Hot Topics in Infection and Immunity in Children IX (Advances in Experimental Medicine and Biology)

Journal of Gastroenterology and Hepatology. Fenner's Veterinary Virology 4th ed. Retrieved 3 May Journal of Infectious Diseases. British Journal of Nursing. The Journal of Infectious Diseases. Journal of Clinical Microbiology. Entry, Assembly and Morphogenesis. Current Topics in Microbiology and Immunology. The Journal of General Virology. Rotavirus RNA replication and gene expression. Current Opinion in Virology.

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Desk Encyclopedia of Human and Medical Virology. Archives of Medical Research. Natural history of human rotavirus infection. Many Targets, Many Questions". Current Opinion in Gastroenterology. Journal of General Virology.

Archived from the original on 26 May Cell Entry by Non-Enveloped Viruses. The Scientific World Journal. Pediatric Infectious Disease Journal. Applied and Environmental Microbiology. Surveillance and Burden of Disease Studies". In Desselberger U, Gray J. Methods in Molecular Medicine. The Lancet Infectious Diseases. The Journal of Nutrition. The Investigational Drugs Journal. Clinical and Vaccine Immunology: A systematic review of in vivo studies". Beneficial Effects against Rotavirus Infection".

Advances in Virus Research. Reviews in Medical Virology. Journal of the Indian Medical Association. A systematic review and meta-analysis". Caspian Journal of Internal Medicine. Journal of Pediatric Gastroenterology and Nutrition. Expert Review of Anti-infective Therapy. Morbidity and Mortality Weekly Report. A rotavirus vaccine for prevention of severe diarrhoea of infants and young children: Expert Review of Vaccines. The New England Journal of Medicine. Retrieved 8 May Epidemiology, Burden of Disease, and Strain Diversity". UK Department of Health.

Retrieved 10 November Archived from the original on 12 July Retrieved 29 July Proceedings of the Royal Society B: International Journal of Epidemiology. American Journal of Infection Control. American Journal of Public Health. American Journal of Epidemiology. Journal of Medical Virology. Clinical Microbiology and Infection. Berliner und Munchener Tierarztliche Wochenschrift. A primary route for S. By focusing on the M-protein, Bessen and Fischetti demonstrated the ability of peptides that represent the conserved region of the M-protein of an M6 S.

Expanding on this concept, these peptides were conjugated to cholera toxin B subunit CTB. Mice vaccinated with these peptide-CTB conjugates had significantly reduced pharyngeal colonization following intranasal S. When taken together, these data highlighted the role of conserved region peptide-specific Ig in controlling S.

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An advantage of targeting the C-repeat region as a vaccine candidate is the potential to induce host protection against all S. Only one of the 19 monoclonal antibodies was capable of opsonizing the M6 strain, and this antibody was shown to target the amino-terminal region of the M-protein. Notably, the monoclonal antibodies targeting the C-repeat region, while not opsonic, were capable of fixing complement. This highlighted the importance of defining minimal epitopes for inclusion in an S.

The search for S. Interestingly, it was observed that opsonization with pimmune sera only occurred when stationary-phase organisms were used Brandt, et al. This mer epitope within P, referred to as J8i, was a B cell epitope that did not stimulate T cells in the different mouse strains examined Hayman, et al. As a result, J8i was poorly immunogenic. Furthermore, J8i was too small to maintain its helical structure, which is required for its antigenicity. Therefore, a technology was developed to fold J8i as a helix to result in J8, a mer synthetic peptide where only the central 12 amino acids J8i are derived from S.

The short synthetic peptide, J8, was immunologically non-responsive in some outbred genetically diverse mouse populations. To overcome this limitation, the peptide was conjugated to the diphtheria toxoid DT Batzloff, et al. The induction of opsonic IgG following vaccination with J8-DT was demonstrated and the formulation was also able to significantly protect outbred mice from challenge with a S. Both active and passive immunization using J8-DT induced significant protection following intraperitoneal S. Most importantly, it was observed that exposure to S. Recent data have demonstrated that J8-DT can also prevent pyoderma in an animal model that closely mimics human S.

