Factors responsible for the high rate of kidney disease in Indigenous Australians: a multifaceted approach focusing on streptococcal disease

Boon, Virginia (2007) Factors responsible for the high rate of kidney disease in Indigenous Australians: a multifaceted approach focusing on streptococcal disease. PhD thesis, James Cook University.

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Indigenous communities in rural Australia have high rates of streptococcal disease including post-streptococcal glomerulonephritis (PSGN). The epidemiology of PSGN and streptococcal infection and the pathogenesis of streptococcal disease in these lower socioeconomic communities is complex and not well understood. To gain an understanding of some aspects of this problem, this study tested several hypotheses. The major hypothesis underlying this project was that streptococci isolated from these communities will produce particular virulence factors (proteins) that will cause PSGN and that this can be demonstrated both in an animal model and in individuals with end-stage renal failure (ESRF). A second hypothesis was that dogs in these communities will play a role in the epidemiology of human streptococcal disease. These hypotheses gave rise to three objectives. Firstly; to determine if dogs residing in Indigenous communities carry streptococci that may be implicated in the high rate of streptococcal disease in the human residents of these communities. Secondly; to develop a murine model of PSGN to investigate the role of streptococcal inhibitor of complement mediated cell lysis (SIC) and the genetics of host in the pathogenesis of PSGN. Thirdly; to determine the association between elevated streptococcal antibody levels in patients to several streptococcal virulence factors and the presence of ESRF.

The first objective was achieved by sampling dogs residing in two geographically distinct Australian Indigenous rural communities to reduce the possibility of location bias. Both pharyngeal and skin swabs were obtained from the study animals. Utilising routine microbiological tests and culturing methods, presumptive streptococcal species were isolated. Following this, the isolate was identified to the species level with biochemical tests and Lancefield serological grouping was also performed. The study isolated streptococcal species of Lancefield’s group A, B, C, D, G and L from the dogs. The specific species isolated were Streptococcus orisratti (Lancefield group A), Streptococcus dysgalactiae subsp. equisimilis (Lancefield’s group A, C, G or L), Streptococcus agalactiae (Lancefield’s group B), Streptococcus dysgalactiae subsp. dysgalactiae (Lancefield’s group C), Streptococcus equi subsp. equi (Lancefield’s group C), Streptococcus canis (Lancefield’s group G), Streptococcus bovis I (Lancefield’s group D), Streptococcus minor (no Lancefield’s group identified) and Streptococcus suis sp. (no Lancefield’s group identified) . In this study the fact that the two species that carried the Lancefield’s group A antigen were not biochemically identified as Streptococcus pyogenes highlights the need to assign species based on biochemical tests and not rely solely on serological grouping systems. The overall prevalence of pharyngeal and skin carriage (including the following genera’s: Streptococcus, Enterococcus, Lactococcus and Aerococcus) was 47 and 10.8%, respectively.

Furthermore, in the current study, ten strains of large-colony forming beta-haemolytic S. dysgalactiae subsp. equisimilis were identified from the pharynx of dogs which were taxonomically identical to ‘human strains’. This species of Lancefield group C and G are important human pathogens that share virulence factors with S. pyogenes and pharyngeal carriage of this bacterium in Australian Indigenous communities is high. Therefore, molecular studies were undertaken on the dog isolates to determine if they share virulence factors with the ‘human’ strains. Specifically, bacterial isolates of Lancefield’s group A, B, C, G or L were included in the molecular study and an isolate of Streptococcus minor which is a newly recognised species. To determine if these bacteria possessed virulence factors which have been identified in S. pyogenes of pathogenic origin, the isolates were screened by polymerase chain reaction using oligonucleotides that were specific for S. pyogenes virulence genes. The gene for the M or M-like protein was found in isolates of S. canis, S. dysgalactiae subsp. equisimilis and S. equi subsp. equi at a prevalence of 23.1, 90 and 100%, respectively. Tested isolates of S. agalactiae, S. canis, S. dysgalactiae subsp. equisimilis and S. orisratti harboured the streptokinase (ska) gene at prevalence rates of 62- 100%. None of the dog isolates tested harboured a gene encoding the streptococcal C5a peptidase protein. The gene encoding streptococcal pyrogenic exotoxin type G was found in 80% of S. dysgalactiae subsp. equisimilis strains and 100% of S. minor strains. Ten percent of S. dysgalactiae subsp. equisimilis strains carried a gene encoding the fibronectin binding protein.

