Morphologic and Cytokine Profile Characterization ofSalmonella entericaSerovar Typhimurium Infection in Calves With Bovine Leukocyte Adhesion Deficiency

Abstract

The role of neutrophils in the pathogenesis of Salmonella enterica Typhimurium-induced ruminant and human enteritis and diarrhea has yet to be characterized with in vivo models. To address this question, the in vivo bovine ligated ileal loop model of nontyphoidal salmonellosis was used in calves with the naturally occurring bovine leukocyte adhesion deficiency (BLAD) mutation whose neutrophils are unable to extravasate and infiltrate the extravascular matrix. Data obtained from 4 BLAD Holstein calves homozygous for BLAD (CD18-), 1 to 5 weeks of age, were compared with 4 controls, age-matched Holstein calves negative for BLAD (CD18þ). Morphologic studies revealed that infection of CD18-calves with S Typhimurium resulted in no significant tissue infiltration by neutrophils, less tissue damage, reduced luminal fluid accumulation, and increased bacterial invasion, when compared with CD18þ calves. Ultrastructurally, lesions in enterocytes induced by S Typhimurium infection in CD18-calves-including attachment and disruption of the brush border, apical membrane ruffling formation, and cellular degeneration-were similar to the ones reported in the literature for CD18-calves. Study of cytokine gene expression by quantitative real-time polymerase chain reaction revealed that early stages of acute infection (4-8 hours postinfection) were associated with increased interleukin 8 gene expression in the absence of tissue influx of neutrophils in CD18-calves, whereas later stages of infection (12 hours postinfection) were associated with increased expression of growth-related oncogene a in the presence of neutrophil influx in CD18þ calves. In contrast, the proinflammatory cytokines interleukin 1b and tumor necrosis factor a were poorly correlated with the presence or absence of tissue neutrophils.

Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

“…Consistent with the important role of IFN-␥ in driving inflammatory changes in tissue (7,8), the severity of histopathological lesions in the cecal mucosa was significantly reduced in S. Typhimurium-infected neutrophil-depleted mice. A marked reduction in the severity of histopathological changes in response to S. Typhimurium infection is also observed in ligated ileal loops of calves with CD18 deficiency, a primary immunodeficiency resulting in an inability to recruit neutrophils into the intestinal mucosa because CD18/CD11B (CR3) is required for neutrophil extravasation (24). However, neutrophil deficiency affects many aspects of host-microbe interaction that have to be considered when interpreting these data.…”

Salmonella, the host and its microbiota

“…Once S. Typhimurium has crossed the epithelial lining, a second type III secretion (T3SS-2) system enables the pathogen to survive within tissue mononuclear cells (macrophages and dentritic cells) [10]. Finally, S. Typhimurium invasion of host tissue is detected by the innate immune surveillance (Figure 1) [11], resulting in the rapid induction of intestinal inflammation, which is largely responsible for the signs of disease [12]. Mechanisms by which S. Typhimurium first induces and then benefits from the host inflammatory response have been elucidated using a mouse colitis model [2].…”

Immunomodulation for gastrointestinal infections

“…Salmonella enterica induces intestinal epithelial damage by poly-morphonuclear cells influx and an increase in IL-17A, IL-17F as well as arrangement of chemokines [84]. IL-17 has been indicated as a major player in Salmonella Typhimurium induced diarrhea, as it is strongly induced in the infected gut.…”