Human Toll-Like Receptor 4 Mutations Are Associated With Susceptibility to Invasive Meningococcal Disease in Infancy

Faber, Joerg; Meyer, Claudius U.; Gemmer, Christina; Russo, Alexandra; Finn, Adam; Murdoch, Craig; Zenz, Werner; Mannhalter, Christine; Zabel, Bernhard; Schmitt, H. J.; Habermehl, Pirmin; Zepp, Fred; Knuf, Markus

doi:10.1097/01.inf.0000195595.22547.fe

Cited by 78 publications

(49 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For instance, Mockenhaupt et al found that African children with a TLR4 polymorphism were more susceptible to severe malaria infections, which showed the importance of this molecule in initiation of the immune response against P. falciparum (28). Furthermore, it has been reported that a mutation in TLR4 increased the risk of invasive meningococcal disease in infants less than 12 months old (10).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Optimal CD8 T-Cell Response againstEncephalitozoon cuniculiIs Mediated by Toll-Like Receptor 4 Upregulation by Dendritic Cells

2010

View full text Add to dashboard Cite

CD8؉ T-cell immunity has been shown to play an important role in the protective immune response against Encephalitozoon cuniculi. Although earlier studies suggest that dendritic cells (DC) are important for the induction of this response, the factors responsible for initiation of the dendritic cell response against this pathogen have not been evaluated. In the current study, we demonstrate that E. cuniculi infection causes strong Toll-like receptor 4 (TLR4)-dependent dendritic cell activation and a blockade of this molecule reduces the ability of DC to prime an antigen-specific CD8 ؉ T-cell response. Pretreatment of DC with anti-TLR4 antibody causes a defect in both in vitro and in vivo CD8 ؉ T-cell priming. These findings, for the first time, emphasize the contribution of TLR4 in the induction of CD8 ؉ T-cell immunity against E. cuniculi infection.Microsporidia are small obligate intracellular parasites that, until recently, were thought to be protozoans; however, evidence now suggests that they are related to fungi (15,17). Microsporidia can infect a vast number of species of vertebrates and invertebrates; of the 150 genera of microsporidia, however, only 7 have been found to infect humans (13). Severe infections have been reported predominantly for immunocompromised patients, such as patients with HIV and organ transplant recipients (2,7,23,37). Acute infections have also been reported in travelers and the elderly (26, 27), and there is evidence of colonization of healthy, nonsymptomatic patients (34).Due to the prevalence of opportunistic microsporidian infections associated with the HIV-AIDS pandemic, recent research has focused on the host's immune response to these pathogens. Early animal studies showed that cellular immunity was necessary to protect SCID mice from a lethal Encephalitozoon cuniculi challenge. Moreover, depletion of CD8 ϩ T cells caused mice to succumb to intraperitoneal (i.p.) E. cuniculi infection (21), and previous studies in our laboratory have shown that cytotoxic lymphocytes play a major role in protection against this effect (20,21).Recent reports from our laboratory have demonstrated that dendritic cells (DC) play an important role in the priming of the immune response against E. cuniculi (31, 32). T cells incubated with E. cuniculi-pulsed DC exhibited antigen-specific characteristics, specifically gamma interferon (IFN-␥) production, cytotoxicity, and proliferation (31, 32). In order to mount an immune response against a foreign pathogen, DC must first recognize the pathogen to initiate an appropriate response. One key method of recognition is through Toll-like receptors (TLRs), which were first discovered in Drosophila in response to infection with fungal pathogens (24). However, specific TLR molecules involved in DC activation during E. cuniculi infection have not been identified previously. We evaluated the upregulation of specific molecules involved in activation of the DC response after E. cuniculi infection. Different TLR molecules were tested, and TLR4 expression was found ...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Specifically, TLR4 has been demonstrated to be one of the molecules stimulated in several infectious diseases (3,6,(8)(9)(10). Additionally, it has been shown that TLR polymorphism increases susceptibility to certain diseases.…”

Section: Discussionmentioning

confidence: 99%

Optimal CD8 T-Cell Response againstEncephalitozoon cuniculiIs Mediated by Toll-Like Receptor 4 Upregulation by Dendritic Cells

