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Group A Streptococcus Infections in Children

From Virulence to Clinical Management

Anne Botteaux; Isolda Budnik; Pierre R. Smeesters

Curr Opin Infect Dis. 2018;31(3):224-230.

Abstract and Introduction

Abstract

Purpose of review: Recent findings have open new perspectives on group A Streptococcus (GAS) virulence understanding
with special focus on the carrier stage and new hopes for an efficient vaccine against this important pathogen.

Recent findings: Understanding of carriage state, transmission and role of virulence factors in invasive infections have been
recently active research fields questioning the link between carriage and infections and highlighting the potential to prevent
invasive diseases. New roles for already well known virulence factors, such as Streptolysin O, M protein or NAD(+)-
glycohydrolase have been discovered. Immunological studies have also shown diversity in both clinical and immunological
responses toward various GAS antigens raising questions, and hopes, for the development of an efficient global vaccine
candidate.

Summary: A greater understanding of GAS virulence strategies, and their associated clinical manifestations, may be obtained
by shifting our research scope toward virulence determinant interactions and cooperation rather than focusing on individual
virulence factor or specific strain characterization only.

Introduction

Streptococcus pyogenes, also known as group A Streptococcus (GAS), can cause a broad range of infections and
complications, from minor illnesses, such as pharyngitis and impetigo (noninvasive disease), to very serious and deadly
infections such as necrotizing fasciitis, streptococcal toxic shock syndrome (invasive disease) or postinfectious sequelae such
as rheumatic heart diseases.[1] The burden of invasive GAS (iGAS) disease in the United States is approximately 11 000–13
000 cases per year, including cellulitis with blood infection, pneumonia and necrotizing fasciitis, with more than 500 000
deaths per year worldwide.[2] Much remains to be understood regarding the pathogenic mechanisms underlying these
infections, as well as the interactions between the human host defense mechanisms and specific virulence factors from this
organism. This review will focus on very recent publications that have shed some new insights about GAS throat carriage,
immune response after GAS infections, new understand about virulence and new recommendation about GAS diagnostic,
treatment and potential prevention. Only few of those studies were undertaken in the pediatric population.

Carriage, Infection and Recurrence

A better understanding of the underlying mechanisms allowing for GAS to be asymptomatically carried in human being would
be valuable not only to prevent disease but also to facilitate development of effective vaccine candidates. Vaccine effect on
carriage and transmission is one of the important criteria for successful impact of vaccination on clinical manifestations. Throat
carriage prevalence in asymptomatic children has been reported with rates varying between 5 and 21%.[3,4] On the other
hand, adult reports of asymptomatic carriage in adults have shown a wide range of results, from 0.6 to 11.5%.[5,6]

A recent prospective observational study by Pearson et al.[7] has investigated the GAS throat carriage and the incidence of
soft-tissue infections in marine recruits. They found a very low carriage rate (less than 0.49%) among asymptomatic healthy
young male adults in nonoutbreak setting and no association between GAS carriage and the development of skin and soft-
tissue infection. These data highlight the limited evidence existing between the carrier stage and GAS transmission
highlighting the ongoing debate about the interest of carriage eradication in epidemiological outbreaks.[8] However, carriage
could be an important source for iGAS, notably in children.[9–11] Whole-genome sequencing (WGS) analysis comparing
carrier strains to those associated with diseases have previously identified specific mutations that may contribute to carriage.
[12–14] For example, some carrier strains present a mutation in the promoter of a stand-alone regulator, called Mga, leading to
decrease in transcription of many genes including the emm gene encoding for the surface M protein. GAS M protein has been
widely studied for its immunogenic and virulence properties,[15] and allows the differentiation of GAS strains into more than
230 emm-types,[16,17] from which 175 can be grouped to 48 distinct emm-clusters, based on sequence homology and binding
capacities[18,19] (Figure 1). As protective antibodies can be generated against the M protein, it represents one of the most
characterized vaccine candidates to date.[20]

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Figure 1.

Schematic representation of group A Streptococcus M, Mrp and Enn proteins: use in typing system and future directions. The
HVR, for hypervariable region, of the M protein is composed of the 50 N-terminal residues which define the emm-type. Binding
partners of the M protein are represented with a reduced size compared with M and M-like proteins for visual clarity.

