TcdB-specific plasma cell and memory B cell responses in recurring Clostridioides difficile infection-associated disease

Abstract

Abstract Recurrence of C. difficile infection with progressively worsening disease is a serious problem. Serum IgG specific to the secreted toxin B (TcdB) is the best-known correlate of protection against disease symptoms and pathology. However, little is known as to whether and how infection stimulates protective humoral immunity. We hypothesized that recurring disease is due to an inadequate development of a TcdB-specific memory B cell response following an initial infection. We measured TcdB-specific antibody and memory B-cell responses following two sequential infections in microbiome-disrupted B6 mice. A mild infection caused by a low dose spore challenge did not induce an isotype-switched antibody response against the toxin and failed to protect against recurring disease. However, a higher-dose infection resulted in a TcdB-specific primary serum IgG1 and IgG2b response but did not boost titers. Also, in mice with TcdB-specific serum IgG1 there was a strong correlation with fecal TcdB-specific IgG1 and an attenuation of subsequent disease. Following infection of TcdB-immunized mice, IgG1 titers did not increase and ELISPOT analyses detected TcdB-specific IgG1-secreting plasma cells primarily in the bone marrow. Infection of pre-immunized mice also resulted in increased amounts of TcdB-specific IgG1 reaching the gut lumen. These findings indicate that a more severe initial encounter with the pathogen may be required to elicit a protective systemic TcdB-specific IgG1 response. Re-infection or infection of pre-immunized mice does not stimulate a B cell memory response and protection appears to be mediated by transport of plasma cell-derived systemic IgG1 to the gut lumen.