Circulating Gut-Homing (α ₄ β ₇ ⁺ ) Plasmablast Responses against Shigella Surface Protein Antigens among Hospitalized Patients with Diarrhea

Abstract

dDeveloping countries are burdened with Shigella diarrhea. Understanding mucosal immune responses associated with natural Shigella infection is important to identify potential correlates of protection and, as such, to design effective vaccines. We performed a comparative analysis of circulating mucosal plasmablasts producing specific antibodies against highly conserved invasive plasmid antigens (IpaC, IpaD20, and IpaD120) and two recently identified surface protein antigens, pan-Shigella surface protein antigen 1 (PSSP1) and PSSP2, common to all virulent Shigella strains. We examined blood and stool specimens from 37 diarrheal patients admitted to the Infectious Diseases & Beliaghata General Hospital, Kolkata, India. The etiological agent of diarrhea was investigated in stool specimens by microbiological methods and real-time PCR. Gut-homing (␣ 4 ␤ 7 ؉ ) antibodysecreting cells (ASCs) were isolated from patient blood by means of combined magnetic cell sorting and two-color enzymelinked immunosorbent spot (ELISPOT) assay. Overall, 57% (21 of 37) and 65% (24 of 37) of the patients were positive for Shigella infection by microbiological and real-time PCR assays, respectively. The frequency of ␣ 4 ␤ 7 ؉ IgG ASC responders against Ipas was higher than that observed against PSSP1 or PSSP2, regardless of the Shigella serotype isolated from these patients. Thus, ␣ 4 ␤ 7 ؉ ASC responses to Ipas may be considered an indirect marker of Shigella infection. The apparent weakness of ASC responses to PSSP1 is consistent with the lack of cross-protection induced by natural Shigella infection. The finding that ASC responses to IpaD develop in patients with recent-onset shigellosis indicates that such responses may not be protective or may wane too rapidly and/or be of insufficient magnitude.

Immune Response Characterization after Controlled Infection with Lyophilized Shigella sonnei 53G

“…Additionally, a heterologous challenge-rechallenge study to investigate the potential of cross-protection provided across different Shigella species is in the planning stages. The S. sonnei 53G CHIM has confirmed the relevance of robust mucosal immune responses postinfection and their potential role as a mechanistic correlate of protection in this model (36), while suggesting that systemic immune responses may play a lesser role, as they were not as reflective of disease outcome and severity in this study. The observations that baseline levels of LPS-specific serum IgA and IgA-secreting memory B cells are associated with reduced odds of disease point to these immune measures as being potentially more sensitive markers for underlying protective immunity, and therefore, they should be further studied.…”

“…As previously reported, lipopolysaccharide (LPS)-specific serum and fecal IgG and IgA responses postchallenge were not associated with challenge dose or clinical disease outcomes, including dysentery, diarrhea severity, and disease severity score (25). These findings highlight potential gaps in understanding the contribution of other immunological or nonimmunological protective mechanisms and may also confirm the importance of immune responses to nonpolysaccharide antigens (36)(37)(38).…”

Trafficking receptor signatures define blood plasmablasts responding to tissue-specific immune challenge

“…PBs are present in low numbers in the peripheral blood of healthy individuals. After acute infection or in settings of active immune responses, however, the frequency of blood PBs increases dramatically, peaking 7 to 9 days after immunization or the onset of illness (1)(2)(3) and reflects the dissemination of recently antigen-activated B cells (4, 5; reviewed in refs. 6, 7).…”

Shigella Vaccine Development: Finding the Path of Least Resistance

“…Another correlate of immunoprotection is the induction of gut-homing anti-LPS antibody-secreting cells which can be detected in the circulation approximately 1 week after oral immunization, challenge, or infection as an indicator of intestinal immune priming (11,17,18). Antibodies in lymphocyte supernatants (ALS) have also been evaluated in Shigella vaccine studies, as they parallel circulating antibody-secreting cell (ASC) responses (19).…”