Other mutations associated with carriage eliminate GAS capsule production (hasA negative strains).[12,13] Similarly, Flores et
al.[21] have just shown that the pilus, a long filamentous surface structure facilitating adhesion of GAS to numerous surfaces,
is also implicated in carriage status.[22] Indeed, point mutation in a three-component system, lipid-II interacting antibiotics (Lia)
FSR, results in upregulation of pilus genes transcription. Pilus overexpression could result in increased
adherence/colonization and decreased virulence (less resistant to neutrophil killing), features of the carriage state. Pilus
proteins are encoded by a variable genetic region called FCT (fibrinonectin-binding and collagen-binding T-antigen), for which
nine variants are described to date (FCT 1–9). Currently, some of the most common pilus proteins (FCT regions 3 and 4)
representing 70% of the clinical isolates,[23,24] are being investigated as mucosal vaccine antigens, and are shown to be
protective in mice by intranasal immunization.[25] This finding gives hope in developing a vaccine able to reduce carriage and
potentially transmission.

Recurrence of GAS infections, defined by an infection with the same strain occurring within 1 month after the first episode, is a
common (i.e. around one-third after pharyngo-amygdalitis) but poorly understood phenomenon in children.[26,27] Different
hypotheses have been advanced to explain recurrence of penicillin-treated GAS infections. Among them, coinfection with a
beta-lactamase producer,[28] biofilms formation on tonsils[29] or entry into epithelial cell[30] could protect GAS from antibiotic
activity. Clinical isolates from recurrent infections in 38 patients (children), accounting for 81 strains, were analyzed by
Wozniak et al.[31] between March 2002 and March 2012. Within 1 month, 94% of the strains isolated form recurrent cases
could be assigned to the same emm-types than the GAS isolate recovered from the first infection. Between 1 and 3 months,
62% of the cases were due to the same emm-type. After 3 months, 100% were due to another emm-type and are not
considered as recurrence but as reinfection. The emm-12 was the most common isolate found in recurrence cases, in contrast
to emm-1 in reinfection cases. In all cases, isolates have shown low capacity for biofilms formation, regardless of the emm-
types, suggesting, in their experimental conditions, no correlation between biofilm formation and recurrence. Sixty-seven

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percent of the recurrence strains harbor the FCT region 4 which encodes for the pilus proteins and also two fibronectin-binding
protein, PrtF1 and PrtF2. The expression of those fibronectin-binding proteins of could explain a stronger tissue/cell adhesion
and the consequent persistence of the strain.

Penicillin treatment failure has been associated with GAS being found intracellularly and its potential link with severe
infections.[32] A recent study shows the efficiency of disorazole to block entry of GAS in host epithelial cells by targeting the
ezrin, a novel identified host factor involved in GAS invasion.[33] This study provides a beautiful proof of concept that
'pathoblockers' could enhance efficacy of classical treatment in streptococcal infections.[33]

Risk Factors and Transmission

It is already known that disease onset and progression can be very rapid, with high fatality rates, especially in young children
and elderly, patients with comorbidities (diabetes or cardiovascular disease), immunocompromised, alcohol abuse,
intravenous drug users, pregnant women and previous varicella infection. Environmental factors such as number of household
inhabitants and residential overcrowding have been associated with iGAS. Saavedra-Campos et al.[34] compared the risk of
iGAS in residents of long-term care facilities (LTCFs) and community residents, showing that LTCF residents are at increased
risk, being almost two times higher for cases aged over 75 years and almost three times higher between 75 and 84 years of
age. Other high-risk groups for iGAS are indigenous populations, such as the community in Northwestern Ontario, Canada,
described recently by Bocking et al.,[35] in which iGAS infections occurred at a rate 10 times higher than national average.
High prevalence of substance abuse has been thought to be a contributing factor, as well as high prevalence of skin
conditions in these communities, such as eczema and impetigo, which may be related to overcrowding housing and social
disparities in access and quality health.[36]

A population-based study carried out by Mearkle et al. has quantified the risk of secondary transmission in household contacts
of iGAS cases. It was found to be substantially elevated overall, with attack rates over 4000 per 100 000 person-years at risk
and particularly in mothers and newborns during the neonatal period and in couples aged 75 years or older, rising to over 25
000 and 15 000, respectively, during the 30 days after exposure.[37]

The ability of GAS to transmit quickly and efficiently throughout a closed population during outbreaks may potentially cause an
upraise in invasive infection and may indicate a need for intervention to control GAS transmission, as it is done in healthcare
facilities and households. These new studies add some evidence to the four previous prospective studies about secondary
prevention of iGAS (recently reviewed by Carr et al.[38]). Taken together, there is increasing data supporting the use of routine
antibiotic prophylaxis in household contacts after iGAS infections.[38]

