Assistant Professor
ASOD Oral Craniofacial Health Science
Research
By 2035, more than 500 million people worldwide will be diagnosed with diabetes. Individuals with diabetes are prone to frequent and invasive infections that commonly manifest as skin and soft tissue infections (SSTIs). S. aureus is the most commonly isolated pathogen from diabetic SSTI. S. aureus is a problematic pathogen that is responsible for tens of thousands of invasive infections and deaths annually in the US. Most S. aureus infections manifest as skin and soft tissue infections (SSTIs) that are usually self-resolving. However, in patients with comorbidities, particularly diabetes, S. aureus SSTIs can disseminate resulting in systemic disease including osteomyelitis, endocarditis and sepsis. The goal of my research is to understand the complex interactions between bacterial pathogens and the host innate immune response with focus on Staphylococcus aureus and invasive infections associated with diabetes. My research is roughly divided into two project areas in order to understand the contributions of the pathogen and the host response to invasive infections associated with diabetes.
Project 1: Mechanisms of immune suppression in diabetic infections
1A: We have found that the innate immune response to S. aureus SSTIs can be loosely divided into two distinct phases: the initial inflammatory phase and a subsequent resolution phase. During the inflammatory phase, infiltrating M1-like macrophages and neutrophils produce high levels of nitric oxide (NO) and reactive oxygen species (ROS). Conversely, the hallmark of the resolution phase is the presence of Arginase-1 (Arg-1) expressing M2-like macrophages. We discovered that the transition of the immune response to the resolution phase is necessary for clearing S. aureus SSTIs. Additionally, we demonstrated that transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) is essential for transition to the resolution phase, and that mice lacking PPARγ develop more severe and non-resolving S. aureus SSTIs. We have observed that infections in diabetic mice never transition to the resolution phase. There are numerous ligands that act as PPARγ agonists, including lipid mediators such as nitrated conjugated linoleic acid. I hypothesize that the lack of endogenous PPARγ ligands in diabetics is responsible for absence of a resolution phase. Furthermore, my preliminary studies show that topical application of natural PPARγ ligands accelerates infection resolution. The goals of this project are to a) identify endogenous ligands for PPARγ activation during infection and b) determine the potential of PPARγ agonists as immunomodulatory therapeutics.
1B: While the resolution of phase of the immune response is essential for clearing infection, we found that the inflammatory phase is important for preventing dissemination of S. aureus from the SSTI. We found that phagocytes from diabetic infections do not produce immune radicals, and consequently display diminished respiratory burst. However the mechanism(s) underlying this defect have not been elucidated. Upon stimulation in a normal infection environment inflammatory phagocytes activate a distinctive Warburg-like metabolic program, consisting of elevated glucose uptake, increased glycolytic flux, and increased pentose phosphate pathway (PPP) metabolism. This change in metabolism significantly increases NADPH levels, leading to an increase in the production of immune radicals. We have observed diminished glucose consumption in phagocytes from diabetic infections that could explain the inability of diabetic phagocytes to generate a respiratory burst. The goal of this project is to understand how metabolic deficiencies in diabetic phagocytes result in diminished respiratory burst, and define the deficiencies in cell signaling in diabetic phagocytes that suppress immunometabolism.
Project 2: . Determine the role of S. aureus metabolism in host-pathogen and pathogen-pathogen interactions. S. aureus and Pseudomonas aeruginosa are frequently co-cultured from the lungs of cystic fibrosis patients. A common comorbidity in CF patients is cystic fibrosis-related diabetes (CFRD). CFRD is associated with accelerated pulmonary decline, increased infections, and earlier mortality. In cystic fibrosis patients the dominant pathogen in the lungs is initially S. aureus, but over time S. aureus is eventually replaced by P. aeruginosa as the dominant pathogen. Conversely, in patients with CFRD S. aureus re-emerges in the presence of P. aeruginosa where the two account for a significant amount of pulmonary infections. I have recently developed a murine co-infection model that mimics what is observed in CF patients. I have observed the ability of P. aeruginosa to outcompete S. aureus during co-infection in normal mice where glucose is limiting. However, in diabetic mice where glucose is abundant in the infection site, I observed increased growth and virulence potential of both S. aureus and P. aeruginosa compared to normal mice. The goals of this project are to a) define the mechanisms that allow P. aeruginosa to out compete S. aureus during co-infection in a non-diabetic environment and b) define the mechanisms that allow for S. aureus survival and increased virulence potential in diabetic co-infection.
Publications:
Thurlow LR, Stephens A, Hurly K, and Richardson AR. Lack of Nutritional Immunity in Diabetic Skin Infections Promotes Staphylococcus aureus Virulence. Sci. Adv. 2020. Nov 13;6(13):eabc5569 doi: 10.1126/sciadv.abc5569
Thurlow LR, Joshi GS, and Richardson AR. The peroxisome proliferator-activated receptorgamma is essential for controlling Staphylococcus aureus skin infection. Cell Host Microbe. 2018 Aug 8;24(2):261-270.