This aspect of the study found that genes for various virulence factors considered significant to human health were present in the dog isolates at varying prevalence rates. This study showed that dogs residing in Australian Indigenous communities, where socioeconomic factors such as overcrowded housing conditions and poor water quality exist, carry streptococci which may mediate human disease. Furthermore, these findings suggest that in these populations where humans and animals live in close proximity, gene-transfers have occurred between traditional human and animal streptococcal populations.

The findings of this study are highly significant and support the hypothesis that streptococci carried by dogs are important in the epidemiology of streptococcal disease in Indigenous residents of rural communities. This project has provided the justification for integrated epidemiological studies of humans and dogs in these communities to further test the hypothesis.

To investigate the pathogenesis of PSGN a murine model for PSGN was developed using the congenic variant (NOD.C-Hc) of the non-obese diabetic (NOD) mouse and the streptococcal virulence protein SIC. We found that the production of complement component 5 was a genetic factor that was involved in the development of PSGN. Furthermore, using this murine model for PSGN, we showed that the production of SIC protein by nephritic strains of S. pyogenes is related to the capacity of the strain to induce nephritis.

Finally, to investigate whether streptococci played a role in ESRF, ELISA tests were developed to detect antibodies against virulence factors in human serum and used to screen patients on haemodialysis. A significantly higher proportion of patients compared to controls were seropositive to SIC (P=0.018), CRS (P=0.0098) and DRS (P=0.0003). Regression analysis showed seroreactivity to DRS (R2=0.85, P=0•001) predicted the development of ESRF. These results suggest that these ESRF patients were exposed to strains of S. pyogenes that secrete SIC, CRS and DRS and may have a pathological significance. No significant difference was observed between Indigenous patients and the non-Indigenous patients.

The studies described in this thesis have resulted in significant advances in our understanding of streptococcal disease, particularly as it relates to renal disease in Indigenous communities in rural Australia. The project has contributed significantly to knowledge in the three study topics. Firstly, carriage of streptococci by dogs has been demonstrated. Furthermore, the horizontal transfer of genes for virulence factors present in human streptococcal strains to canine streptococci is a major advance. It highlights the necessity to consider dogs in the epidemiology of streptococcal disease in Indigenous communities. Secondly, the rodent model for PSGN appears to be arguably the best developed so far and will allow testing of more virulence factors. Finally, the demonstration of an association between ESRF and antibody levels to particular virulence factors supports the hypothesis that chronic streptococcal infection plays a role in this disease and justifies further studies to test the hypothesis, even antibiotic prophylaxis to prevent progression of PSGN.

Item ID: 5463
Item Type: Thesis (PhD)
Keywords: kidney disease, Indigenous Australians, Indigenous health, Australia, streptococcal disease, post-streptococcal glomerulonephritis, streptococci, animal to human infection transmission, canine epidemiology
Date Deposited: 04 Nov 2009 21:42
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1117 Public Health and Health Services > 111701 Aboriginal and Torres Strait Islander Health @ 34%
11 MEDICAL AND HEALTH SCIENCES > 1108 Medical Microbiology > 110801 Medical Bacteriology @ 33%
11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110312 Nephrology and Urology @ 33%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920119 Urogenital System and Disorders @ 33%
92 HEALTH > 9203 Indigenous Health > 920302 Aboriginal and Torres Strait Islander Health - Health Status and Outcomes @ 34%
92 HEALTH > 9203 Indigenous Health > 920301 Aboriginal and Torres Strait Islander Health - Determinants of Health @ 33%
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