Strains Emergence

Chochua et al.[39] have recently studied iGAS isolates recovered in the United States during 2015 through WGS providing
more insight into underlying strain emergence and strain features (for genotype, antimicrobial resistance, surface proteins,
GAS carbohydrate, hyaluronate capsule and others). They found that GAS is phylogenetically subdivided into defined
multilocus sequence type-based clusters consisting of sof-negative or sof-positive strains, with seasonal preference. A clear
seasonality has also been recently described when analyzing Centers for Disease Control surveillance data from 11 years of
iGAS infections in the USA.[40] GAS isolates from A to C and E emm-clusters may possess different capacity for transmission
or infection during the summer.[40,41]

Chochua et al. found that emm-1, emm-89 and emm-12 account for 78.9% of the infections and that most of these strains
were positive for Pnga3. Pnga3 variant results from a single nucleotide polymorphism in the promoter region of the nga
operon, which increases production of Streptolysin O (SLO) and nicotinamide adenine dinucleotide (NAD+)-glycohydrolase
(NADase).[42] NADase is a translocated virulence factor inducing cell death by depletion of NAD+.[43] Its function is intimately
related to the SLO toxin as they act together to protect GAS from autophagy, to inhibit phagocytosis and to increase survival in
keratinocytes.[44,45] SLO is cytotoxic by creating pores in cell membranes resulting in macrophages, neutrophils or red blood
cells death. Recently, Hancz et al.[46] have shown that NADase could also present an extracellular activity and reduce IL-1β
signaling after inflammasome activation in macrophages in response to SLO. Overexpression of NADase in invasive strains
could be a strategy to downregulate Il-1β signaling which is required for GAS infection control as indirectly shown by high GAS
infection rate in patients treated with Anakinra, an antagonist of the Il-1β receptor.[47]

In tandem with the Pnga3 promoter, the majority of invasive strains express also a mutated variant of the NADase protein.[42]
Significantly, this NADaseG330D variant does not have any enzymatic activity (less toxic) but seems to be positively select in
invasive strains. One possible explanation has been found by Velarde et al.[48] showing that the NADase, even inactive, is
required to stabilize and protect SLO after it secretion, by a direct interaction. The same kind of synergistic effect between
virulence factors, and they potential role in iGAS has been observed in a hypervirulent emm3 strain (MGAS315). A recent
study has shown that the deletion of both sse and sagA, encoding Sse and the streptolysin S, respectively, synergistically
enhanced neutrophil recruitment, reduced skin invasion and bacterial loads in the liver and spleen of mice and conduct to
systemic infections.[49]

Versatility of the M Protein

Even if one of the best characterized virulence factors, the M protein still gives us new lesson in virulence. In addition to its
classical role in phagocytosis inhibition and adhesion, the M protein has recently shown multiple functions in different host

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cells. For example, in some invasive strains, harboring a covRS mutation like the M1T1 clone, the loss of SpeB expression
probably leads to a higher amount of soluble M protein, released from the GAS surface. The role of this soluble form in
macrophages has recently been identified by Nizet's team who showed that some, but not all, M proteins can activate
inflammasome, release of Il-1β and macrophage pyroptosis.[50] In cultured human keratinocytes cells, soluble M1 protein has
been shown to induce Il-8 secretion which recruits polymorphonuclears neutrophils on the infection site. This proinflammatory
response leads to tissue destruction and dissemination.[51] Döhrmann et al.[52] have elegantly shown that the M protein, by
directly binding histones in neutrophil extracellular traps, is able to inhibit the histone-mediated antimicrobial activity. Finally,
recent data highlighted a novel interaction between M1 protein and blood group antigens (glycan) suggesting a potential link
between host blood group antigen and GAS susceptibility.[53]

Immune Response, Cross-protection and Vaccine Hopes

Several publications from the 1950s showed that the presence of type-specific antibodies in animal and human serum is
responsible for immunity against the homologous emm-type.[54–57] In contrast, no effect on infection by heterologous GAS
types was observed. This type-specific paradigm of GAS immunity has led to concerns about potential low coverage of the
multivalent vaccine is tropical settings in which the GAS emm-type diversity if the highest.[58–63]

Hysmith et al. conducted a prospective longitudinal study on pediatric population, over a 2-year period of observation, to
evaluate the immune response after new pharyngeal acquisition of GAS. They found that 65% of the proven immunological
responses to several GAS antigens were clinically asymptomatic.[64] They also found that, when preexisting high levels of
antibodies exist against one emm-type, no new immunologically significant acquisition of GAS belonging to the same emm-
types could be observed suggesting an association (although not statistically significant) between the presence of M
antibodies and resistance to new pharyngeal acquisition of the homologous emm-type.

