WASP- mice exhibit defective immune responses to influenza A virus, Streptococcus pneumoniae, and Mycobacterium bovis BCG

Abstract

Objective: To quantify the immune response of WASP- mice to three different pathogens: influenza A virus, Streptococcus pneumoniae, and Mycobacterium bovis.

Methods: Primary and secondary T-cell responses to influenza A virus were quantified via tetramer assays. Viral clearance from lung was also measured. Lethality of intranasal inoculation with luminescent S. pneumoniae was assessed by dose escalation and direct luminescence imaging. After intravenous inoculation with M. bovis, residual mycobacteria in lung, liver, and spleen were measured by standard culture methods.

Results: The reduced secondary T-cell response to influenza A virus correlates with a relative but not absolute loss of splenic T and B cells similar to that seen in clinical Wiskott-Aldrich Syndrome (WAS), and slower clearance of virus from lung. The reduced magnitude of the secondary T-cell response correlates with a progressive loss of influenza-specific T cells after primary inoculation. WASP- mice show an increased susceptibility to lethal pneumonia after intranasal inoculation with S. pneumoniae, which is among the most frequent causes of clinical complications in WAS patients. WASP- mice clear M. bovis bacille Calmette-Guerin (BCG) more slowly from lung, liver, and spleen. Bone marrow-derived macrophages, however, show normal ex vivo cytokine secretion in response to M. bovis.

Conclusions: These results demonstrate that WASP- mice are functionally immunodeficient in regard to three different pathogens, and provide relevant end points for the study of treatment modalities in this model. They also suggest a specific physiologic mechanism, failure to accumulate memory T cells, for at least one of the defective immune responses.