Broad Up-Regulation of Innate Defense Factors during Acute Cholera

Abstract

We used a whole-genome microarray screening system (Affymetrix human GeneChips covering 47,000 different transcripts) to examine the gene expression in duodenal mucosa during acute cholera. Biopsies were taken from the duodenal mucosa of seven cholera patients 2 and 30 days after the onset of diarrhea, and the gene expression patterns in the acute-and convalescent-phase samples were compared pairwise. Of about 21,000 transcripts expressed in the intestinal epithelium, 29 were defined as transcripts that were up-regulated and 33 were defined as transcripts that were down-regulated during acute cholera. The majority of the up-regulated genes characterized were found to have an established or possible role in the innate defense against infections; these genes included the LPLUNC1, LF, VCC1, TCN1, CD55, SERPINA3, MMP1, MMP3, IL1B, LCN2, SOCS3, GDF15, SLPI, CXCL13, and MUC1 genes. The results of confirmative PCR correlated well with the microarray data. An immunohistochemical analysis revealed increased expression of lactoferrin in lamina propria cells and increased expression of CD55 in epithelial cells, whereas increased expression of the SERPINA3 protein (␣ 1 -antichymotrypsin) was detected in both lamina propria and epithelial cells during acute cholera. The expression pattern of CD55 and SERPINA3 in cholera toxin (CT)-stimulated Caco-2 cells was the same as the pattern found in the intestinal mucosa during acute cholera, indicating that the activation of the CD55 and SERPINA3 genes in intestinal epithelium was induced by CT. In conclusion, during acute cholera infection, innate defense mechanisms are switched on to an extent not described previously. Both direct effects of CT on the epithelial cells and changes in the lamina propria cells contribute to this up-regulation.

Neutrophils Are Essential for Containment of Vibrio cholerae to the Intestine during the Proinflammatory Phase of Infection

“…However, histological studies demonstrated a low abundance of neutrophils in a patient pool from Vellore, India, with moderate-to-severe cholera disease, suggesting that they may not have a significant impact on V. cholerae infection (32). In contrast, other reports do indicate a neutrophil response during the acute phase of V. cholerae infection (12,43,44). In the present study, we use mice depleted of neutrophils to determine whether and how neutrophils contribute to cholera disease during the proinflammatory phase of infection.…”

“…Increased numbers of circulating neutrophils, as well as increased concentration of neutrophil products, Lf and MPO, indicate a specific neutrophil response to V. cholerae early during natural human infection (12,43,44). Further, biopsies of acutely ill cholera patients demonstrate infiltration of neutrophils into the lamina propria, accompanied by congestion of the vasculature and endothelial damage (32).…”

“…Recent studies in humans of the immune response to natural V. cholerae El Tor O1 infection reveal that persons who naturally acquire cholera transition through an early proinflammatory phase characterized by an increase in markers of inflammation as demonstrated by gut biopsy, stool sample, and peripheral blood analysis. Patients show increased levels of C-reactive protein, total white blood cells, neutrophils, and bactericidal proteins lactoferrin (Lf) and myeloperoxidase (MPO) (12,43,44). This proinflammatory phase persists during acute, symptomatic illness and is then followed by a noninflammatory convalescent phase, during which expression of inflammatory markers are suppressed (44).…”

Lactoferrin Acts as an Alarmin to Promote the Recruitment and Activation of APCs and Antigen-Specific Immune Responses

“…This is particularly noticeable in blood, where lactoferrin concentration can be as low as 0.5ϳ1 g/ml under normal conditions, but increases to 200 g/ml with systemic bacterial infection (6,7). Recent reports indicate that lactoferrin expression in both neutrophils and epithelial cells can be induced (8,9).…”

Short Communication on: Study of Avidity of Antigen-Specific Antibody as a Means of Understanding Development of Long-Term Immunological Memory after Vibrio cholerae O1 Infection

“…It should be recall that cholera toxin is a potent immunoadjuvant in addition to being an enterotoxin [9]. The toxin and LPS may activate mucosal innate immune responses also [10], and abnormalities in innate immune factors have been repetitively associated with susceptibility to cholera [11,12]. Thus, assessing the correlation between innate immune response and protection following cholera warrant further investigation.…”