Grosser MR, Paluscio E, Thurlow LR, Dillon MM, Cooper VS, Kawula TH, Richardson AR. Genetic requirements for Staphylococcus aureus nitric oxide resistance and virulence. PLoS Pathog. 2018 Mar 19;14(3).
Dunn JLM, Kartchner LB, Gast K, Sessions M, Hunter RA, Thurlow L, Richardson A, Schoenfisch M, Cairns BA, Maile R. Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury. J Leukoc Biol. 2018 May;103(5):909-918.
Jones JE, Long KM, Whitmore AC, Sanders W, Thurlow LR, Brown JA, Morrison CR, Vincent H, Peck KM, Browning C, Moorman N, Lim JK, Heise MT. Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology. MBio. 2017 Nov 14;8(6).
Keener AB, Thurlow LT, Kang S, Spidale NA, Clarke SH, Cunnion KM, Tisch R, Richardson AR, Vilen BJ. Staphylococcus aureus Protein A Disrupts Immunity Mediated by Long-Lived Plasma Cells. J Immunol. 2017 Feb 1;198(3):1263-1273.
Vitko NP, Grosser MR, Khatri D, Thurlow LR, Richardson AR. Expanded glucose import capability affords Staphylococcus aureus optimized glycolytic flux during infection. 2016. mBio Jun 21;7(3).
Spahich NA, Vitko NP, Thurlow LR, Temple B, Richardson AR. Staphylococcus aureus lactate- and malate-quinone oxidoreductases contribute to nitric oxide resistance and virulence. 2016. Mol Microbiol. Jun;100(5):759-73.
Long KM, Ferris MT, Whitmore AC, Montgomery SA, Thurlow LR, McGee CE, Rodriguez CA, Lim JK, Heise MT. γδ T cells play a role in Chikungunya virus-induced disease. 2015. J Virol. 90(1): 433-43.
Maharshak N, Huh EY, Paiboonrungruang C, Shanahan M, Thurlow L, Herzog J, Djukic Z, Orlando R, Pawlinski R, Ellermann M, Borst L, Patel S, Dotan I, Sartor RB, Carroll IM. Enterococcus faecalis gelatinase mediates intestinal permeability via protease- activated receptor 2. 2015. Infect Immun. 83(7): 2762-70.
Thurlow, L. R., G. S. Joshi, J. R. Clark, J. S. Spontak, and A. R. Richardson. The arginine catabolic mobile element modulates the host immune response and contributes to the success of USA300 Staphylococcus aureus. 2013. Cell Host Microbe. 13(1): 100-7.
Thurlow, L. R., G. S. Joshi, and A. R. Richardson. 2012. Virulence strategies of the dominant USA300 lineage of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). 2012. FEMS Immunol Med Microbiol. (65): 5-22.
Fuller, J. R., N. P, Vitko, E. F. Perkowski, E. Scott, D. Khatri, J. S. Spontak, L. R. Thurlow, and A. R. Richardson. 2011. Identification of a lactate-quinone oxidoreductase in Staphylococcus aureus that is essential for virulence. Front. Cell. Inf. Microbio. 1:19.
Thurlow, L. R., M. L. Hanke, T. Fritz, A. Angle, A. Aldrich, S. H. Williams, I. L. Engesbrtsen, K. W. Bayles, A. R. Horswill, and T. Kielian. 2011. Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. J Immunol. 186(11):6585-96.
Thurlow, L. R., V. C. Thomas, S. Narayan, S. Olson, S. D. Fleming, and L. E. Hancock. 2010. Gelatinase contributes to the pathogenesis of endocarditis caused by Enterococcus faecalis. Infect Immun. 78(11):4936-43.
Thurlow, L. R., V. C. Thomas, S. D. Fleming, and L. E. Hancock. 2010. Enterococcus faecalis capsular polysaccharide serotypes C and D and their contributions to host innate immune evasion. Infect Immun. (77)12:5551-7.
Thurlow, L. R., V. C. Thomas, and L. E. Hancock. Capsular polysaccharide production in Enterococcus faecalis and the contribution of cpsF to capsule serospecificity. 2009. J Bacteriol. 191(20);6203-10.
Thomas, V. C., Y. Hiromasa, N. Harms, L. Thurlow, J. M. Tomich, and L.E. Hancock. 2009. A fratricidal mechanism is responsible for eDNA release and biofilm development of Enterococcus faecalis. Mol. Microbiol. 72:1022-36.
Thomas, V. C., L. R. Thurlow, D. Boyle, and L. E. Hancock. 2008. Regulation of autolysisdependent eDNA release by Enterococcus faecalis extracellular proteases influences biofilm development. J Bacteriol. 190:5690-8.
