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Group A Streptococcus: Infection, Immunity and Vaccine Development

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A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Medical Microbiology".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 12853

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Special Issue Editors

Prof. Dr. Thomas Proft

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Guest Editor

1. Department of Molecular Medicine & Pathology, School of Medical Sciences, The University of Auckland, Auckland 1142, New Zealand
2. Maurice Wilkins Center, The University of Auckland, Auckland 1142, New Zealand
Interests: Group A Streptococcus; bacterial virulence; streptococcal pili; superantigens; bacterial toxins; bacterial immune evasion; microbial genomics; Group A Streptococcus vaccine

Dr. Jacelyn Loh

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Guest Editor

1. Department of Molecular Medicine & Pathology, School of Medical Sciences, The University of Auckland, Auckland 1142, New Zealand
2. Maurice Wilkins Center, The University of Auckland, Auckland 1142, New Zealand
Interests: Group A Streptococcus; bacterial vaccines; pili; correlates of protection; infection models; rheumatic fever; bacterial virulence; bacterial immune evasion

Dr. Catherine Jia-Yun Tsai

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Co-Guest Editor

1. Department of Molecular Medicine & Pathology, School of Medical Sciences, The University of Auckland, Auckland 1142, New Zealand
2. Maurice Wilkins Center, The University of Auckland, Auckland 1142, New Zealand
Interests: Group A Streptococcus; pili; peptide vaccines; innate immune responses; Galleria mellonella infection model; streptococcal virulence

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to this Special Issue entitled “Group A Streptococcus: Infection, Immunity, and Vaccine Development”. Group A Streptococcus (GAS), or Streptococcus pyogenes, is responsible for diseases. These range from superficial skin and soft tissue infections such as impetigo (pyoderma, or ‘school sores’), pharyngitis (‘strep throat’), and tonsillitis to more severe invasive infections such as necrotizing fasciitis (‘flesh-eating disease’) and streptococcal toxic shock syndrome 1–3. If left untreated, pharyngitis/tonsillitis can develop into a systemic and toxin-mediated disease known as scarlet fever or into autoimmune sequelae such as acute rheumatic fever or acute glomerulonephritis.

GAS remains mostly sensitive to beta-lactam antibiotics, and penicillin is the first-line treatment for pharyngitis/tonsillitis. However, GAS treatment failure has been reported since the 1980s. After the 71st World Health assembly in 2018, the World Health Organization (WHO) published a resolution on rheumatic fever and rheumatic heart disease, recognizing the public health need for a vaccine against GAS. In 2019, the WHO listed GAS in the top 10 most important human pathogens.

There are currently several experimental GAS vaccines in various stages of development, but no GAS vaccine has yet been licensed. Many knowledge gaps still exist regarding immunity to infection, and filling these will underpin future GAS vaccine development.

We invite you to submit a review article or original research article related to the abovementioned topics.

Prof. Dr. Thomas Proft
Dr. Jacelyn Loh
Dr. Catherine Jia-Yun Tsai
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Group A Streptococcus
Streptococcus pyogenes
necrotizing fasciitis
streptococcal toxic shock syndrome
pharyngitis
impetigo
erysipelas
skin and soft tissue infection
tonsillitis
scarlet fever
acute rheumatic fever
rheumatic heart disease
acute glomerulonephritis
vaccine

Published Papers (6 papers)

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Research

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11 pages, 921 KiB

Open AccessArticle

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Syndrome: A 10-Year Retrospective Cohort Study in an Italian Centre of Pediatric Rheumatology

by Saverio La Bella, Marina Attanasi, Armando Di Ludovico, Giovanna Scorrano, Francesca Mainieri, Francesca Ciarelli, Federico Lauriola, Luisa Silvestrini, Virginia Girlando, Francesco Chiarelli and Luciana Breda

Microorganisms 2024, 12(1), 8; https://doi.org/10.3390/microorganisms12010008 - 19 Dec 2023

Cited by 2 | Viewed by 2643

Abstract

Background. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is a rare pediatric disorder consisting of a sudden onset of obsessive–compulsive disorder (OCD) and/or tics after a group A Streptococcus (GAS) infection. Methods. In the period between 2013 and 2023, 61 children presented to our Pediatric Rheumatology unit with a suspicion of PANDAS syndrome. Among these, a retrospective analysis was conducted, and 19 fulfilled the current classification criteria and were included in this study. Results. The male-to-female ratio was 14:5, the median age at onset was 7.0 (2.0–9.5) years, and the median age at diagnosis was 8.0 (3.0–10.4) years. The median follow-up period was 16.0 (6.0–72.0) months. Family and personal history were relevant in 7/19 and 6/19 patients. Tics were present in all patients. Details for motor tics were retrospectively available in 18/19 patients, with the eyes (11/18) and neck/head (10/18) being most often involved. Vocal tics were documented in 8/19, behavioral changes in 10/19, and OCD in 2/19. Regarding the therapeutic response, all patients responded to amoxicillin, 12/13 to benzathine benzylpenicillin, and 7/9 to azithromycin. Conclusions. Our findings partially overlap with previous reports. Larger prospective studies are needed to improve treatment strategies and classification criteria. Full article

