Oral Presentation Lorne Infection and Immunity 2019

Busting a century old myth - new insights into the immunopathogenesis of rheumatic heart disease and potential for immunotherapy (#16)

Natkunam Ketheesan 1 , Suchandan Sikder 2 , Nikki J Moreland 3 , Cathy M Rush 2 , Scott R Simpson 4 , Brenda L Govan 2 , Robert E Norton 5 , David J McMillan 6 , Michael R Batzloff 7 , Kaddaba S Sriprakash 8 , Madeleine W Cunningham 9 , David Horn 10 , Miachale F Good 7
  1. Science and Technology, University of New England, New South Wales, Australia
  2. College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia
  3. School of Medical Sciences, University of Auckland, Auckland, New Zealand
  4. Barwon Health, Geelong, Australia , Geelong, Victoria, Australia
  5. Queensland Pathology, Townsville Teaching Hospital, Douglas, Queensland, Australia
  6. School of Health and Sport Sciences, University of the Sunshine Coast, Maroochydore, Queensland, Australia
  7. Institute of Glycomics, Griffith University, Gold Coast, Queensland, Australia
  8. Bacterial Pathogenesis Laboratory, QIMR Berghofer , Brisbane, Queensland, Australia
  9. Department of Microbiology & Immunology, Oklahoma University Health Sciences Center, Oklahoma , USA
  10. Mid-Atlantic BioTherapeutics Inc, Doylestown, USA

Streptococcus pyogenes (group A streptococcus; GAS) is annually responsible for over 700 million cases of infection. If untreated, it can lead to autoimmune sequelae including Post Streptococcal Glomerulonephritis (PSGN), neurological complications, Acute Rheumatic Fever and Rheumatic Heart Disease (ARF/RHD). For over a century, ARF/RHD was considered to be triggered by GAS M protein, a protein with structural homology to host proteins. Although a safe vaccine can prevent these infections, an animal model that encompasses the immunopathological and functional characteristics of ARF/RHD is required to test their safety.

Using an array of immunological, histological, electro and echocardiographic techniques we developed the Rat Autoimmune Valvulitis model that is similar to ARF/RHD in human. Using adoptive transfer experiments we identified that both streptococcal M protein specific antibodies and T-cells can initiate and independently drive the autoimmune pathology. We also found that upregulation of VCAM-1 and ICAM-1 facilitates the migration of M protein specific T-cells into cardiac tissue. More importantly, we discovered that Streptococcus dysgalactiae subspecies equisimilis (SDSE) can also induce carditis mediated by interleukin 17A and interferon-γ indistinguishable to the pathology initiated by GAS [1].

Therefore, ARF/RHD can no longer be considered as a complication unique to GAS. Testing vaccines based on streptococcal immunodominant epitopes in our model allows the deletion of epitopes that could initiate a deleterious response [2]. Current studies are also aimed at: (a) identifying antibodies to specific streptococcal peptides that are common in animals that develop carditis, regardless of streptococcal group or M type used to induce carditis. Antibodies to these pathognomonic peptides will be more specific as diagnostics than the currently available non-specific ASOT and anti-DNAse tests and (b) evaluating the potential of using IMT504, a non-CpG oligonucleotide that increases mesenchymal stem cells and T regulatory cells, to prevent progression of chronic tissue damage.

  1. 1. Sikder S, Williams NL, Sorenson AE, Alim MA, Vidgen ME, Moreland NJ, Rush CM, Simpson RS, Govan BL, Norton RE, Cunningham MW, McMillan DJ, Sriprakash KS, Ketheesan N (2018) Group G Streptococcus induces an autoimmune carditis mediated by interleukin 17A and interferon γ in the Lewis rat model of Rheumatic Heart Disease. Journal of Infectious Diseases: 218(2):324-335. Front Cover Illustration (Volume 218, Issue 2, 15 July 2018).
  2. 2. Batzloff MR, Fane A, Gorton D, Pandey M, Rivera-Hernandez T, Calcutt A, Yeung G, Hartas J, Johnson L, Rush CM, McCarthy J, Ketheesan N, Good MF (2016) Preclinical immunogenicity and safety of a Group A streptococcal M protein-based vaccine candidate. Human Vaccine Immunotherapy 12(12):3089-3096