Intranasal immunization with J14 using CTB, as well as the lipid amino terminal derivative Pam2Cys or a proteasome adjuvant, protected outbred mice from a lethal S. In both cases, Jspecific mucosal IgA was generated, which resulted in reduced throat colonization following intranasal S. In addition to the experimental data described here, there is indirect evidence from studies of natural immunity in humans that supports the role of these epitopes in providing broad-based immunity. An earlier study in the Northern Territory of Australia found that p was a cryptic epitope, being poorly immunogenic as a result of natural exposure to S.

However, after many years of S. J8 is hypothesized to be highly conserved because it is cryptic and as a result, it is hidden from the immune system following natural exposure, which results in the need for extensive exposure for the development of antibodies; however, a critical observation is that antibodies induced by J8 peptide immunization do recognize and opsonize S. Moving forward on the basis of these immunogenicity and other safety data, J8-DT has successfully completed a human double-blinded Phase I pilot trial with no adverse events reported to date and with volunteers developing an antibody response to J8 unpublished data.

To define the vaccine epitope, a large panel of approximately sera and peripheral blood mononuclear cells PBMC were used. This enabled the identification of both B and T immunodominant epitopes, which led to the construction of StreptInCor, which is composed of 55 amino acid residues Guilherme, et al. Mice vaccinated subcutaneously with this peptide using CFA as an adjuvant developed high levels of antigen-specific antibodies. The vaccine did not induce cross-reactivity with cardiac proteins Postol, et al.

Recent data demonstrated that anti-StreptInCor antibodies were able to opsonize several S. Without a doubt, the completion of the genome sequence of Haemophilus influenzae in Fleischmann, et al. Indeed, the possibility of simultaneously exploring each of the single genes of an organism offered completely new insights on how the synthesis of its proteome is coordinated in response to the environment and on the phylogenetic relationships both between and within different species.

The omics revolution had also a great impact in vaccinology. It became apparent that in silico data mining for bacterial secreted and surface proteins could successfully be exploited for the discovery of vaccine antigen candidates against relevant bacterial pathogens. The genes that encode potentially suitable vaccine targets could be expressed and purified by such high throughput methods as recombinant proteins in non-pathogenic hosts and tested in pre-clinical models for their immunogenicity and their ability to neutralize the original infectious agent.

This genomic approach to vaccine discovery, which was termed reverse vaccinology RV , was first applied with success to the newly available vaccine against the N. In this section we will discuss how genomic based information has guided the discovery of protective antigen candidates against the group A streptococcus, one of the most elusive bacterial targets for which an effective vaccine is still not available, despite decades of intense research.

The genome-based discovery of S. They are heteropolymeric structures that consist of a major protein subunit that constitutes the pilus backbone BP , plus one or two minor subunits AP1 and AP2 present at the tip and on its base respectively, all covalently assembled by a series of transpeptidase reactions catalyzed by class B and class C sortases. The sortase A that is responsible for linking proteins that bear an LPXTG motif to the peptidoglycan cell wall also anchors the pilus structure.

The observation that the genes encoding the group B streptococci pilus proteins and sortase enzymes appeared clustered together in a pathogenicity island has prompted the search for a similar island in the genomes of S. The main candidate appeared to be the highly variable FCT genomic island, previously known for encoding fibronectin-binding proteins, collagen-binding proteins, and the T antigens.

Antibodies specific to three of the proteins encoded in this region were shown to react with high molecular weight polymers on S. Knockout mutants lacking this protein, or the sortase machinery encoded in the FCT region, were deprived of pilus polymers on their surface. The relevance of pili to S. Streptococcal pili visualized by electron microscopy after labeling with subunit antibodies coupled to gold particles.

Notably, immunization of mice with a combination of recombinant pilus proteins was shown to confer protection against S. However, as anticipated above, the S. As a consequence of this variability, protection by S. Therefore, since immunization with the pilus backbone confers protection against S. More recently, we investigated cross-protection between strains that carry pili with homologous backbone proteins.

