The Lamplit Hour

https://digitalcommons.library.umaine.edu/mmb-vp/3929/thumbnail.jp

A Metabolic Dependency for Host Isoprenoids in the Obligate Intracellular Pathogen Rickettsia parkeri Underlies a Sensitivity to the Statin Class of Host-Targeted Therapeutics.

Gram-negative bacteria in the order Rickettsiales have an obligate intracellular growth requirement, and some species cause human diseases such as typhus and spotted fever. The bacteria have evolved a dependence on essential nutrients and metabolites from the host cell as a consequence of extensive genome reduction. However, it remains largely unknown which nutrients they acquire and whether their metabolic dependency can be exploited therapeutically. Here, we describe a genetic rewiring of bacterial isoprenoid biosynthetic pathways in the Rickettsiales that has resulted from reductive genome evolution. Furthermore, we investigated whether the spotted fever group Rickettsia species Rickettsia parkeri scavenges isoprenoid precursors directly from the host. Using targeted mass spectrometry, we found that infection caused decreases in host isoprenoid products and concomitant increases in bacterial isoprenoid metabolites. Additionally, we report that treatment of infected cells with statins, which inhibit host isoprenoid synthesis, prohibited bacterial growth. We show that growth inhibition correlates with changes in bacterial size and shape that mimic those caused by antibiotics that inhibit peptidoglycan biosynthesis, suggesting that statins lead to an inhibition of cell wall synthesis. Altogether, our results describe a potential Achilles' heel of obligate intracellular pathogens that can potentially be exploited with host-targeted therapeutics that interfere with metabolic pathways required for bacterial growth.IMPORTANCE Obligate intracellular pathogens, which include viruses as well as certain bacteria and eukaryotes, are a subset of infectious microbes that are metabolically dependent on and unable to grow outside an infected host cell because they have lost or lack essential biosynthetic pathways. In this study, we describe a metabolic dependency of the bacterial pathogen Rickettsia parkeri on host isoprenoid molecules that are used in the biosynthesis of downstream products, including cholesterol, steroid hormones, and heme. Bacteria make products from isoprenoids, such as an essential lipid carrier for making the bacterial cell wall. We show that bacterial metabolic dependency can represent a potential Achilles' heel and that inhibiting host isoprenoid biosynthesis with the FDA-approved statin class of drugs inhibits bacterial growth by interfering with the integrity of the cell wall. This work supports the potential to treat infections by obligate intracellular pathogens through inhibition of host biosynthetic pathways that are susceptible to parasitism

Leveraging Epidemiology to Improve Risk Assessment.

The field of environmental public health is at an important crossroad. Our current biomonitoring efforts document widespread exposure to a host of chemicals for which toxicity information is lacking. At the same time, advances in the fields of genomics, proteomics, metabolomics, genetics and epigenetics are yielding volumes of data at a rapid pace. Our ability to detect chemicals in biological and environmental media has far outpaced our ability to interpret their health relevance, and as a result, the environmental risk paradigm, in its current state, is antiquated and ill-equipped to make the best use of these new data. In light of new scientific developments and the pressing need to characterize the public health burdens of chemicals, it is imperative to reinvigorate the use of environmental epidemiology in chemical risk assessment. Two case studies of chemical assessments from the Environmental Protection Agency Integrated Risk Information System database are presented to illustrate opportunities where epidemiologic data could have been used in place of experimental animal data in dose-response assessment, or where different approaches, techniques, or studies could have been employed to better utilize existing epidemiologic evidence. Based on the case studies and what can be learned from recent scientific advances and improved approaches to utilizing human data for dose-response estimation, recommendations are provided for the disciplines of epidemiology and risk assessment for enhancing the role of epidemiologic data in hazard identification and dose-response assessment

Thomas W. Burke, MD, Oral History Interview, March 11, 2014

Major Topics Covered: Personal and educational background Military service A portrait of a clinician with an “entrepreneurial spirit” Research: combination therapies for gynecologic cancershttps://openworks.mdanderson.org/mchv_interviewsessions/1218/thumbnail.jp

Thomas W. Burke, MD, Oral History Interview, March 18, 2014

Major Topics Covered: Gynecologic Oncology at MD Anderson and multi-disciplinary care Development of multi-disciplinary care at MD Anderson Roles as Physician-in-Chief Developing MD Anderson support serviceshttps://openworks.mdanderson.org/mchv_interviewsessions/1219/thumbnail.jp

Thomas W. Burke, MD, Oral History Interview, April 29, 2014

Major Topics Covered: Developing networks to serve MD Anderson MD Anderson culture: changes and continuities amid growth MD Anderson’s financial challenges and strategies to navigate themhttps://openworks.mdanderson.org/mchv_interviewsessions/1220/thumbnail.jp

Genetic instrumental variable regression: Explaining socioeconomic and health outcomes in nonexperimental data

Identifying causal effects in nonexperimental data is an enduring challenge. One proposed solution that recently gained popularity is the idea to use genes as instrumental variables [i.e., Mendelian randomization (MR)]. However, this approach is problematic because many variables of interest are genetically correlated, which implies the possibility that many genes could affect both the exposure and the outcome directly or via unobserved confounding factors. Thus, pleiotropic effects of genes are themselves a source of bias in nonexperimental data that would also undermine the ability of MR to correct for endogeneity bias from nongenetic sources. Here, we propose an alternative approach, genetic instrumental variable (GIV) regression, that provides estimates for the effect of an exposure on an outcome in the presence of pleiotropy. As a valuable byproduct, GIV regression also provides accurate estimates of the chip heritability of the outcome variable. GIV regression uses polygenic scores (PGSs) for the outcome of interest which can be constructed from genome-wide association study (GWAS) results. By splitting the GWAS sample for the outcome into nonoverlapping subsamples, we obtain multiple indicators of the outcome PGSs that can be used as instruments for each other and, in combination with other methods such as sibling fixed effects, can address endogeneity bias from both pleiotropy and the environment. In two empirical applications, we demonstrate that our approach produces reasonable estimates of the chip heritability of educational attainment (EA) and show that standard regression and MR provide upwardly biased estimates of the effect of body height on EA

The Limnetic zooplankton community of Boulder Basin, Lake Mead in relation to the metalimnetic oxygen minimum

The limnetic zooplankton community of Boulder Basin, Lake Mead, was examined to determine the role of this community in the development of a metalimnetic oxygen minimum which regularly occurs in the lake. Analysis of the community from May 1975 to April 1976 revealed that zooplankton maintain high populations within the metalimnion during summer stratification. The species composition of the community changes noticeably during the summer, but due to advanced stages excysting from resting forms, a complete assemblage of individuals are found throughout the 74 day period studied. Thermal stratification was weak, covering a 30 meter metalimnion. Eddy currents powered by wind action brought oxygen into this zone from the surface, and mixing at the metalimnion-hypolimnion due to internal waves and density flows brought oxygen up into this zone. The metalimnion was sectioned into two 15 meter layers. The zooplankton consumed 33 to 69 percent of the daily oxygen lost from the upper section and 12 to 42 percent from the lower section of the metalimnion from June 17 to August 28, 1975. The metalimnetic oxygen depletion of Boulder Basin is due to the oxygen consumption of the complete aquatic community of producers, consumers, and reducers. The zooplankton, representing the major consumers, account for a significant portion of the oxygen depletion