Review
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/19/15 For personal use only.
Neisseria meningitidis infection: who, when and where? Expert Rev. Anti Infect. Ther. Early online, 1–15 (2015)
Elena Gianchecchi1, Alessandro Torelli1, Giulia Piccini1, Simona Piccirella1 and Emanuele Montomoli2 1 VisMederi Srl, via Fiorentina 1, Siena 53100, Italy 2 Department of Molecular and Developmental Medicine, University of Siena, via Aldo 3, Siena, Italy *Author for correspondence: Tel.: +390577231254 Fax: +39057743444 [email protected]
Neisseria meningitidis is a Gram-negative b-proteobacterium responsible for an endemic worldwide infection. The epidemiology and serogroup distribution can change very quickly. The incidence of meningitis infection varies from very rare to more than 1000 cases per 100,000 of the population yearly. The carriage of N. meningitidis, which represents an exclusive human commensal, is asymptomatic, but in rare cases bacteria proliferate in the CNS and rapidly lead to the death of the affected subjects. Host genetic factors, such as single nucleotide polymorphisms, can promote meningococcal disease, being able to influence the individual predisposition to the pathology. Although a reduction in meningococcal disease has been observed in Europe, a continuous surveillance is necessary to control any possible outbreaks of new hypervirulent clones into populations that could modify the epidemiology of meningococcal infections and the clinical spectrum of affected subjects. KEYWORDS: epidemiology . hypervirulent clonal complexes . invasive meningococcal disease . Neisseria meningitidis .
single nucleotide polymorphisms
Neisseria meningitidis, also known as ‘meningococcus’, is a Gram-negative b-proteobacterium, which belongs to the family of Neisseriaceae [1–3]. It was described by Marchiafava and Celli in the cerebrospinal fluid for the first time in 1884 and isolated 3 years later by Weichselbaum [4,5]. This bacterium is characterized by the presence of an outer membrane made of lipids, lipopolysaccharide and outer membrane proteins. When isolated the outer membrane of pathogenic meningococci is usually surrounded by a polysaccharide capsule [6,7], accordingly with its critical virulence function [7]. A high antigenic diversity in both inter- and intra-strain characterizes N. meningitidis [8]. This is partially due to high mutation levels in selective loci, horizontal genetic recombination [9,10] and incorporation between different species of Neisseriae [9]. In addition, events of recombination such as gene transfers have been observed between gonococci, meningococci, commensal Neisseriae and other bacteria [11,12]. The high degree of antigenic changes allows these bacteria, as well as many others that infect the CNS, to escape from the immunological defense mechanisms of the host [13].
informahealthcare.com
10.1586/14787210.2015.1070096
Based on different polysaccharide structures present on the capsule, 12 serogroups (serogroup D capsule is now classified as an unencapsulated serogroup C variant) [14] of N. meningitidis have been isolated [6,15] through the use of antibodies recognizing epitopes localized on the capsule surface itself [6]. However, only A, B, C, W-135 (recently renamed W by Harrison et al. [16]), X and Y capsular serogroups are responsible for most of the cases of meningococcal disease [1,17–19]. Among the serogroups, different sequence types (STs) can be identified. Groups of STs sharing common genotype characteristics have been classified into clonal complexes by means of MultiLocus Sequence Type [20]. Clonal complexes such as ST-11, ST-32 or ST-41/44 are associated with a propensity to cause invasive meningococcal disease (IMD) and are consequently called hyperinvasive lineages, while lineages such as ST-23 or ST-53 are commonly related to asymptomatic carriage [21]. Transmission & carriage of N. meningitidis
N. meningitidis transmission occurs through a close contact with saliva or respiratory
2015 Informa UK Ltd
ISSN 1478-7210
1
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/19/15 For personal use only.