To address this question, advantage was taken of the well-established opsonophagocytic assay in group B streptococci. This data showed that cross-protection could potentially be achieved between some of the T types that share sufficiently high homology levels, which potentially further restricts the number of backbone proteins that are required for wide coverage Buccato, Regardless the number of proteins needed to achieve broad coverage, the development of an S.

Reverse vaccinology is based on the straightforward consideration that if all annotated proteins from a given pathogen are available for instance, by high throughput cloning and expression and if all proteins can be screened against a robust and reliable surrogate-of-protection assay for instance, by in vitro bactericidal assays or animal challenge models , then protective antigens will be identified. The meningococcal and group B streptococci examples demonstrate that the strategy works.

However, since most of the assays available for protective antigen selection involve animal immunization, the number of antigens to be tested represents a severe bottleneck in the entire process. For this reason, more selective strategies have been applied over the last few years in order to quickly identify protective antigens. With this objective in mind, a three-technology strategy that allows narrowing the number of antigens to be tested in the animal models down to less than ten was recently described Bensi, et al.

This approach has been successfully applied to S. The overall approach is based on the assumption that the antigens that induce broadly protective antibody responses are those that are conserved, well expressed, and either secreted or surface-associated. To identify this specific group of antigens, the genome sequences of all S. These genes were then expressed in E.

Polyclonal antibodies were subsequently exploited to establish which of the corresponding surface proteins were expressed at a high level in a battery of S. Once available, the lists of antigens identified by MS, FACS, and protein array were merged in order to establish which proteins were identified by all three technologies. The three-technology strategy led to a global list of 40 antigens, with only six of these identified by all three experimental approaches.

Remarkably, four of these six antigens were protective in three different mouse models internasal, intraperitoneal and air pouch infection models that used four S. The protective antigens include three particularly interesting proteins. One of them is SpyCEP, a serine protease that degrades IL-8 and other chemokines, which prevents neutrophil recruitment at the infection site Edwards, et al.

A second one is streptolysin O SLO , a secreted toxin that kills eukaryotic cells through the formation of membrane pores. The third antigen is Spy, a previously uncharacterized hypothetical protein involved in bacterial cell division and probably also involved in adhesion to host cells Gallotta, et al. Such protection is mediated by antibodies with different biological functions.

In addition, the antibodies have bactericidal activity, as established by a whole blood bactericidal assay. Finally, the antibodies have the capacity to interfere with bacterial cell division and adhesion.

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Therefore, this multi-facet mechanism of protection makes this three-antigen COMBO vaccine particularly attractive for testing in human trials. The binding of fibronectin Fn is an important function for S. All of these Fn-binding proteins have been found to contribute to virulence and most are multifunctional. This section will focus on evidence concerning their potential as vaccine candidates, but reviews detailing their functions and contributions to virulence are also available Walker, et al.

The Fn-binding proteins of S. Figure 4 shows a generic model of these proteins. A schematic of S. A single repeat more Antisera to this variable N-terminal domain have been used to serotype strains of S. These findings suggested that SOF may contain shared protective epitopes. Antibodies to SOF that were affinity-purified from human serum were found to opsonize and kill S. The Fn-binding domain was also deleted in these constructs. It is not clear why the non-opacifying mutants of SOF75 failed to provide adequate protection. However, these findings did indicate that SOF from one serotype can provide protection against a heterologous serotype of S.

In contrast to the above findings, Schulze et al. Although a significant immune response was generated against SOF, it was not determined if the antibodies were opsonic. Perhaps the intranasal route is not an optimal route for SOF to generate protection against a lethal challenge. SOF is expressed in other streptococci. Thus, a vaccine against SOF may target other pathogenic streptococci, in addition to S.

It is not known if Sfbx elicits a protective immune response, but antibodies against its Fn-binding domain should cross-react with those of SOF, because their Fn-binding repeats are almost identical. Rabbit antiserum to the N-terminal domain of Sfbx did not opsonize S. A number of studies have reported that IN vaccination of mice with SfbI conjugated to a variety of adjuvants provided protection against IN challenges with various serotypes of S.