(This article belongs to the Special Issue Group A Streptococcus: Infection, Immunity and Vaccine Development)

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21 pages, 3177 KiB

Open AccessArticle

Streptococcal Arginine Deiminase Inhibits T Lymphocyte Differentiation In Vitro

by Eleonora A. Starikova, Jennet T. Mammedova, Arina Ozhiganova, Tatiana A. Leveshko, Aleksandra M. Lebedeva, Alexey V. Sokolov, Dmitry V. Isakov, Alena B. Karaseva, Larissa A. Burova and Igor V. Kudryavtsev

Microorganisms 2023, 11(10), 2585; https://doi.org/10.3390/microorganisms11102585 - 19 Oct 2023

Cited by 1 | Viewed by 1423

Abstract

Pathogenic microbes use arginine-metabolizing enzymes as an immune evasion strategy. In this study, the impact of streptococcal arginine deiminase (ADI) on the human peripheral blood T lymphocytes function in vitro was studied. The comparison of the effects of parental strain (Streptococcus pyogenes M49-16) with wild type of ArcA gene and its isogenic mutant with inactivated ArcA gene (Streptococcus pyogenes M49-16delArcA) was carried out. It was found that ADI in parental strain SDSC composition resulted in a fivefold decrease in the arginine concentration in human peripheral blood mononuclear cell (PBMC) supernatants. Only parental strain SDSCs suppressed anti-CD2/CD3/CD28-bead-stimulated mitochondrial dehydrogenase activity and caused a twofold decrease in IL-2 production in PBMC. Flow cytometry analysis revealed that ADI decreased the percentage of CM (central memory) and increased the proportion of TEMRA (terminally differentiated effector memory) of CD4+ and CD8+ T cells subsets. Enzyme activity inhibited the proliferation of all CD8+ T cell subsets as well as CM, EM (effector memory), and TEMRA CD4+ T cells. One of the prominent ADI effects was the inhibition of autophagy processes in CD8+ CM and EM as well as CD4+ CM, EM, and TEMRA T cell subsets. The data obtained confirm arginine’s crucial role in controlling immune reactions and suggest that streptococcal ADI may downregulate adaptive immunity and immunological memory. Full article

(This article belongs to the Special Issue Group A Streptococcus: Infection, Immunity and Vaccine Development)

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16 pages, 3559 KiB

Open AccessArticle

Concurrent Brain Subregion Microgliosis in an HLA-II Mouse Model of Group A Streptococcal Skin Infection

by Suba Nookala, Santhosh Mukundan, Bryon Grove and Colin Combs

Microorganisms 2023, 11(9), 2356; https://doi.org/10.3390/microorganisms11092356 - 20 Sep 2023

Viewed by 838

Abstract

The broad range of clinical manifestations and life-threatening infections caused by the Gram-positive bacterium, Streptococcus pyogenes or Group A Streptococcus (GAS), remains a significant concern to public health, with a subset of individuals developing neurological complications. Here, we examined the concurrent neuroimmune effects of subcutaneous GAS infections in an HLA-Class II (HLA) transgenic mouse model of subcutaneous GAS infection. To investigate changes in the skin–brain axis, HLA-DQ8 (DQA1*0301/DQB1*0302) mice (DQ8) were randomly divided into three groups: uninfected controls (No Inf), GAS infected and untreated (No Tx), and GAS infected with a resolution by clindamycin (CLN) treatment (CLN Tx) (10 mg/kg/5 days) and were monitored for 16 days post-infection. While the skin GAS burden was significantly reduced by CLN, the cortical and hippocampal GAS burden in the male DQ8 mice was not significantly reduced with CLN. Immunoreactivity to anti-GAS antibody revealed the presence of GAS bacteria in the vicinity of the neuronal nucleus in the neocortex of both No Tx and CLN Tx male DQ8 mice. GAS infection-mediated cortical cytokine changes were modest; however, compared to No Inf or No Tx groups, a significant increase in IL-2, IL-13, IL-22, and IL-10 levels was observed in CLN Tx females despite the lack of GAS burden. Western blot analysis of cortical and hippocampal homogenates showed significantly higher ionized calcium-binding adaptor-1 (Iba-1, microglia marker) protein levels in No Tx females and males and CLN Tx males compared to the No Inf group. Immunohistochemical analysis showed that Iba-1 immunoreactivity in the hippocampal CA3 and CA1 subregions was significantly higher in the CLN Tx males compared to the No Tx group. Our data support the possibility that the subcutaneous GAS infection communicates to the brain and is characterized by intraneuronal GAS sequestration, brain cytokine changes, Iba-1 protein levels, and concurrent CA3 and CA1 subregion-specific microgliosis, even without bacteremia. Full article

