Brandon Garcia, Ph.D.
Associate Professor
Contact informationOffice: 304 Ackert Hall EducationB.S. (Biology) 2008, University of Missouri – Kansas City |
Areas of Specialty
- Lyme Disease Pathogenesis
- Mechanisms of Bacterial Immune Evasion
- Protein Structure-Function
- Drug discovery
Research
Projects in our lab are centered on: i) broadening our knowledge of immune evasion mechanisms used by disease-causing bacteria, ii) and translating basic research of host-pathogen interactions into the development of novel therapeutics for controlling human autoimmune, inflammatory, infectious, and neurodegenerative diseases and conditions.
Vector-borne diseases which spread by the bite of arthropod vectors are responsible for an enormous worldwide public health burden. Globalization, changes in climate, and urbanization are contributing to the increasing prevalence of many vector-borne agents. This is exemplified by Lyme disease, which is caused by the tick-borne bacterium Borrelia burgdorferi in the United States, and related spirochetal pathogens across the Northern Hemisphere. The CDC recently estimated that nearly half a million cases of Lyme disease occur in the US each year, making it the country’s most common vector-borne illness.
A primary research focus in our lab is understanding the ways in which vector-borne spirochetes protect themselves from the human immune system. We are currently using a multifaceted biophysical, biochemical, and structural biology approach to explore the molecular interface between the human complement system and pathogens of the Borrelia genus. We have discovered that these bacteria express multiple, functionally overlapping, complement evasion mechanisms which contribute to the remarkable ability of these spirochetes to survive and persist in immunocompetent hosts. We are also leveraging this work to better understand the molecular mechanisms of host complement regulation and to initiate discovery of new complement-directed therapeutics.
Some of the ongoing research questions being answered in our lab are:
- What are the molecular mechanisms that faciliate complement evasion by vector-borne spirochetes?
- Can we determine the structures and functions of the outer surface lipoproteome of Lyme disease spirochetes?
- What is the structural basis of gene regulation in Lyme disease spirochetes?
- What is the molecular basis of classical pathway complement regulation by C1 esterase inhibitor?
- Can bacteria help us develop novel synthetic inhibitors for the treatment of complement-related diseases?
Selected Publications
Garrigues RJ, Garrison MP, Garcia BL. The Crystal Structure of the Michaelis-Menten Complex of C1 Esterase Inhibitor and C1s Reveals Novel Insights into Complement Regulation. J Immunol. 2024 Sep 1;213(5):718-729. doi: 10.4049/jimmunol.2400194. PubMed PMID: 38995166; PubMed Central PMCID: PMC11333171.
Thomas S, Schulz AM, Leong JM, Zeczycki TN, Garcia BL. The molecular determinants of classical pathway complement inhibition by OspEF-related proteins of Borrelia burgdorferi. J Biol Chem. 2024 May;300(5):107236. doi: 10.1016/j.jbc.2024.107236. Epub 2024 Mar 27. PubMed PMID: 38552741; PubMed Central PMCID: PMC11066524.
Xu X, Herdendorf TJ, Duan H, Rohlik DL, Roy S, Zhou H, Alkhateeb H, Khandelwal S, Zhou Q, Li P, Arepally GM, Walker JK, Garcia BL, Geisbrecht BV. Inhibition of the C1s Protease and the Classical Complement Pathway by 6-(4-Phenylpiperazin-1-yl)Pyridine-3-Carboximidamide and Chemical Analogs. J Immunol. 2024 Feb 15;212(4):689-701. doi: 10.4049/jimmunol.2300630. PubMed PMID: 38149922; PubMed Central PMCID: PMC10872613.
Rohlik DL, Patel E, Gilbert NC, Offenbacher AR, Garcia BL. Investigating membrane-binding properties of lipoxygenases using surface plasmon resonance. Biochem Biophys Res Commun. 2023 Aug 30;670:47-54. doi: 10.1016/j.bbrc.2023.05.066. Epub 2023 May 27. PubMed PMID: 37276790; PubMed Central PMCID: PMC10330842.