In contrast to the above studies, McArthur et al. In addition, mouse and rabbit antisera against Sfb1 failed to opsonize S. The lack of protection in this study may be related to the failure to stimulate opsonic antibodies. However, there is no significant homology between the central domains of protein F2 and FbaB, and it is unlikely that epitopes within these domains would stimulate a significant cross-protective immune response.

FbaA is a Fn-binding protein expressed by a limited number of serotypes Table 5. Immunization of mice with either the full-length FbA or with its Fn-binding domain provided significant protection against S. It is interesting to note that purified antibodies to FbaA also opsonized S. The name Fbp54 is actually a misnomer and was based on the calculated mass of the cloned protein, which was thought to contain the entire gene at the time of cloning.

Subsequent work Courtney, and its sequence in S. Immmunization with Fbp54 by various routes in mouse models was found to evoke protection against challenges with multiple serotypes of S. Fbp54 is conserved in many streptococcal species with high identity to pavA of S. Glyceraldehydephosphate dehydrogenase GAPDH is a multifunctional, intracellular enzyme that is also found on the surface of S. Scl1 is a collagen-like protein expressed by S. Antibodies against Scl1 have been found in human serum and in mice infected with S.

However, none of these responses have been shown to provide protection against infections. Shr is highly conserved and is found in all sequenced genomes of S. Furthermore, mice passively immunized with rabbit antiserum to Shr were protected against challenges with M1 and M3 S. Other serotypes of M proteins that have been tested do not bind Fn.

However, the binding of Fn to M proteins has not been extensively investigated, and as a result, it is not clear if other M types may also bind Fn. The vaccine potential of both the conserved and non-conserved regions of M proteins is discussed elsewhere in this chapter.

In summary, many of the Fn-binding proteins have been found to provide protection against S. Some of these were expressed by all types of S. Some of the Fn-binding proteins are expressed only by a limited number of serotypes FbaA, FbaB and may not be the best candidates to include in a multi-component vaccine. Although there is a fair degree of homology between the Fn-binding repeat domain of these proteins Figure 3 , the degree of cross-reactive immune responses to these domains has not yet been investigated.

Thus, it is not known if the Fn-binding domain of one Fn-binding protein will provide cross-protection against serotypes of GAS expressing a different Fn-binding protein. The enzyme also binds fibronectin and functions as a low level invasin for S. The genetic diversity of S.

The specific inhibition of complement C5a that mediates phagocyte recruitment was first discovered in S. Other streptococcal species and unrelated bacteria, including staphylococci and borrelia, also interfere with C5a recruitment of phagocytes to infectious foci. The high degree of sequence similarity of SCP from different serotypes of S. Protection studies used truncated forms of recombinant SCP with mutations in the active site and employed subcutaneous, intranasal, or intravaginal rodent infection models.

Although GBS infections are less common, neonatal infections are associated with significant mortality. SCP is also an important virulence determinant for groups B and C streptococci, and vaccination with SCP prevented lethal infections of mice when challenged by either species Wei, et al.

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Vaccination of mice with SCP also prevented vaginal colonization of dams and protected their pups against challenge with Type III group B streptococci. Lessons learned from peptide vaccines for prevention of pertussis and other mucosal infections suggests that an efficacious vaccine will likely require multiple surface antigens. Toward this end, Severin et al. As described above, the slow progress toward developing a vaccine for S. Although subsequent review of this study casts doubt on the role of the vaccine in the onset of rheumatic fever, in , the United States Food and Drug Administration FDA prohibited the administration of S.

Since the lifting of the ban in the last decade, only a few clinical trials of candidate S. As with any vaccine, potential S. Dose-ranging studies will explore the optimal dose of the vaccine antigens, based on findings from pre-clinical animal studies. The number of doses and dose intervals will also be determined, which are typically based on both animal studies and clinical trials of vaccines with similar antigen compositions. For example, a purified or recombinant protein-based vaccine may initially be studied using a three-dose schedule, similar to that used with hepatitis B vaccines two closely spaced injections and a third injection after a longer interval.