Review
Gianchecchi, Torelli, Piccini, Piccirella & Montomoli
secretions; however the inoculum size necessary for transmission is still unknown at the moment [22]. The unique reservoir of N. meningitidis is represented by humans, wherein it constitutes a commensal diplococcus of the nasopharynx [1,23–26] in about 10% of the total population [19,26]. N. meningitidis colonization can be asymptomatic, resulting in upper respiratory and pharyngeal meningococcal carriage that can last from days to months [22]. It has been estimated that each person can be characterized by the carriage of N. meningitidis 10-times during the first 30 years of life [27]. The same individual can carry more than one meningococcal strain for months [28]. In rare cases, the infection can cause local inflammation and, as a consequence of the penetration into the bloodstream and then in the meninges, it can lead to IMD [1,15,29]. IMD is a rare pathology highly correlated to permanent disability and mortality [30]. After rabies, meningococcal disease shows the highest fatality rate among other diseases that can be prevented by vaccines [31]. Mortality can reach up to 10%, and even 40% in presence of meningococcal septicemia [32]. Although the initial clinical presentation often resembles influenza-like illness [30], the early clinical picture of rash, photophobia, nuchal rigidity, meningeal signs and altered mental status is characteristic of IMD. Meningitis represents the most common clinical symptom of IMD. In industrialized countries, it is present without shock in 60% of patients [15]. The presence of ecchymoses often characterizes patients with severe disseminated intravascular coagulation involving several organs. The destructive and marked process of intravascular inflammation leads to the progressive circulatory collapse and severe coagulopathy. Bacteria and meningococcal endotoxin can reach elevated concentrations. Up to 20% of survivors can present serious handicaps, including brain damage, deafness, kidney failure and amputation of digits or limbs [33]. During endemic and epidemic outbreaks, 28–77% of IMD patients are characterized by typical hemorrhagical skin lesions [19] all over the body and even on sclera and mucous membranes in some cases. IMD also represents the main cause of death due to bacterial infections in about 1 per 40,000–100,000 healthy young individuals [34] by inducing the development of meningococcal meningitis (MM) and septicemia [15,35]. Since rash and meningeal signs may not be present, an early diagnosis of MM can be hard. The confirmation of the diagnosis of meningococcal disease occurs by Gram stain in association with cerebrospinal fluid, or blood, or skin lesion cultures. Recently, the use of PCR without cultures has enhanced [15]. Moreover, it can be fatal if not promptly and adequately treated [22]. Thus, meningococcal disease remains a serious public worldwide health problem. Meningococcal carriage represents an immunizing process [36]. Goldschneider et al. [36] described that 2 weeks after the first contact with bacteria, the release of specific antibodies, IgG, IgM and IgA, against N. meningitidis was induced [22] and it was associated with an increased bactericidal titer [36]. Furthermore, these antibodies combined with groupspecific meningococcal polysaccharides first isolated by Rake and Scherp [37] and cross-reactive antigens. Heterologous strains doi: 10.1586/14787210.2015.1070096
of N. meningitidis can share at least two common antigens. The presence of serum bactericidal antibodies (SBA) against meningococcus during the first 12 years of life was inversely proportional to age-specific MD incidence. Although the presence of antibodies in the serum has been associated with a lower incidence of meningococcal disease, constituting a natural selective immunity [36], this protection is not total and meningococcemia can also develop in subjects presenting antibodies directed against N. meningitidis [22]. Several factors can damage the mucosal barrier and such changes in the mucosal immunity can predispose to IMD. These include environmental factors (low humidity, dust concentration, tobacco) [15,22], co-infections (mycoplasma, viral respiratory and HIV infections), meningococcal virulence factors, lack of immune response caused by acquired immunoglobulin deficiencies and genetic polymorphisms in components of the host immune system [22,38]. Contrasting data emerged from the association between meningococcal disease and HIV comparing African outbreaks and those reported in the USA; in fact, no relationship between HIV infection and disease was found in African countries, while a sevenfold risk increase was observed in the USA [22]. The role of polymorphisms in influencing meningococcal disease
