Factors associated with social functioning among long-term cancer survivors treated with hematopoietic stem cell transplantation as adolescents or young adults.

OBJECTIVE: Hematopoietic stem cell transplantation (HSCT) can compromise long-term health and social functioning. We examined the impact of physical and social-emotional factors on the social functioning of long-term adolescent and young adult (AYA) HSCT survivors. METHODS: This cross-sectional analysis included HSCT recipients from the INSPIRE trial [NCT00799461] who received their first transplant between ages 15-39. Patient-reported outcome measures included the Short Form-36v2, Fatigue Symptom Inventory, Cancer and Treatment Distress, and the ENRICHD Social Support Inventory. We used hierarchical multiple linear regression to identify physical and social-emotional factors associated with social functioning at the baseline assessment, with the first block including sociodemographic and clinical factors significant at P = <0.10 in univariate testing, the second block including fatigue and physical function, and the third block including social support and distress. RESULTS: Participants (N = 279) were 52% male and 93.5% white, non-Hispanic, with a mean age of 30.3 (SD 6.6) at first transplant. Social Functioning mean was 48.5 (SD 10.5), below age-adjusted norms (t = -13.6, P = <0.001). In the first block, current chronic graft-vs-host disease accounted for 5.5% of the variance (P = <0.001). Adding fatigue and physical function explained an additional 46.6% of the variance (P = <0.001). Adding distress and social support explained an additional 7.7% of the variance (P = <0.001). The final model explained 59.8% of the variance; distress, fatigue, and physical function were significantly associated with social functioning. CONCLUSIONS: Distress, fatigue, and physical function are associated with social functioning and interventions targeting these symptoms may help to improve SF among long-term cancer survivors treated with HSCT as AYAs.

Iron and citrate export by a major facilitator superfamily pump regulates metabolism and stress resistance in Salmonella Typhimurium.

The efficacy of antibiotics and host defenses has been linked to the metabolic and redox states of bacteria. In this study we report that a stress-induced export pump belonging to the major facilitator superfamily effluxes citrate and iron from the enteric pathogen Salmonella Typhimurium to arrest growth and ameliorate the effects of antibiotics, hydrogen peroxide, and nitric oxide. The transporter, formerly known as MdtD, is now designated IceT (iron citrate efflux transporter). Iron efflux via an iron-chelating tricarboxylic acid cycle intermediate provides a direct link between aerobic metabolism and bacterial stress responses, representing a unique mechanism of resistance to host defenses and antimicrobial agents of diverse classes.

The phage shock protein PspA facilitates divalent metal transport and is required for virulence of Salmonella enterica sv. Typhimurium.

The phage shock protein (Psp) system is induced by extracytoplasmic stress and thought to be important for the maintenance of proton motive force. We investigated the contribution of PspA to Salmonella virulence. A pspA deletion mutation significantly attenuates the virulence of Salmonella enterica serovar Typhimurium following intraperitoneal inoculation of C3H/HeN (Ity(r) ) mice. PspA was found to be specifically required for virulence in mice expressing the natural resistance-associated macrophage protein 1 (Nramp1) (Slc11a1) divalent metal transporter, which restricts microbial growth by limiting the availability of essential divalent metals within the phagosome. Salmonella competes with Nramp1 by expressing multiple metal uptake systems including the Nramp-homologue MntH, the ABC transporter SitABCD and the ZIP family transporter ZupT. PspA was found to facilitate Mn(2+) transport by MntH and SitABCD, as well as Zn(2+) and Mn(2+) transport by ZupT. In vitro uptake of (54) Mn(2+) by MntH and ZupT was reduced in the absence of PspA. Transport-deficient mutants exhibit reduced viability in the absence of PspA when grown under metal-limited conditions. Moreover, the ZupT transporter is required for Salmonella enterica serovar Typhimurium virulence in Nramp1-expressing mice. We propose that PspA promotes Salmonella virulence by maintaining proton motive force, which is required for the function of multiple transporters mediating bacterial divalent metal acquisition during infection.

Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2.

Mutations of HFE are associated with hereditary hemochromatosis, but their influence on host susceptibility to infection is incompletely understood. We report that mice lacking one or both Hfe alleles are protected from septicemia with Salmonella Typhimurium, displaying prolonged survival and improved control of bacterial replication. This increased resistance is paralleled by an enhanced production of the enterochelin-binding peptide lipocalin-2 (Lcn2), which reduces the availability of iron for Salmonella within Hfe-deficient macrophages. Accordingly, Hfe(-/-)Lcn2(-/-) macrophages are unable to efficiently control the infection or to withhold iron from intracellular Salmonella. Correspondingly, the protection conferred by the Hfe defect is abolished in Hfe(-/-) mice infected with enterochelin-deficient Salmonella as well as in Hfe(-/-)Lcn2(-/-) mice infected with wild-type bacteria. Thus, by induction of the iron-capturing peptide Lcn2, absence of functional Hfe confers host resistance to systemic infection with Salmonella, thereby providing an evolutionary advantage which may account for the high prevalence of genetic hemochromatosis.

Slc11a1 limits intracellular growth of Salmonella enterica sv. Typhimurium by promoting macrophage immune effector functions and impairing bacterial iron acquisition.

The natural resistance-associated macrophage protein 1, Slc11a1, is a phagolysosomal transporter for protons and divalent ions including iron that confers host protection against diverse intracellular pathogens including Salmonella. We investigated and compared the regulation of iron homeostasis and immune function in RAW264.7 murine phagocytes stably transfected with non-functional Slc11a1 and functional Slc11a1 controls in response to an infection with Salmonella enterica serovar Typhimurium. We report that macrophages lacking functional Slc11a1 displayed an increased expression of transferrin receptor 1, resulting in enhanced acquisition of transferrin-bound iron. In contrast, cellular iron release mediated via ferroportin 1 was significantly lower in Salmonella-infected Slc11a1-negative macrophages in comparison with phagocytes bearing Slc11a1. Lack of Slc11a1 led to intracellular persistence of S. enterica serovar Typhimurium within macrophages, which was paralleled by a reduced formation of nitric oxide, tumour necrosis factor-alpha and interleukin-6 in Slc11a1-negative macrophages following Salmonella infection, whereas interleukin-10 production was increased. Moreover, Slc11a1-negative phagocytes exhibited higher cellular iron content, resulting in increased iron acquisition by intracellular Salmonella. Our observations indicate a bifunctional role for Slc11a1 within phagocytes. Slc11a restricts iron availability, which first augments pro-inflammatory macrophage effector functions and second concomitantly limits microbial iron access.

Biosynthesis and IroC-dependent export of the siderophore salmochelin are essential for virulence of Salmonella enterica serovar Typhimurium.

In response to iron deprivation, Salmonella enterica serovar Typhimurium secretes two catecholate-type siderophores, enterobactin and its glucosylated derivative salmochelin. Although the systems responsible for enterobactin synthesis and acquisition are well characterized, the mechanisms of salmochelin secretion and acquisition, as well as its role in Salmonella virulence, are incompletely understood. Herein we show by liquid chromatography-mass spectrometry analysis of culture supernatants from wild type and isogenic mutant bacterial strains that the Major Facilitator Superfamily pump EntS is the major exporter of enterobactin and the ABC transporter IroC exports both salmochelin and enterobactin. Growth promotion experiments demonstrate that IroC is not required for utilization of Fe-enterobactin or Fe-salmochelin, as had been previously suggested, but the ABC transporter protein FepD is required for utilization of both siderophores. Salmonella mutants deficient in salmochelin synthesis or secretion exhibit reduced virulence during systemic infection of mice.