Frost et al. conducted a population-based descriptive study in Fiji, evaluating the serological response to GAS impetigo in
school children, focusing on three major emm-clusters (that account for one-third of all emm-types and GAS infection
worldwide[59,60]), finding an increase in antibody titers against infective type and cluster, suggesting that a combination of
'cluster-specific' and 'type-specific' responses may occur in endemic settings[65] (Figure 1). Likewise, bactericidal assays
against selected cluster-related and nonrelated strains were performed observing in numerous instances cross-reactive killing.
[65] These data therefore suggest that cross-protective immunity has the potential to induce broader protection than type-
specific immunity would predict. The first mention of the theoretical hypothesis of cross-protective immunity was raised in 2008
and 2010 after genetic analyses on GAS strains collected in Brazil.[58,66,67] Cross-protective opsonization after rabbit
vaccination with M protein multivalent vaccine was then demonstrated with the 30-valent vaccine candidate in 2011[68] and
with an experimental 4-valent vaccine designed to protect against the 17 emm-types belonging to the E4 emm-cluster in 2017.
[69] Finally, the recent epidemiological study of GAS skin infections in Fiji showed the presence of both emm-type specific and
emm-cluster specific immunity.[65] Moreover, no correlates of protection has so far been clearly defined for GAS[70] and
serotype replacement may become an issue for GAS with multivalent vaccines as has been the case for Streptococcus
pneumoniae.[71]

A vaccine combining a multivalent M type-specific protein and a more conserved M-like protein could potentially target the
majority of GAS strains.[72] M-related protein (Mrp) is an additional antigen that contains protective epitopes that are shared
among many serotypes of GAS and that evoke a protective antibody response in humans[72,73] (Figure 1). Courtney et al.
evaluated the immunogenicity and bactericidal activity of a recombinant form containing a trivalent Mrp construct, alone and in
combination with M antibodies of the 30-valent M protein vaccine, with findings that indicate that combinations of antisera
would provide more effective opsonization than either vaccine alone. The current WGS data from USA indicates that nearly all
(98.3%) of study isolates would be covered by a combination of M-Mrp vaccine, with more than half of this isolates covered by
both vaccine components.[39] All these suggest that Mrp peptide would be a beneficial addition to next-generation M protein-
based vaccines, to broaden coverage and enhance global efficacy.

Clinical Diagnosis of Sore Throat

Improvement of treatment is undeniably also driven by an efficient diagnostic method. When clinicians are attending patients
with sore throat, it is difficult, if not impossible, to make a clinical discrimination between viral and GAS cause, leading to high
rates of inaccurate diagnosis, redundant throat cultures, misuse of antibiotics and increase in bacterial resistance. Various
strategies have been proposed in the past including clinical scores designed to identify viral sore throat, therefore allowing for
well tolerated antibiotic abstention.[74–76] McIsaac rule is a clinical tool identifying GAS throat infections based on age,
tonsillar swelling or exudates, anterior cervical lymphadenopathy, absence of cough and temperature more than 38 °C, and
has been proven to help improving GAS diagnosis and proper use of antibiotics.[77] In a retrospective pediatric review of sore
throat, Thillaivanam et al.,[77] found a significant reduction of unnecessary throat swab cultures (40%), of redundant antibiotic
prescriptions (26.5%) and of overall use of antibiotics (22.1%), showing the use of a sore throat clinical score to be a cheap,
simple and useful method for use in our pediatric care centers.

Conclusion

Recent data on virulence factors or vaccine antigens teach us that their study cannot be compartmentalized. Indeed, a holistic
way of studying virulence is currently needed to have a more realistic view of GAS virulence strategies, synergistic interactions
and cooperation of virulence factors. Efforts should be made to consider GAS as a puzzle, in which pieces are not
independent players but linked to make a global image. This will allow a better understanding of the pathogen, the progression
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of the disease and its implications, thus contributing to improve intervention strategies. This view will also help in developing
broad coverage vaccines for the future by using combination of antigens, and maybe limit future strains emergence under
vaccine pressure.

Sidebar
Key Points

Antibiotic prophylaxis should be considered for household contacts after invasive GAS infections.

Pilus and fibrinonectin-binding and collagen-binding Tantigen region seem to be important factors implicated in carriage
state.

Study of the role of NADase and Streptolysin O helps understanding the high frequency of invasive strains carrying
point mutation in NADase and upregulated expression of nga operon.

Efforts should be made to consider GAS as a puzzle, in which pieces are not independent players but interrelated, to
understand the progression of the disease and the ways we could interfere with it.

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Acknowledgements
None.

Financial support and sponsorship

The work related to the topic discussed in the present review is supported by FNRS research grants (PDR T.0255.16 and
CDR J.0019.17).

Curr Opin Infect Dis. 2018;31(3):224-230. © 2018 Lippincott Williams & Wilkins

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