Genetic factors of the host play a fundamental role in meningococcal disease; in fact, they are able to influence the clinical presentation of patients affected by meningococcal infection, ranging from a mild form of bacteremia even to deadly septic shock syndrome [38]. Risk factors for IMD are properdin [39,40] and complement deficiencies [22,41,42], congenital or acquired immunoglobulin deficiencies [43–45] and single nucleotide polymorphisms (SNPs). More in detail, the ability of some SNPs in innate host determinants to influence the individual predisposition to meningococcal disease is well known [15,46,47], both promoting it or protecting the subject from meningococcemia. Among these genetic variants, there are mannose-binding lectin [22], TLR2, TLR4 [22,34,47], TLR9 and NOD2 SNPs [47]. It has been estimated that a third of meningococcal disease cases could be ascribed to genetic variants in mannose-binding lectin that may induce also a milder form of disease, although further investigations are needed to confirm these data [48]. Whereas TLR2 and the common white TLR4 (TLR4B) variants do not influence susceptibility to meningococcal infections, only rare co-dominant mutations at TLR4 locus and in particular only missense mutations increase the susceptibility to meningococcal infection [34]. Recently, van Well et al. [47] evaluated genotype distributions of seven single and combined SNPs in five immune response genes (TLR2, TLR4, TLR9, nucleotide oligomerization domain [NOD] proteins and caspase-1). A total of 391 Dutch Caucasian children affected by meningococcal disease (86% of those were serogroup B patients) and 1141 healthy subjects have been analyzed. They found for the first time a strong association between NOD2 (SNP8), TLR2 and TLR4 (+896) SNPs and susceptibility to MM. Contrasting data regarding the role of TLR4 (+896) SNP as a risk factor for the Expert Rev. Anti Infect. Ther.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/19/15 For personal use only.
Neisseria meningitidis infection
development or severity of meningococcal disease were reported both in an English [49] and in Gambian cohorts [47]. The results reported by van Well et al. were in accordance with a previous study which described an association between TLR4 (+896) SNP and mortality, skin grafting and limb loss caused by IMD [50]. Furthermore, the data reported in the study by van Well et al. are in accordance with in vivo results obtained in NOD2 knockout mice, which were characterized by diminished demyelination, astrogliosis and inflammatory cytokine release in the CNS after meningococcal infection, confirming the critical role of this gene in the induction of damaging inflammation [51]. An increased susceptibility to MM was also observed in case of the following combined carriages: TLR2 +2477 and TLR4 +896 mutants, as well as TLR4 +896 and NOD2 (SNP8) mutants [47]. Conversely, TLR9 (-1237 and +2848) SNPs were associated with protection against meningococcemia, fundamental prerequisite for meningeal invasion, and with increased immune response in the CNS in a cohort of MM Caucasian survivors [52], in accordance with the important role played by TLR9 in the prevention of bacteremia [53]. Since the frequency of some polymorphisms in the general population is relatively high, and since they constitute stable gene variants able to strongly influence the progression of MM, the study of SNPs may allow the identification of those subjects carrying the variants associated with a higher risk to develop a severe MM form or die after contracting N. meningitidis [38]. Genome-wide association study can be used to identify genetic variants associated with host susceptibility to meningococcal disease [54]. Current global epidemiology of meningococcal disease by geographic macro-areas
N. meningitidis is responsible for an endemic worldwide infection and the various serogroups show different areas of diffusion (FIGURE 1) (reviewed [rev.] in [6]). The epidemiology and serogroup distribution can change very quickly, as demonstrated by serogroup X and Y incidence in the last 10 years (rev. in [55]). The incidence of meningitis can vary from highly rare till more than 1000 cases of infection per 100,000 population every year [1,18,56,57]. Although the infection can affect people of all ages, the higher rate of cases has been observed in children with age
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/19/15 For personal use only.