Roy S, Booth CE Jr, Powell-Pierce AD, Schulz AM, Skare JT, Garcia BL. Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease- and relapsing fever-causing spirochetes. J Biol Chem. 2023 Aug;299(8):104972. doi: 10.1016/j.jbc.2023.104972. Epub 2023 Jun 27. PubMed PMID: 37380082; PubMed Central PMCID: PMC10413161.
Barnes AP, Khandelwal S, Sartoretto S, Myoung S, Francis SJ, Lee GM, Rauova L, Cines DB, Skare JT, Booth CE Jr, Garcia BL, Arepally GM. Minimal role for the alternative pathway in complement activation by HIT immune complexes. J Thromb Haemost. 2022 Nov;20(11):2656-2665. doi: 10.1111/jth.15856. Epub 2022 Sep 1. PubMed PMID: 35996342; PubMed Central PMCID: PMC9938942.
Garrigues RJ, Thomas S, Leong JM, Garcia BL. Outer surface lipoproteins from the Lyme disease spirochete exploit the molecular switch mechanism of the complement protease C1s. J Biol Chem. 2022 Nov;298(11):102557. doi: 10.1016/j.jbc.2022.102557. Epub 2022 Sep 29. PubMed PMID: 36183830; PubMed Central PMCID: PMC9637899.
Booth CE Jr, Powell-Pierce AD, Skare JT, Garcia BL. Borrelia miyamotoi FbpA and FbpB Are Immunomodulatory Outer Surface Lipoproteins With Distinct Structures and Functions. Front Immunol. 2022;13:886733. doi: 10.3389/fimmu.2022.886733. eCollection 2022. PubMed PMID: 35693799; PubMed Central PMCID: PMC9186069.
Pereira MJ, Wager B, Garrigues RJ, Gerlach E, Quinn JD, Dowdell AS, Osburne MS, Zückert WR, Kraiczy P, Garcia BL, Leong JM. Lipoproteome screening of the Lyme disease agent identifies inhibitors of antibody-mediated complement killing. Proc Natl Acad Sci U S A. 2022 Mar 29;119(13):e2117770119. doi: 10.1073/pnas.2117770119. Epub 2022 Mar 21. PubMed PMID: 35312359; PubMed Central PMCID: PMC9060444.
Garrigues RJ, Powell-Pierce AD, Hammel M, Skare JT, Garcia BL. A Structural Basis for Inhibition of the Complement Initiator Protease C1r by Lyme Disease Spirochetes. J Immunol. 2021 Dec 1;207(11):2856-2867. doi: 10.4049/jimmunol.2100815. Epub 2021 Nov 10. PubMed PMID: 34759015; PubMed Central PMCID: PMC8612984.
Skare JT, Garcia BL. Complement Evasion by Lyme Disease Spirochetes. Trends Microbiol. 2020 Nov;28(11):889-899. doi: 10.1016/j.tim.2020.05.004. Epub 2020 May 29. Review. PubMed PMID: 32482556; PubMed Central PMCID: PMC7572514.
Rushing BR, Rohlik DL, Roy S, Skaff DA, Garcia BL. Targeting the Initiator Protease of the Classical Pathway of Complement Using Fragment-Based Drug Discovery. Molecules. 2020 Sep 3;25(17). doi: 10.3390/molecules25174016. PubMed PMID: 32899120; PubMed Central PMCID: PMC7504721.
Xie J, Zhi H, Garrigues RJ, Keightley A, Garcia BL, Skare JT. Structural determination of the complement inhibitory domain of Borrelia burgdorferi BBK32 provides insight into classical pathway complement evasion by Lyme disease spirochetes. PLoS Pathog. 2019 Mar;15(3):e1007659. doi: 10.1371/journal.ppat.1007659. eCollection 2019 Mar. PubMed PMID: 30897158; PubMed Central PMCID: PMC6445466.