Role of Genetic Resistance in Invasive Pneumococcal Infection: Identification and Study of Susceptibility and Resistance in Inbred Mouse Strains

Gingles, Neill A.; Alexander, Janet E.; Kadioglu, Aras; Andrew, Peter W.; Kerr, A.; Mitchell, Tim; Hopes, Elaine; Denny, Paul; Brown, Steve; Jones, Huw B.; Little, Steven R.; Booth, George H.; McPheat, William L.

doi:10.1128/iai.69.1.426-434.2001

Cited by 115 publications

(149 citation statements)

References 31 publications

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“…inoculation). As C57BL͞6 mice are only partially susceptible to S. pneumoniae i.n., they provide a sensitive model for identifying mouse strains with increased susceptibility (27). Groups of 8-10 immune naïve wild-type and complement-deficient mice were monitored after i.n.…”

Section: Survival Of Mice With Different Complement Deficiencies Aftementioning

confidence: 99%

The classical pathway is the dominant complement pathway required for innate immunity toStreptococcus pneumoniaeinfection in mice

Brown

Hussell

Gilliland

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

332

380

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The complement system is an important component of the innate immune response to bacterial pathogens, including Streptococcus pneumoniae. The classical complement pathway is activated by antibody-antigen complexes on the bacterial surface and has been considered predominately to be an effector of the adaptive immune response, whereas the alternative and mannose-binding lectin pathways are activated directly by bacterial cell surface components and are considered effectors of the innate immune response. Recently, a role has been suggested for the classical pathway during innate immunity that is activated by natural IgM or components of the acute-phase response bound to bacterial pathogens. However, the functional importance of the classical pathway for innate immunity to S. pneumoniae and other bacterial pathogens, and its relative contribution compared with the alternative and mannose-binding lectin pathways has not been defined. By using strains of mice with genetic deficiencies of complement components and secretory IgM we have investigated the role of each complement pathway and natural IgM for innate immunity to S. pneumoniae. Our results show that the proportion of a population of S. pneumoniae bound by C3 depends mainly on the classical pathway, whereas the intensity of C3 binding depends on the alternative pathway. Furthermore, the classical pathway, partially targeted by the binding of natural IgM to bacteria, is the dominant pathway for activation of the complement system during innate immunity to S. pneumoniae, loss of which results in rapidly progressing septicemia and impaired macrophage activation. These data demonstrate the vital role of the classical pathway for innate immunity to a bacterial pathogen.

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Section: Survival Of Mice With Different Complement Deficiencies Aftementioning

confidence: 99%

The classical pathway is the dominant complement pathway required for innate immunity toStreptococcus pneumoniaeinfection in mice

Brown

Hussell

Gilliland

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

332

380

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“…Because of this, the laboratory mouse has been the experimental model of choice to study pathogenesis of infection, including innate and acquired host defense mechanisms. Inbred mouse strains differ significantly in their degree of susceptibility to infection with various human bacterial (eg, Mycobacterium tuberculosis, 15,16 Salmonella enterica, 17 Streptococcus pyogenes, 18 Streptococcus pneumoniae 19 ), fungal (eg, Histoplasma capsulatum, 20 Aspergillus fumigatus 21 ), protozoan (eg, Leishmania major, 22 Plasmodium berghei, 23 Plasmodium chabaudi 24 ), helminthic (eg, Schistosoma mansoni 25,26 ) as well as viral (eg, respiratory syncytial virus 27,28 ) pathogens. This attribute has been exploited to identify novel loci influencing resistance/susceptibility to infection and to provide new insight on host mechanisms involved in response to those pathogens that ultimately affect the onset, progression, and outcome of the infection.…”

mentioning

confidence: 99%

Immunological Mechanisms Underlying the Genetic Predisposition to Severe Staphylococcus aureus Infection in the Mouse Model

