MicrobiologyBytes

Microbiologists at the University of Leicester have worked on Streptococcus pneumoniae (pneumococcus) for many years. This research is now starting to pave the way for more effective vaccines against this pathogen. The pneumococcus is a pathogen of global significance, responsible for millions of deaths annually from pneumonia, meningitis and septicaemia while also causing other less serious infections, such as otitis media and sinusitis. In order to develop improved pneumococcal vaccines it is essential to understand how the bacterium interacts with the host immune system.

Pneumococci produce a range of pathogenicity factors, among which the toxin pneumolysin plays a central role and has potential as a vaccine candidate. A new paper demonstrates that pneumolysin can directly activate innate immune cells and dramatically amplify the production of pro-inflammatory cytokines. These enhancing effects of the toxin do not require Toll-like receptor (TLR)4. In particular, the toxin exerts a potent effect on interleukin (IL)-1, which is an endogenous pyrogen and powerful activator of IL-17A production. This effect results from activation of the NLRP3 inflammasome complex and NLRP3 is required for protection against the pathogen in vivo. To induce protective immunity against pneumococci, IFN-γ and IL-17A are thought to be essential. Pneumolysin plays a key role in promoting these cytokines both in vitro and in vivo during respiratory infection. The results add significantly to our understanding of the interactions between pneumococci and the immune system and support investigations into the inclusion of pneumolysin or its derivatives in novel pneumococcal vaccines.

Pneumolysin Activates the NLRP3 Inflammasome and Promotes Proinflammatory Cytokines Independently of TLR4. (2010) PLoS Pathog 6(11): e1001191. doi:10.1371/journal.ppat.1001191
Pneumolysin (PLY) is a key Streptococcus pneumoniae virulence factor and potential candidate for inclusion in pneumococcal subunit vaccines. Dendritic cells (DC) play a key role in the initiation and instruction of adaptive immunity, but the effects of PLY on DC have not been widely investigated. Endotoxin-free PLY enhanced costimulatory molecule expression on DC but did not induce cytokine secretion. These effects have functional significance as adoptive transfer of DC exposed to PLY and antigen resulted in stronger antigen-specific T cell proliferation than transfer of DC exposed to antigen alone. PLY synergized with TLR agonists to enhance secretion of the proinflammatory cytokines IL-12, IL-23, IL-6, IL-1β, IL-1α and TNF-α by DC and enhanced cytokines including IL-17A and IFN-γ by splenocytes. PLY-induced DC maturation and cytokine secretion by DC and splenocytes was TLR4-independent. Both IL-17A and IFN-γ are required for protective immunity to pneumococcal infection and intranasal infection of mice with PLY-deficient pneumococci induced significantly less IFN-γ and IL-17A in the lungs compared to infection with wild-type bacteria. IL-1β plays a key role in promoting IL-17A and was previously shown to mediate protection against pneumococcal infection. The enhancement of IL-1β secretion by whole live S. pneumoniae and by PLY in DC required NLRP3, identifying PLY as a novel NLRP3 inflammasome activator. Furthermore, NLRP3 was required for protective immunity against respiratory infection with S. pneumoniae. These results add significantly to our understanding of the interactions between PLY and the immune system.

Related:

• Specific pneumococcus serotypes associated with increased mortality
• New Insights Could Lead to a Better Pneumococcal Vaccine
• Pneumococcus: the quorum-sensing killer

Streptococcus pneumoniae is the leading bacterial cause of pneumonia, sepsis and meningitis in children, which together comprise more than 25% of the 10 million deaths estimated to have occurred in 2000 in children under 5 years of age, and preventable by access to appropriate vaccines. The serotypes currently included in existing pneumococcal conjugate vaccine formulations account for 49-88% of deaths in children under 5 in Africa and Asia, where the morbidity and mortality of pneumococcal disease are the highest, and where until recently, most children do not have access to current pneumococcal conjugate vaccines.

Contrary to current thinking, the group of serotypes of S. pneumoniae responsible for most invasive pneumococcal disease worldwide is conserved across regions. After an extensive literature review, which included information on 60,090 isolates of Streptococcus pneumoniae from 70 countries, the authors of a new paper estimate that seven serotypes (1, 5, 6A, 6B, 14, 19F, and 23F) were the most common globally and that these seven serotypes accounted for the majority of invasive pneumococcal disease in every region.

This is good news. These findings mean that health policy makers can assess the potential impact of serotypes included in different conjugate vaccines and vaccine manufacturers can now work from a consensus set of serotype coverage estimates to plan and design future serotype-based vaccine formulations to target local pneumococcal disease burden more accurately. Progress towards increasing access to pneumococcal conjugate vaccines in high-burden countries will contribute to achieving the year 2015 Millennium Development Goal 4 target to reduce child mortality by two-thirds.

