Abstract
Streptococcus pneumoniae is a major human pathogen, causing pneumonia and sepsis. Genetic components strongly influence host responses to pneumococcal infections, but the responsible loci are unknown. We have previously identified a locus on mouse chromosome 7 from a susceptible mouse strain, CBA/Ca, to be crucial for pneumococcal infection. Here we identify a responsible gene, Cd22, which carries a point mutation in the CBA/Ca strain, leading to loss of CD22 on B cells. CBA/Ca mice and gene-targeted CD22-deficient mice on a C57BL/6 background are both similarly susceptible to pneumococcal infection, as shown by bacterial replication in the lungs, high bacteremia and early death. After bacterial infections, CD22-deficient mice had strongly reduced B cell populations in the lung, including GM-CSF producing, IgM secreting innate response activator B cells, which are crucial for protection. This study provides striking evidence that CD22 is crucial for protection during invasive pneumococcal disease.
Highlights
Streptococcus pneumoniae is a major human pathogen responsible for a spectrum of diseases, including pneumonia and sepsis, causing illness and death in millions of individuals
Susceptibility to pneumococcal infections is associated with genetic components that strongly influence how infected individuals respond to infection, but little is known about the causal gene(s) and the mechanisms of control of the infection
Susceptibility to pneumococcal infections is associated with genetic components that strongly influence the host responses to infection, but little is known about the causal gene(s)
Summary
Streptococcus pneumoniae is a major human pathogen responsible for a spectrum of diseases, including pneumonia and sepsis, causing illness and death in millions of individuals. Susceptibility to pneumococcal infections is associated with genetic components that strongly influence the host responses to infection, but little is known about the causal gene(s). Our groups previously used mouse models of respiratory disease as tools to dissect the genetic factors that influence the host immune responses to invasive pneumococcal disease [1]. These previous studies found a clear spectrum of susceptibility and resistance to pneumococcal infections in inbred mouse strains. While resistant BALB/c mice showed a median survival time of > 168 hours after intranasal infection, and some other strains such as C57BL/6 or DBA/2 had intermediate survival times of 70 to 85 hours, the CBA/Ca strain was highly susceptible, with a survival time of only 27 hours after intranasal infection with S. pneumoniae [1]. The high susceptibility of CBA/Ca mice was associated with a high bacteremia, whereas no bacteria were detected in the blood of resistant BALB/c mice
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