Inclusion of an adjuvant will require demonstration of improved immunogenicity compared to the antigen alone. Inclusion of a control either placebo or a licensed, non- S. While smaller phase 1 studies often use a placebo, larger phase 2 studies and studies in children may benefit from use of a licensed, non- S. Although the target age for an S. Although regulatory agencies frequently require vaccines targeting infants to first be studied in older children, it is not clear whether subsequent studies of an S.

An argument could be made that following experience with vaccination of approximately adults with a candidate S. Immunogenicity outcomes will be an important component of any clinical trial of an S. Whatever the antigen employed, demonstrating induction of a specific immune response to the antigen will be required, using validated immunological assays. For M protein vaccine candidates, assessment of antibody response against each component M type will be required; for the valent S. In contrast, single-antigen S.

Vaccine candidates, such as the StrepInCor vaccine that uses B and T cell epitopes from the C-repeat section, will likely require assays that measure T cell response in addition to the antibody responses Guilherme, et al. The lack of a definitive correlate of protection for S. The clinical trials undertaken with the hexavalent and valent M protein-based S. Functional assays are tedious to perform and are not easily adaptable for high throughput methodologies.

While functional assays may be required in the early development of the valent M protein S. For example, 30 opsonophagocyosis assays for each participant at every blood collection would amount to tens of thousands of assays in a large phase 2 or 3 study. It is not yet known whether the development and validation of functional assays will be required for S. The identification of a correlate of protection using an easily performed, high-throughput assay would greatly alleviate these issues. Alternately, performing functional assays on a subset of participants and with a subset of M proteins in the case of a multivalent M protein vaccine might be an acceptable option.

Because of the history of safety concerns, adverse event monitoring in clinical trials of S. Routine adverse event monitoring will be required, including injection site reactions such as erythema, swelling, tenderness and systemic adverse events such as fever, headache, fatigue, anorexia. In addition to these common adverse events and reporting of all serious adverse events, surveillance for adverse events of special interest to S. In early phase trials, monitoring will require regular interval physical examinations, baseline and routine serum chemistry and hematology, and assays to measure complement C3 and inflammatory markers C reactive proteins.

In the clinical trials of the valent M protein vaccine, baseline and follow-up electrocardiograms and echocardiograms were performed, as well as baseline and follow up assays for tissue cross-reactive antibodies heart, kidney, cartilage and brain Kotloff, et al.

As with the functional serological assays, tissue cross-reactive antibodies are not routinely available, and these tests are burdensome to perform. Further discussions with regulatory authorities and scientific experts will be needed to determine the stage in the clinical development process at which these assays will no longer be required.

The use of echocardiograms as a screening tool is problematic, as use during clinical trials of the valent M protein vaccine demonstrated a wide range of normal variation of non-pathological findings in normal, healthy individuals. The standardized, reproducible interpretation of echocardiograms in healthy adults also proved to be a challenge; these challenges may be even greater in healthy pre-school-aged children. The necessity for echocardiograms and electrocardiograms through all phases of the clinical vaccine development program will also be an important topic for discussion with regulatory authorities.

In the absence of a definitive immunological correlate of protection, phase 3 studies of candidate S. Pharyngitis is the most readily measured efficacy outcome, because its clinical symptoms are readily observed, and laboratory confirmation through rapid antigen testing and culture is easily performed and is readily available, inexpensive, and reproducible.

However, the prevalence of asymptomatic streptococcal carriage, and the fact that pharyngitis is most common in school-aged children, yet the target population for vaccination is the pre-school-aged child, are important factors that must be considered, as they may impact the assessment of efficacy when pharyngitis is the outcome of interest. The latter issue could be addressed by focusing enrollment of older pre-school-aged children, prolonging the duration of follow-ups, and marginally increasing the sample size.

Impetigo is another common manifestation of S. However, the J8 vaccine, when administered, subcutaneously does protect mice from pyoderma that is due to multiple strains of S. Acute rheumatic fever and invasive streptococcal infections are the most severe forms of S. However, ARF and invasive infections are uncommon, even in the developing world, where the incidence of these complications far exceeds rates observed in industrialized countries. A phase 3 efficacy study with prevention of rheumatic fever as the outcome would be problematic as it would require follow-up for participants to identify cases of acute rheumatic fever.

