burnetii infection.

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Coxiella burnetii is an obligate intracellular pathogen and the cause of Q fever. The strain Nine Mile Phase I (NMI) is virulent whereas a laboratory passaged avirulent form is referred to as Phase II (NMII). Interferon (IFN)-γ is critical for protection from C. burnetii, but a role for type I IFN has not been determined. Type I IFN supports host protection from a related pathogen, Legionella pneumophila, thus we hypothesized that it would be similarly protective in C. burnetii infection. When murine macrophages were treated with IFN-α in vitro at infection, replication of NMII decreased, however, treatment 24 hours post-infection enhanced replication. Infection of spleen cells from type I IFN receptor (IFNAR)-deficient mice in vitro yielded fewer NMII genomic equivalents compared to wild type, with no change in IFN-γ expression. Thus, type I IFN signaling early in infection protected against NMII replication, but later signaling promoted replication. In vivo studies using the virulent NMI similarly suggested that IFNAR signaling promoted pathogenesis. IFNAR-deficient mice infected with NMI were significantly protected from weight loss compared to wild-type mice, although they had larger spleens and similar C. burnetii genomic equivalents. The data suggest that type I IFN signaling promotes infection with C. burnetii, contrary to the case with L. pneumophila. These results support abrogation of this pathway as a potential therapeutic approach to Q fever.