Adaptive immune response to Clostridium difficile infection: A perspective for prevention and therapy

Abstract

Clostridium difficile infection (CDI) is one of the most important nosocomial illnesses and a major cause of morbidity and mortality. While initial treatment of CDI is usually successful, unprovoked relapses remain an important and frustrating problem. This review examines the literature describing the natural immune response to CDI, and to what extent it can explain the propensity for relapses. In particular, we discuss studies on antibody and, to a lesser extent, B cell and T cell responses in CDI. Despite years of study, there remains incomplete understanding of the natural antibody response to the major pathogenic toxins, TcdA and TcdB, and other bacterial antigens, in CDI. Recent literature suggests that a specific subset of neutralizing antibodies that target the putative carbohydrate-binding domains of TcdB and possibly TcdA have the greatest protective ability. This is further supported by recent successful clinical trials of a humanized monoclonal antibody to the major toxin TcdB. A better understanding of how and why the most protective adaptive immune response develops may lead to improved vaccine and therapeutic targets for recurrent CDI. Keywords:Clostridium difficile r Immunotherapy r TcdA r TcdB r Vaccination IntroductionClostridium difficile is a gram positive, spore-forming anaerobic bacillus that colonizes the large intestine. While asymptomatic colonization is common, Clostridium difficile infection (CDI) typically develops after opportunistic growth that occurs when antibiotic treatment diminishes the host commensal microbiota [1,2]. CDI incidence and mortality have increased dramatically in the United States, Canada, and Europe in the last 20 years [3][4][5]. More than 450 000 cases of CDI occur every year in the United States, resulting in around 29 000 deaths and costs of up to $4.8 billion dollars [5].CDI is characterized by predominantly neutrophilic inflammation within the colonic mucosa and lumen [1,6]. In patients, this causes symptoms ranging from mild diarrhea to more severe or life threatening complications, such as pseudomembranous coliCorrespondence: Dr. Theodore S. Steiner e-mail: tsteiner@mail.ubc.ca tis, toxic megacolon and death [7]. These symptoms stem from two major C. difficile toxins, TcdA and TcdB, encoded by the genes tcdA and tcdB residing in the pathogenicity locus [8][9][10]. These two large glucosyltransferases, weighing 308 and 270 kDa respectively, are believed to bind most commonly via the C-terminal, carbohydrate-binding combined repetitive oligopeptide (CROP) domain to target gut epithelial cells. Once bound, the toxins enter the cell through receptor-mediated endocytosis and autodigest using a protease domain, liberating a glucosyltransferase domain that inactivates Rho GTPases within target cells, ultimately leading to rounding and apoptosis of the target cells [11,12].The most common treatment for CDI is antibiotic therapy. Typically, vancomycin, fidaxomicin, or metronidazole is effective for most patients. However, recurring CDI is an issue for approximatel...

<p>Patient Experiences with <em>Clostridioides difficile</em> Infection: Results of a Canada-Wide Survey</p>

“…However, disruption of host microbiota, most commonly through antibiotic treatment, results in increased susceptibility to infection. 3,4 Furthermore, 20% of adults over the age of 65 are asymptomatically colonized by C. difficile, which increases the chance of CDI and may act as potential vehicles of transmission in a healthcare setting. 5,6 Several research groups and national programs have surveyed health-care sites and treating physicians, to evaluate incidence, prevalence, infection control practices and economic burden of CDI in Canada.…”

Challenges for Clinical Development of Vaccines for Prevention of Hospital-Acquired Bacterial Infections

“…Based on the findings described above it can be speculated that an antibiotic-induced IgA-deficiency could account for susceptibility to C. difficile infection (CDI) ( 114 ). High titers of toxin (TcdA and TcdB)-specific antibodies, in particular IgA in serum and feces, correlate with protection against CDI, while low titers or absence of toxin-specific IgG and IgA were found in patients with acute or recurrent CDI and in non-colonized individuals ( 115 – 118 ). These data indicated that patients with transient deficiency in IgA might be more susceptible for infection.…”

Novel Immunoassay for Diagnosis of Ongoing Clostridioides difficile Infections Using Serum and Medium Enriched for Newly Synthesized Antibodies (MENSA)

“…Clostridioides difficile infections (CDI) afflict nearly half a million patients in the United States on an annual basis, and have progressively increased in incidence as well as severity in recent years. These infections lead to the death of 29,000 patients in the United States annually, most of whom are elderly (1, 2). While typically regarded a hospital acquired entity, the epidemiology of CDI has shifted in the past decade and half the cases are now community acquired among low risk populations (3).…”

“…The development of specific serum antibodies in response to ongoing CDI is well recognized (14, 18). However, the utility of measuring the antibody response is confounded by the sub-population of patients who carry serum antibodies consequent to environmental exposure and subclinical infection (2, 19, 20). Further, the increase in serum anti-CD antibody levels may occur well into the infectious course, typically in the second week following symptom onset (21).…”