Köckritz-Blickwede

Rohde

Oehmcke

et al. 2008

The American Journal of Pathology

121

130

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Host genetic variations play a significant role in conferring predisposition to infection. In this study, we examined the immune mechanisms underlying the host genetic predisposition to severe Staphylococcus aureus infection in different mouse strains. Whereas C57BL/6 mice were the most resistant in terms of control of bacterial growth and survival, A/J, DBA/2, and BALB/c mice were highly susceptible and succumbed to infection shortly after bacterial inoculation. Other strains (C3H/HeN, CBA, and C57BL/10) exhibited intermediate susceptibility levels. Susceptibility of mice to S. aureus was associated with an inability to limit bacterial growth in the kidneys and development of pathology. Resistance to S. aureus in C57BL/6 mice was dependent on innate immune mechanisms because Rag2-IL2R␥ ؊/؊ C57BL/6 mice, which are deficient in B, T, and NK cells, were also resistant to infection. Indeed, neutrophil depletion or inhibition of neutrophil recruitment rendered C57BL/6 mice completely susceptible to S. aureus, indicating that neutrophils are essential for the observed resistance. Although neutrophil function is not inhibited in A/J mice, expression of neutrophil chemoattractants KC and MIP-2 peaked earlier in the kidneys of C57BL/6 mice than in A/J mice, indicating that a delay in neutrophil recruitment to the site of infection may underlie the increased susceptibility of A/J mice to S.

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“…To decipher the impact of virulence or fitness factors mouse infection models are used. However, not all pneumococcal strains are mouse virulent, and more importantly, the susceptibility of mice depends on the genetic background of the animals 22 . Pneumococcal virulence studies and protection studies are nowadays conducted with CD-1 outbred mice.…”

Section: Discussionmentioning

confidence: 99%

“…The genetic background of inbred mouse strains determines the susceptibility to pneumococci. BALB/c mice intranasally infected with pneumococci were found to be resistant, while CBA/Ca and SJL mice were more susceptible against pneumococcal infections 22 . This implies that, similar to humans, the genetic background and the host defense mechanisms determine the outcome of the infection.…”

Section: Introductionmentioning

confidence: 95%

“…The impact of bacterial factors on pathogenesis and inflammatory host responses is investigated in experimental animal models of pneumonia, bacteremia, or meningitis [21][22][23][24][25] . Despite being a human pathogen, these models are well-established to decipher pneumococcal tissue tropism, virulence mechanisms, or protectivity of pneumococcal vaccine candidates.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Following in Real Time the Impact of Pneumococcal Virulence Factors in an Acute Mouse Pneumonia Model Using Bioluminescent Bacteria

Saleh

Abdullah

Schulz

et al. 2014

JoVE

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Pneumonia is one of the major health care problems in developing and industrialized countries and is associated with considerable morbidity and mortality. Despite advances in knowledge of this illness, the availability of intensive care units (ICU), and the use of potent antimicrobial agents and effective vaccines, the mortality rates remain high 1 . Streptococcus pneumoniae is the leading pathogen of community-acquired pneumonia (CAP) and one of the most common causes of bacteremia in humans. This pathogen is equipped with an armamentarium of surface-exposed adhesins and virulence factors contributing to pneumonia and invasive pneumococcal disease (IPD). The assessment of the in vivo role of bacterial fitness or virulence factors is of utmost importance to unravel S. pneumoniae pathogenicity mechanisms. Murine models of pneumonia, bacteremia, and meningitis are being used to determine the impact of pneumococcal factors at different stages of the infection. Here we describe a protocol to monitor in real-time pneumococcal dissemination in mice after intranasal or intraperitoneal infections with bioluminescent bacteria. The results show the multiplication and dissemination of pneumococci in the lower respiratory tract and blood, which can be visualized and evaluated using an imaging system and the accompanying analysis software. Video LinkThe video component of this article can be found at

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Role of Genetic Resistance in Invasive Pneumococcal Infection: Identification and Study of Susceptibility and Resistance in Inbred Mouse Strains

Cited by 115 publications

References 31 publications

The classical pathway is the dominant complement pathway required for innate immunity toStreptococcus pneumoniaeinfection in mice

The classical pathway is the dominant complement pathway required for innate immunity toStreptococcus pneumoniaeinfection in mice

Immunological Mechanisms Underlying the Genetic Predisposition to Severe Staphylococcus aureus Infection in the Mouse Model

Following in Real Time the Impact of Pneumococcal Virulence Factors in an Acute Mouse Pneumonia Model Using Bioluminescent Bacteria

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