Identification of novel strategies to prevent pneumonia in diabetic individuals
Scientific interest within the context of the graduate college:
Diabetics have a higher risk of various infectious diseases including pneumonia.1-3 Current estimates suggest that 450 million people worldwide have diabetes, and this number will increase to approximately 700 million by 2045.4 The increase in diabetes prevalence is thus likely to cause an increase in pneumonia-related morbidity and mortality. A better understanding of the mechanisms underlying diabetes-related dysregulation of the antibacterial immune response may allow to develop more targeted prophylactic strategies to prevent pneumonia in diabetic individuals.
Lower respiratory tract infections represent the fifth leading cause of death worldwide. In the coming years, pneumonia-associated morbidity and mortality may continue to rise as the number of individuals with risk factors for pneumonia, such as diabetes mellitus (among others) growths in many parts of the world.4 However, the mechanism underlying the enhanced susceptibility of diabetic patients to pneumonia is incompletely understood. Preliminary results indicate that diabetic animals exhibit decreased IFNg production and influx of monocyte-derived macrophages into the lung and are higher susceptibility to Legionella pneumophila infection. Moreover, IFNs are crucial for innate defense against L. pneumophila infection.5,6 The aim of the proposed project is to further characterize the impact of diabetes on early IFN-dependent antibacterial immune defense. A better understanding of these mechanisms has the potential to enable more targeted prophylactic strategies to prevent pneumonia in individuals with diabetes mellitus.
Aim 1: To characterize the effect of diabetes mellitus on susceptibility towards L. pneumophila:
diabetic animals (db/db, TallyHo) and controls
use of established mouse model of L. pneumophila-induced pneumonia5,7
Aim 2: To characterize the effect of diabetes mellitus on IFN-dependent defense:
Which cells produce IFNg?
How are upstream regulators of IFNg such IL-12 and IL-18 influenced by diabetes?
What is the consequence of impaired IFNg production on macrophage-intrinsic antibacterial defense?
Aim 3: To explore prophylactic intervention strategies to rescue impaired antibacterial immunity in diabetic animals – treatment with e.g. rIFNg, rIL-12 or rIL-18 in diabetic animals and controls to rescue antibacterial defense
Muller LMAJ, Groter KJ, Hak E, […], Schellevis FG, Hoepelman AIM, Rutten GEHM. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis. 2005; 41: 281-288. doi: 10.1086/431587.
Lepper PM, Ott S, Nüesch E, […], Jüni P, Bals L, Rohde G; German Community Acquired Pneumonia Competence Network. Serum glucose levels for predicting death in patients admitted to hospital for community acquired pneumonia: prospective cohort study. BMJ. 2012; 344:e3397. doi: 10.1136/bmj.e3397.
Yende S, von der Poll T, Lee M, […], Bauer D, Satterfield S, Angus DC; GenIMS and Health ABC study. The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: analysis of two multicentre cohort studies. Thorax. 2010; 65:870-877. doi: 10.1136/thx.2010.136317.
Cho NH, Shaw JE, Karuranga S, […], da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018; 138:271-281. doi: 10.1016/j.diabres.2018.02.023.
Naujoks J, Tabeling C, Dill BD, […], Hilbi H, Trost M, Opitz B. IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid. PLoS Pathog. 2016; 12:e1005408. doi: 10.1371/journal.ppat.1005408.
Opitz B, van Laak V, Eitel J, Suttorp N. Innate immune recognition in infectious and noninfectious diseases of the lung. Am J Respir Crit Care Med. 2010; 181:1294-1309. doi: 10.1164/rccm.200909-1427SO.
Ruiz-Moreno JS, Hamann L, Shah JA, […], Schumann RR, JinL, Hawn TR, Opitz B; CAPNETZ Study Group. The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires’ disease in humans. PLoS Pathog. 2018;14:e1006829. doi: 10.1371/journal.ppat.1006829.
Manage Cookie Consent
The technical storage or access is strictly necessary for the legitimate purpose of enabling the use of a specific service explicitly requested by the subscriber or user, or for the sole purpose of carrying out the transmission of a communication over an electronic communications network.
The technical storage or access is necessary for the legitimate purpose of storing preferences that are not requested by the subscriber or user.
The technical storage or access that is used exclusively for statistical purposes.The technical storage or access that is used exclusively for anonymous statistical purposes. Without a subpoena, voluntary compliance on the part of your Internet Service Provider, or additional records from a third party, information stored or retrieved for this purpose alone cannot usually be used to identify you.
The technical storage or access is required to create user profiles to send advertising, or to track the user on a website or across several websites for similar marketing purposes.