2010

View full text Add to dashboard Cite

show abstract

“…It has been well described that TLR4 plays an important role in the host response against N. meningitidis. Polymorphisms in the TLR4 gene have been reported to be associated with meningococcal sepsis, as well as invasive disease in children (10,31). We have previously demonstrated that nonlipooligosaccharide meningococcal pathogen-associated molecular patternss also contribute to disease progression in a MyD88-dependent manner (25), indicating a role for other TLRs.…”

mentioning

confidence: 99%

Important Role for Toll-Like Receptor 9 in Host Defense against Meningococcal Sepsis

et al. 2008

View full text Add to dashboard Cite

Neisseria meningitidis is a leading cause of meningitis and sepsis. The pathogenesis of meningococcal disease is determined by both bacterial virulence factors and the host inflammatory response. Toll-like receptors (TLRs) are prominent activators of the inflammatory response, and TLR2, -4, and -9 have been reported to be involved in the host response to N. meningitidis. While TLR4 has been suggested to play an important role in early containment of infection, the roles of TLR2 and TLR9 in meningococcal disease are not well described. Using a model for meningococcal sepsis, we report that TLR9 ؊/؊ mice displayed reduced survival and elevated levels of bacteremia compared to wild-type mice. In contrast, TLR2؊/؊ mice controlled the infection in a manner comparable to that of wild-type mice. TLR9 deficiency was also associated with reduced bactericidal activity in vitro, which was accompanied by reduced production of nitric oxide by TLR9-deficient macrophages. Interestingly, TLR9؊/؊ mice recruited more macrophages to the bloodstream than wild-type mice and produced elevated levels of cytokines at late time points during infection. At the cellular level, activation of signal transduction and induction of cytokine gene expression were independent of TLR2 or TLR9 in macrophages and conventional dendritic cells. In contrast, plasmacytoid dendritic cells relied entirely on TLR9 to induce these activities. Thus, our data demonstrate an important role for TLR9 in host defense against N. meningitidis.

show abstract

“…Meningococcal surface components induce excessive host inflammatory response, the level of which correlates with the severity of disease (11). An unexpected finding was that both the wild-type and the ⌬NhhA mutant induced similar local inflammatory responses at the nasal mucosa, including the recruitment of neutrophils to the mucosal surface and the production of cytokines and chemokines.…”

Section: Discussionmentioning

confidence: 91%

Meningococcal Outer Membrane Protein NhhA Is Essential for Colonization and Disease by Preventing Phagocytosis and Complement Attack

et al. 2008

View full text Add to dashboard Cite

Neisseria meningitidis is a leading cause of meningitis and septicemia worldwide, with a rapid onset of disease and a high morbidity and mortality. NhhA is a meningococcal outer membrane protein included in the family of trimeric autotransporter adhesins. The protein binds to the extracellular matrix proteins heparan sulfate and laminin and facilitates attachment to host epithelial cells. In this study, we show that NhhA is essential for bacterial colonization of the nasopharyngeal mucosa in a murine model of meningococcal disease. Successful colonization depends on bacterial attachment but also to the capacity to overcome innate host immune responses. We found that NhhA protected bacteria from phagocytosis, which is important for the mucosal survival of bacteria. In addition, NhhA mediated extensive serum resistance that increased bacterial survival in blood and promoted lethal sepsis. The presence of NhhA protected bacteria from complement-mediated killing by preventing the deposition of the membrane attack complex. Taken together, the results of this work reveal that NhhA inhibits phagocytosis and protects bacteria against complement-mediated killing, which enhances both nasal colonization and the development of sepsis in vivo.

show abstract

Human Toll-Like Receptor 4 Mutations Are Associated With Susceptibility to Invasive Meningococcal Disease in Infancy

Cited by 78 publications

References 6 publications

Optimal CD8 T-Cell Response againstEncephalitozoon cuniculiIs Mediated by Toll-Like Receptor 4 Upregulation by Dendritic Cells

Optimal CD8 T-Cell Response againstEncephalitozoon cuniculiIs Mediated by Toll-Like Receptor 4 Upregulation by Dendritic Cells

Important Role for Toll-Like Receptor 9 in Host Defense against Meningococcal Sepsis

Meningococcal Outer Membrane Protein NhhA Is Essential for Colonization and Disease by Preventing Phagocytosis and Complement Attack

Contact Info

Product

Resources

About