M-Protein Analysis of Streptococcus pyogenes Isolates Associated with Acute Rheumatic Fever in New Zealand

Abstract

We applied an emm cluster typing system to group A Streptococcus strains in New Zealand, including those associated with acute rheumatic fever (ARF). We observed few so-called rheumatogenic emm types but found a high proportion of emm types previously associated with pyoderma, further suggesting a role for skin infection in ARF.T wo of the most significant consequences of group A streptococcal (GAS) infection are acute rheumatic fever (ARF) and its sequelae, rheumatic heart disease (RHD). New Zealand has among the highest incidences of ARF in the developed world, with the greatest burden of disease in indigenous New Zealand (Ma ori) and Pacific populations (1).Contemporary molecular typing of GAS is carried out by sequence analysis of the hypervariable region of the emm gene that encodes the M protein (2). Studies in the United States have suggested an association between distinct GAS emm types (so-called rheumatogenic strains, such as emm3, emm5, emm6, and emm18) and ARF (3). However, more recent epidemiological studies in areas where ARF is common today have found that ARF is not restricted to these rheumatogenic strains (4), raising questions around the concept of rheumatogenicity and emm type. It has further been postulated that certain GAS emm types (most notably emm3) may be rheumatogenic due to the presence of a specific collagen-binding motif, designated peptide associated with rheumatic fever (PARF), which elicits an immune response to type IV collagen (5, 6). To date, however, the presence of the PARF motif has not been systematically assessed in a large collection of GAS strains temporally associated with ARF.Recently, an Australian and New Zealand GAS vaccine development program (the Coalition to Accelerate New Vaccines Against Streptococcus [CANVAS]) was formed with the aim of identifying suitable vaccine GAS candidates for both the Australian and New Zealand settings, and more widely (7). At present, the most clinically advanced GAS vaccine candidates are those that target the N-terminal region of the M protein, such as an experimental 30-valent M-protein vaccine (8). While this vaccine includes the classical rheumatogenic emm types, there have been few analyses to inform the coverage of contemporary ARF strains. Recently, an emm cluster-based typing system that classifies known emm types into 48 related emm clusters has been applied to several collections of GAS isolates and has shed new insights into the epidemiology of GAS and the potential vaccine coverage of M-protein-based vaccines (9, 10). The emm cluster system also predicts an emm pattern type that in turn correlates well with tissue tropism (pattern A-C for pharyngeal, pattern D for skin, and pattern E for either) (9). Accordingly, the aims of this study were to (i) compare the molecular epidemiology and theoretical vaccine coverage of GAS isolates associated with ARF in New Zealand with those of GAS isolates recovered from other GAS-related clinical syndromes, and (ii) identify GAS isolates containing the PARF motif and associate the pre...

Canada-Wide Epidemic of emm74 Group A Streptococcus Invasive Disease

“…During the first 5 years of the emm59 iGAS disease epidemic, emm59 -specific pharyngitis was rarely observed, leading to the notion that emm59 organisms had a restricted population size [18]. Similarly, emm74 organisms appear to be also very rarely associated with pharyngitis [40]. Thus, a restricted emm74 population size may be 1 reason for the minimal strain genetic variation reported here.…”

“…Similarly, it can be hypothesized that the epidemic emm74 clone has recently been introduced to Canada from elsewhere. Although rare in North America and Europe, emm74 iGAS disease, including clusters of emm74 infections, has been described in Africa, India, New Zealand, New Caledonia, and Hawaii [8, 20, 40, 43–46]. We were unable to obtain isolates or genomic data for emm74 organisms isolated in these other geographic locations to test this hypothesis.…”

Acute rheumatic fever and rheumatic heart disease

“…In some tropical areas where ARF is common, GAS carriage and GAS pharyngitis seem to be less common than in temperate areas, but impetigo (a superficial skin infection that results in sores and crusting) caused by GAS occurs at very high levels 167 . In New Zealand, the GAS isolates associated with ARF come from classically skin-associated emm types and emm cluster types 168,169 . These observations, and other data, have led to the hypothesis that GAS impetigo might contribute to the pathogenesis of ARF 46,167 , but no definitive link has been found between the two conditions and no studies on the treatment of GAS impetigo for primary prevention of ARF have been carried out.…”

The inequitable burden of group A streptococcal diseases in Indigenous Australians

“…35 The Coalition to Accelerate New Vaccines for group A Streptococcus (CANVAS), a joint initiative between the Australian and New Zealand governments, is tackling these barriers to advance GAS vaccine research. 18 Long-acting penicillins for secondary prevention of ARF The mainstay of secondary prevention of ARF remains intramuscular injections of benzathine penicillin every 28 days for a minimum of 10 years. 36 A longer-acting, less painful way of administering penicillin would overcome some of the avoidance and acceptability issues with the current formulation.…”

“…6,12 Recently, a New Zealand molecular epidemiological study using M-protein (emm) cluster typing found that 49% of ARF-associated GAS strains from isolates were emm pattern D (skin pattern) types. 18 Further studies examining the causal link between GAS impetigo and RHD remain a priority if we are to make further progress towards the primary prevention of RHD. 12 …”