(This article belongs to the Special Issue Group A Streptococcus: Infection, Immunity and Vaccine Development)

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Review

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15 pages, 1164 KiB

Open AccessReview

Group A Streptococcus Pili—Roles in Pathogenesis and Potential for Vaccine Development

by Catherine Jia-Yun Tsai, Risa Takahashi, Jacelyn Mei-San Loh and Thomas Proft

Microorganisms 2024, 12(3), 555; https://doi.org/10.3390/microorganisms12030555 - 11 Mar 2024

Viewed by 812

Abstract

The Gram-positive human pathogen Group A Streptococcus (GAS, Streptococcus pyogenes) employs an arsenal of virulence factors that contribute to its pathogenesis. The pilus is an important factor that enables the pathogen to adhere to and colonize host tissues. Emerging research in pilus function shows that pili’s involvement in establishing infection extends beyond host adhesion. The diversity of GAS pilus types reflect the varying characteristics identified in different pili. With the development of new experimental systems and animal models, a wider range of biological functions have been explored. This brief review summarizes recent reports of new functions in different GAS pilus types and the methodologies that contributed to the findings. The established importance of the pilus in GAS pathogenesis makes this surface structure a promising vaccine target. This article also reviews recent advancements in pilus-based vaccine strategies and discusses certain aspects that should be considered in vaccine development according to the newly defined properties of pili. Full article

(This article belongs to the Special Issue Group A Streptococcus: Infection, Immunity and Vaccine Development)

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28 pages, 4258 KiB

Open AccessReview

Immunomodulating Enzymes from Streptococcus pyogenes—In Pathogenesis, as Biotechnological Tools, and as Biological Drugs

by Lotta Happonen and Mattias Collin

Microorganisms 2024, 12(1), 200; https://doi.org/10.3390/microorganisms12010200 - 18 Jan 2024

Cited by 1 | Viewed by 2739

Abstract

Streptococcus pyogenes, or Group A Streptococcus, is an exclusively human pathogen that causes a wide variety of diseases ranging from mild throat and skin infections to severe invasive disease. The pathogenesis of S. pyogenes infection has been extensively studied, but the pathophysiology, especially of the more severe infections, is still somewhat elusive. One key feature of S. pyogenes is the expression of secreted, surface-associated, and intracellular enzymes that directly or indirectly affect both the innate and adaptive host immune systems. Undoubtedly, S. pyogenes is one of the major bacterial sources for immunomodulating enzymes. Major targets for these enzymes are immunoglobulins that are destroyed or modified through proteolysis or glycan hydrolysis. Furthermore, several enzymes degrade components of the complement system and a group of DNAses degrade host DNA in neutrophil extracellular traps. Additional types of enzymes interfere with cellular inflammatory and innate immunity responses. In this review, we attempt to give a broad overview of the functions of these enzymes and their roles in pathogenesis. For those enzymes where experimentally determined structures exist, the structural aspects of the enzymatic activity are further discussed. Lastly, we also discuss the emerging use of some of the enzymes as biotechnological tools as well as biological drugs and vaccines. Full article

(This article belongs to the Special Issue Group A Streptococcus: Infection, Immunity and Vaccine Development)

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15 pages, 1378 KiB

Open AccessReview

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Myth or Reality? The State of the Art on a Controversial Disease

by Saverio La Bella, Giovanna Scorrano, Marta Rinaldi, Armando Di Ludovico, Francesca Mainieri, Marina Attanasi, Alberto Spalice, Francesco Chiarelli and Luciana Breda

Microorganisms 2023, 11(10), 2549; https://doi.org/10.3390/microorganisms11102549 - 13 Oct 2023

Cited by 1 | Viewed by 3063

Abstract

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is one of the most controversial diseases in pediatric rheumatology. Despite first being described more than 25 years ago as the sudden and rapid onset of obsessive–compulsive disorder (OCD) and/or tic disorder symptoms as complications of a Group A beta-hemolytic Streptococcus (GAS) infection, precise epidemiological data are still lacking, and there are no strong recommendations for its treatment. Recent advances in the comprehension of PANDAS pathophysiology are largely attributable to animal model studies and the understanding of the roles of Ca++/calmodulin-dependent protein kinase (CaM kinase) II, disrupted dopamine release in the basal ganglia, and striatal cholinergic interneurons. The diagnosis of PANDAS should be made after an exclusion process and should include prepubescent children with a sudden onset of OCD and/or a tic disorder, with a relapsing/remitting disease course, a clear temporal association between GAS infection and onset or exacerbation of symptoms, and the association with other neurological abnormalities such as motoric hyperactivity and choreiform movements. Antibiotic medications are the primary therapeutic modality. Nonetheless, there is a paucity of randomized studies and validated data, resulting in a scarcity of solid recommendations. Full article

(This article belongs to the Special Issue Group A Streptococcus: Infection, Immunity and Vaccine Development)

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