Systematic Evaluation of Serotypes Causing Invasive Pneumococcal Disease among Children Under Five: The Pneumococcal Global Serotype Project. (2010) PLoS Med 7(10): e1000348. doi:10.1371/journal.pmed.1000348
Background: Approximately 800,000 children die each year due to pneumococcal disease and .90% of these deaths occur in developing countries where few children have access to life-saving serotype-based vaccines. Understanding the serotype epidemiology of invasive pneumococcal disease (IPD) among children is necessary for vaccine development and introduction policies. The aim of this study was to systematically estimate the global and regional distributions of serotypes causing IPD in children ,5 years of age.
Methods and Findings: We systematically reviewed studies with IPD serotype data among children, 5 years of age from the published literature and unpublished data provided by researchers. Studies conducted prior to pneumococcal conjugate vaccine (PCV) introduction, from 1980 to 2007, with 12 months of surveillance, and reporting 20 serotyped isolates were included. Serotype-specific proportions were pooled in a random effects meta-analysis and combined with PD incidence and mortality estimates to infer global and regional serotype-specific PD burden. Of 1,292, studies reviewed, 169 were included comprising 60,090 isolates from 70 countries. Globally and regionally, six to 11 serotypes accounted for 70% of IPD. Seven serotypes (1, 5, 6A, 6B, 14, 19F, 23F) were the most common globally; and based on year 2000 incidence and mortality estimates these seven serotypes accounted for 300,000 deaths in Africa and 200,000 deaths in Asia. Serotypes included in both the 10- and 13-valent PCVs accounted for 10 million cases and 600,000 deaths worldwide.
Conclusions: A limited number of serotypes cause most IPD worldwide. The serotypes included in existing PCV formulations account for 49%–88% of deaths in Africa and Asia where PD morbidity and mortality are the highest, but few children have access to these life-saving vaccines.

Related:

• Specific pneumococcus serotypes associated with increased mortality
• New Insights Could Lead to a Better Pneumococcal Vaccine
• Germ Warfare

Invasive pneumococcal disease (IPD) remains a major cause of morbidity and mortality worldwide despite the availability of antibiotic therapy and vaccines. Developing countries bear the major burden of IPD along with significantly higher rates of death and disability. The introduction of a 7-valent pneumococcal conjugate vaccine (PCV7) for infants has significantly reduced rates of bacteremic and nonbacteremic pneumococcal disease in the United States and other industrialized countries, yet the emergence of nonvaccine pneumococcal serotypes may threaten the continued efficacy of conjugate vaccines. Unfortunately, since the prevalence of pneumococcal serotypes varies among geographical regions, the formulation of PCV7 is not optimal against the most prevalent serotypes found in the developing world. In addition, some controversy surrounds the use of the available 23-valent polysaccharide vaccine (PPV23), which is recommended for patients of 2 years and older with high-risk conditions and for the elderly, since controlled trials were inconclusive and observational data suggested that PPV23 may prevent bacteremic but not non-bacteremic disease.

In research published this week, doctors analyzed population-based data collected over 30 years in more than 18,000 patients with invasive pneumococcal infection, finding specific pneumococcal serotypes to be associated with increased mortality. The results confirm that age, co-existing conditions and clinical presentation affect the serotype distribution as well as determine outcomes from IPD. This work is the largest and most comprehensive population-based study to date that evaluates short-term mortality associated with invasive pneumococcal serotypes after adjustment for possible confounders. The results support the hypothesis that specific pneumococcal capsular serotypes are significantly and independently associated with short-term mortality in patients with IPD. This is of particular interest in the era of conjugate vaccination, because a limited number of serotypes are included in the vaccines and because of the current emergence of nonvaccine serotypes.

Pneumococcal Serotypes and Mortality following Invasive Pneumococcal Disease: A Population-Based Cohort Study. PLoS Med 6(5): e1000081
Pneumococcal disease is a leading cause of morbidity and mortality worldwide. The aim of this study was to investigate the association between specific pneumococcal serotypes and mortality from invasive pneumococcal disease (IPD). In a nationwide population-based cohort study of IPD in Denmark during 1977–2007, 30-day mortality associated with pneumococcal serotypes was examined by multivariate logistic regression analysis after controlling for potential confounders. A total of 18,858 IPD patients were included. Overall 30-day mortality was 18%, and 3% in children younger than age 5 y. Age, male sex, meningitis, high comorbidity level, alcoholism, and early decade of diagnosis were significantly associated with mortality. Among individuals aged 5 y and older, serotypes 31, 11A, 35F, 17F, 3, 16F, 19F, 15B, and 10A were associated with highly increased mortality as compared with serotype 1. In children younger than 5 y, associations between serotypes and mortality were different than in adults but statistical precision was limited because of low overall childhood-related mortality. Specific pneumococcal serotypes strongly and independently affect IPD associated mortality.

Related:

• New Insights Could Lead to a Better Pneumococcal Vaccine
• Pneumococcus: the quorum-sensing killer
• Germ Warfare