Neisseria meningitidis infection: who, when and where? Expert Rev. Anti Infect. Ther. Early online, 1–15 (2015)
Elena Gianchecchi1, Alessandro Torelli1, Giulia Piccini1, Simona Piccirella1 and Emanuele Montomoli2 1 VisMederi Srl, via Fiorentina 1, Siena 53100, Italy 2 Department of Molecular and Developmental Medicine, University of Siena, via Aldo 3, Siena, Italy *Author for correspondence: Tel.: +390577231254 Fax: +39057743444 [email protected]
Neisseria meningitidis is a Gram-negative b-proteobacterium responsible for an endemic worldwide infection. The epidemiology and serogroup distribution can change very quickly. The incidence of meningitis infection varies from very rare to more than 1000 cases per 100,000 of the population yearly. The carriage of N. meningitidis, which represents an exclusive human commensal, is asymptomatic, but in rare cases bacteria proliferate in the CNS and rapidly lead to the death of the affected subjects. Host genetic factors, such as single nucleotide polymorphisms, can promote meningococcal disease, being able to influence the individual predisposition to the pathology. Although a reduction in meningococcal disease has been observed in Europe, a continuous surveillance is necessary to control any possible outbreaks of new hypervirulent clones into populations that could modify the epidemiology of meningococcal infections and the clinical spectrum of affected subjects. KEYWORDS: epidemiology . hypervirulent clonal complexes . invasive meningococcal disease . Neisseria meningitidis .
single nucleotide polymorphisms
Neisseria meningitidis, also known as ‘meningococcus’, is a Gram-negative b-proteobacterium, which belongs to the family of Neisseriaceae [1–3]. It was described by Marchiafava and Celli in the cerebrospinal fluid for the first time in 1884 and isolated 3 years later by Weichselbaum [4,5]. This bacterium is characterized by the presence of an outer membrane made of lipids, lipopolysaccharide and outer membrane proteins. When isolated the outer membrane of pathogenic meningococci is usually surrounded by a polysaccharide capsule [6,7], accordingly with its critical virulence function [7]. A high antigenic diversity in both inter- and intra-strain characterizes N. meningitidis [8]. This is partially due to high mutation levels in selective loci, horizontal genetic recombination [9,10] and incorporation between different species of Neisseriae [9]. In addition, events of recombination such as gene transfers have been observed between gonococci, meningococci, commensal Neisseriae and other bacteria [11,12]. The high degree of antigenic changes allows these bacteria, as well as many others that infect the CNS, to escape from the immunological defense mechanisms of the host [13].
informahealthcare.com
10.1586/14787210.2015.1070096
Based on different polysaccharide structures present on the capsule, 12 serogroups (serogroup D capsule is now classified as an unencapsulated serogroup C variant) [14] of N. meningitidis have been isolated [6,15] through the use of antibodies recognizing epitopes localized on the capsule surface itself [6]. However, only A, B, C, W-135 (recently renamed W by Harrison et al. [16]), X and Y capsular serogroups are responsible for most of the cases of meningococcal disease [1,17–19]. Among the serogroups, different sequence types (STs) can be identified. Groups of STs sharing common genotype characteristics have been classified into clonal complexes by means of MultiLocus Sequence Type [20]. Clonal complexes such as ST-11, ST-32 or ST-41/44 are associated with a propensity to cause invasive meningococcal disease (IMD) and are consequently called hyperinvasive lineages, while lineages such as ST-23 or ST-53 are commonly related to asymptomatic carriage [21]. Transmission & carriage of N. meningitidis
N. meningitidis transmission occurs through a close contact with saliva or respiratory
2015 Informa UK Ltd
ISSN 1478-7210
1
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/19/15 For personal use only.
