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Cefoperazone-treated Mouse Model of Clinically-relevant Clostridium difficile Strain R20291
Published on: December 10, 2016
Protection from Clostridium difficile infection in CD4 T Cell- and polymeric immunoglobulin receptor-deficient mice
Pehga F Johnston1, Dale N Gerding, Katherine L Knight
1Loyola University Chicago Stritch School of Medicine, Department of Microbiology and Immunology, Maywood, Illinois, USA.
Abstract:
Clostridium difficile rivals methicillin-resistant Staphylococcus aureus as the primary hospital-acquired infection. C. difficile infection (CDI) caused by toxins A and/or B can manifest as mild diarrhea to life-threatening pseudomembranous colitis. Although most patients recover fully from CDI, ~20% undergo recurrent disease. Several studies have demonstrated a correlation between anti-toxin antibody (Ab) and decreased recurrence; however, the contributions of the systemic and mucosal Ab responses remain unclear. Our goal was to use the CDI mouse model to characterize the protective immune response to C. difficile. C57BL/6 mice infected with epidemic C. difficile strain BI17 developed protective immunity against CDI and did not develop CDI upon rechallenge; they generated systemic IgG and IgA as well as mucosal IgA Ab to toxin. To determine if protective immunity to C. difficile could be generated in immunodeficient individuals, we infected CD4(-/-) mice and found that they generated both mucosal and serum IgA anti-toxin Abs and were protected from CDI upon rechallenge, with protection dependent on major histocompatibility complex class II (MHCII) expression; no IgG anti-toxin Ab was found. We found that protection was likely due to neutralizing mucosal IgA Ab. In contrast, pIgR(-/-) mice, which lack the receptor to transcytose polymeric Ab across the epithelium, were also protected from CDI, suggesting that although mucosal anti-toxin Ab may contribute to protection, it is not required. We conclude that protection from CDI can occur by several mechanisms and that the mechanism of protection is determined by the state of immunocompetence of the host.
Insights
Clostridium difficile infection (CDI) protection varies by host immunity. Mucosal IgA antibodies are key for protection in immunocompetent mice, while other mechanisms protect immunodeficient mice.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Clostridium difficile infection (CDI) is a major hospital-acquired infection, rivaling MRSA.
- CDI can range from mild diarrhea to severe pseudomembranous colitis, with ~20% of patients experiencing recurrence.
- The roles of systemic versus mucosal antibody (Ab) responses in protection against CDI are not fully understood.
Purpose of the Study:
- To investigate the immune mechanisms conferring protection against Clostridium difficile infection (CDI) using a mouse model.
- To characterize the systemic and mucosal antibody responses involved in protection from CDI.
- To explore if protective immunity can be generated in immunodeficient hosts.
Main Methods:
- Utilized a Clostridium difficile infection (CDI) mouse model with C57BL/6 mice and an epidemic strain (BI17).
- Infected immunodeficient mice (CD4(-/-) and pIgR(-/-)) to assess protective immunity.
- Analyzed systemic and mucosal antibody responses (IgG, IgA) and major histocompatibility complex class II (MHCII) expression.
Main Results:
- Immunocompetent mice developed protective immunity with systemic IgG and IgA, and mucosal IgA anti-toxin antibodies upon rechallenge.
- CD4(-/-) mice generated mucosal and serum IgA anti-toxin Abs, showing protection dependent on MHCII expression, but no IgG.
- pIgR(-/-) mice were protected, indicating mucosal anti-toxin antibodies are not strictly required for protection.
Conclusions:
- Protection from Clostridium difficile infection (CDI) can be achieved through multiple immune mechanisms.
- The specific protective mechanism against CDI depends on the host's immunocompetence.
- Neutralizing mucosal IgA antibodies appear crucial for protection in immunocompetent hosts.
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