In the context of this follow-up, should episodes of pharyngitis be identified, treatment with antibiotics would be required and cases of rheumatic fever would be avoided. As a result, the ethical issues involved in the design of such a study would be challenging. Moreover, Th17 polarized T cells from both controls and MS patients respond when incubated with vitamin D; both are downregulated with diminished production of IL and gamma interferon[ 27 ].

Cytokine production by monocytes from both normal controls and from patients with autoimmune diabetes type 1 or latent autoimmune diabetics is significantly diminished by vitamin D[ 47 ]. Lupus DCs are susceptible to the effects of vitamin D. The response of lupus cells to LPS stimulation is similarly suppressed by vitamin D[ 48 ]. We have observed that interferon inducible genes are overexpressed in lupus patients with low serum vitamin D compared to normal serum vitamin D Figure 2A. Expression of these interferon inducible genes may be diminished in lupus patients after receiving vitamin D supplementation Figure 2B.

Vitamin D has important functions beyond those of calcium and bone homeostasis which include modulation of the innate and adaptive immune responses. Vitamin D deficiency is prevalent in autoimmune disease. Cells of the immune system are capable of synthesizing and responding to vitamin D. Immune cells in autoimmune diseases are responsive to the ameliorative effects of vitamin D suggesting that the beneficial effects of supplementing vitamin D deficient individuals with autoimmune disease may extend beyond effects on bone and calcium homeostasis.

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Food as Medicine: Preventing and Treating the Most Common Diseases with Diet

National Center for Biotechnology Information , U. Author manuscript; available in PMC Aug 1. Cynthia Aranow , MD, Investigator. Find articles by Cynthia Aranow. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at J Investig Med. See other articles in PMC that cite the published article. Abstract It is now clear that vitamin D has important roles in addition to its classic effects on calcium and bone homeostasis. Vitamin D and Protective Immunity Vitamin D has been used unknowingly to treat infections such as tuberculosis before the advent of effective antibiotics.

Vitamin D and Autoimmune Disease There is increasing epidemiologic evidence linking vitamin D deficiency and autoimmune diseases including multiple sclerosis MS , rheumatoid arthritis RA , diabetes mellitus DM , inflammatory bowel disease and systemic lupus erythematosus SLE reviewed in reference[ 20 ]. Open in a separate window. Conclusions Vitamin D has important functions beyond those of calcium and bone homeostasis which include modulation of the innate and adaptive immune responses.

Footnotes Address for reprints: N Engl J Med. Nonclassic actions of vitamin D. J Clin Endocrinol Metab. Townsend K, et al. Biological actions of extra-renal hydroxyvitamin D-1alpha-hydroxylase and implications for chemoprevention and treatment. J Steroid Biochem Mol Biol. Noncalcemic actions of vitamin D receptor ligands.



Wu S, et al. Splice variants of the CYP27b1 gene and the regulation of 1,dihydroxyvitamin D3 production. Regulation of vitamin D homeostasis: On the use and administration of cod-liver oil in pulmonary consumption. London Journal of Medicine. Association between serum hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Laaksi I, et al. Am J Clin Nutr. Cannell JJ, et al. Epidemic influenza and vitamin D. Maternal vitamin D deficiency is associated with bacterial vaginosis in the first trimester of pregnancy.

A potential role for vitamin D on HIV infection? Rodriguez M, et al. Yamshchikov AV, et al. Vitamin D for treatment and prevention of infectious diseases: Urashima M, et al. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Gallo RL, et al. Biology and clinical relevance of naturally occurring antimicrobial peptides. J Allergy Clin Immunol. Liu PT, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Wang TT, et al. Munger KL, et al. Serum hydroxyvitamin D levels and risk of multiple sclerosis. Littorin B, et al.

Lower levels of plasma hydroxyvitamin D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: Merlino LA, et al.