Review
Gianchecchi, Torelli, Piccini, Piccirella & Montomoli
secretions; however the inoculum size necessary for transmission is still unknown at the moment [22]. The unique reservoir of N. meningitidis is represented by humans, wherein it constitutes a commensal diplococcus of the nasopharynx [1,23–26] in about 10% of the total population [19,26]. N. meningitidis colonization can be asymptomatic, resulting in upper respiratory and pharyngeal meningococcal carriage that can last from days to months [22]. It has been estimated that each person can be characterized by the carriage of N. meningitidis 10-times during the first 30 years of life [27]. The same individual can carry more than one meningococcal strain for months [28]. In rare cases, the infection can cause local inflammation and, as a consequence of the penetration into the bloodstream and then in the meninges, it can lead to IMD [1,15,29]. IMD is a rare pathology highly correlated to permanent disability and mortality [30]. After rabies, meningococcal disease shows the highest fatality rate among other diseases that can be prevented by vaccines [31]. Mortality can reach up to 10%, and even 40% in presence of meningococcal septicemia [32]. Although the initial clinical presentation often resembles influenza-like illness [30], the early clinical picture of rash, photophobia, nuchal rigidity, meningeal signs and altered mental status is characteristic of IMD. Meningitis represents the most common clinical symptom of IMD. In industrialized countries, it is present without shock in 60% of patients [15]. The presence of ecchymoses often characterizes patients with severe disseminated intravascular coagulation involving several organs. The destructive and marked process of intravascular inflammation leads to the progressive circulatory collapse and severe coagulopathy. Bacteria and meningococcal endotoxin can reach elevated concentrations. Up to 20% of survivors can present serious handicaps, including brain damage, deafness, kidney failure and amputation of digits or limbs [33]. During endemic and epidemic outbreaks, 28–77% of IMD patients are characterized by typical hemorrhagical skin lesions [19] all over the body and even on sclera and mucous membranes in some cases. IMD also represents the main cause of death due to bacterial infections in about 1 per 40,000–100,000 healthy young individuals [34] by inducing the development of meningococcal meningitis (MM) and septicemia [15,35]. Since rash and meningeal signs may not be present, an early diagnosis of MM can be hard. The confirmation of the diagnosis of meningococcal disease occurs by Gram stain in association with cerebrospinal fluid, or blood, or skin lesion cultures. Recently, the use of PCR without cultures has enhanced [15]. Moreover, it can be fatal if not promptly and adequately treated [22]. Thus, meningococcal disease remains a serious public worldwide health problem. Meningococcal carriage represents an immunizing process [36]. Goldschneider et al. [36] described that 2 weeks after the first contact with bacteria, the release of specific antibodies, IgG, IgM and IgA, against N. meningitidis was induced [22] and it was associated with an increased bactericidal titer [36]. Furthermore, these antibodies combined with groupspecific meningococcal polysaccharides first isolated by Rake and Scherp [37] and cross-reactive antigens. Heterologous strains doi: 10.1586/14787210.2015.1070096
of N. meningitidis can share at least two common antigens. The presence of serum bactericidal antibodies (SBA) against meningococcus during the first 12 years of life was inversely proportional to age-specific MD incidence. Although the presence of antibodies in the serum has been associated with a lower incidence of meningococcal disease, constituting a natural selective immunity [36], this protection is not total and meningococcemia can also develop in subjects presenting antibodies directed against N. meningitidis [22]. Several factors can damage the mucosal barrier and such changes in the mucosal immunity can predispose to IMD. These include environmental factors (low humidity, dust concentration, tobacco) [15,22], co-infections (mycoplasma, viral respiratory and HIV infections), meningococcal virulence factors, lack of immune response caused by acquired immunoglobulin deficiencies and genetic polymorphisms in components of the host immune system [22,38]. Contrasting data emerged from the association between meningococcal disease and HIV comparing African outbreaks and those reported in the USA; in fact, no relationship between HIV infection and disease was found in African countries, while a sevenfold risk increase was observed in the USA [22]. The role of polymorphisms in influencing meningococcal disease
Genetic factors of the host play a fundamental role in meningococcal disease; in fact, they are able to influence the clinical presentation of patients affected by meningococcal infection, ranging from a mild form of bacteremia even to deadly septic shock syndrome [38]. Risk factors for IMD are properdin [39,40] and complement deficiencies [22,41,42], congenital or acquired immunoglobulin deficiencies [43–45] and single nucleotide polymorphisms (SNPs). More in detail, the ability of some SNPs in innate host determinants to influence the individual predisposition to meningococcal disease is well known [15,46,47], both promoting it or protecting the subject from meningococcemia. Among these genetic variants, there are mannose-binding lectin [22], TLR2, TLR4 [22,34,47], TLR9 and NOD2 SNPs [47]. It has been estimated that a third of meningococcal disease cases could be ascribed to genetic variants in mannose-binding lectin that may induce also a milder form of disease, although further investigations are needed to confirm these data [48]. Whereas TLR2 and the common white TLR4 (TLR4B) variants do not influence susceptibility to meningococcal infections, only rare co-dominant mutations at TLR4 locus and in particular only missense mutations increase the susceptibility to meningococcal infection [34]. Recently, van Well et al. [47] evaluated genotype distributions of seven single and combined SNPs in five immune response genes (TLR2, TLR4, TLR9, nucleotide oligomerization domain [NOD] proteins and caspase-1). A total of 391 Dutch Caucasian children affected by meningococcal disease (86% of those were serogroup B patients) and 1141 healthy subjects have been analyzed. They found for the first time a strong association between NOD2 (SNP8), TLR2 and TLR4 (+896) SNPs and susceptibility to MM. Contrasting data regarding the role of TLR4 (+896) SNP as a risk factor for the Expert Rev. Anti Infect. Ther.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/19/15 For personal use only.
Neisseria meningitidis infection
development or severity of meningococcal disease were reported both in an English [49] and in Gambian cohorts [47]. The results reported by van Well et al. were in accordance with a previous study which described an association between TLR4 (+896) SNP and mortality, skin grafting and limb loss caused by IMD [50]. Furthermore, the data reported in the study by van Well et al. are in accordance with in vivo results obtained in NOD2 knockout mice, which were characterized by diminished demyelination, astrogliosis and inflammatory cytokine release in the CNS after meningococcal infection, confirming the critical role of this gene in the induction of damaging inflammation [51]. An increased susceptibility to MM was also observed in case of the following combined carriages: TLR2 +2477 and TLR4 +896 mutants, as well as TLR4 +896 and NOD2 (SNP8) mutants [47]. Conversely, TLR9 (-1237 and +2848) SNPs were associated with protection against meningococcemia, fundamental prerequisite for meningeal invasion, and with increased immune response in the CNS in a cohort of MM Caucasian survivors [52], in accordance with the important role played by TLR9 in the prevention of bacteremia [53]. Since the frequency of some polymorphisms in the general population is relatively high, and since they constitute stable gene variants able to strongly influence the progression of MM, the study of SNPs may allow the identification of those subjects carrying the variants associated with a higher risk to develop a severe MM form or die after contracting N. meningitidis [38]. Genome-wide association study can be used to identify genetic variants associated with host susceptibility to meningococcal disease [54]. Current global epidemiology of meningococcal disease by geographic macro-areas
N. meningitidis is responsible for an endemic worldwide infection and the various serogroups show different areas of diffusion (FIGURE 1) (reviewed [rev.] in [6]). The epidemiology and serogroup distribution can change very quickly, as demonstrated by serogroup X and Y incidence in the last 10 years (rev. in [55]). The incidence of meningitis can vary from highly rare till more than 1000 cases of infection per 100,000 population every year [1,18,56,57]. Although the infection can affect people of all ages, the higher rate of cases has been observed in children with age
