Colonization of C57BL/6J and BALB/c Wild-Type and Knockout Mice withHelicobacter pylori: Effect of Vaccination and Implications for Innate and Acquired Immunity

Abstract

The gram-negative bacterial pathogen Helicobacter pylori is a major cause of peptic ulcer disease and a risk factor for gastric cancer in humans. Adapted H. pylori strains, such as strain SS1, are able to infect mice and are a useful model for gastric colonization and vaccination studies. In this study we used a streptomycinresistant derivative of H. pylori SS1 to analyze the colonization behavior and the success of vaccination in wild-type (wt) and various knockout mice of the BALB/c and C57BL/6J genetic backgrounds. We here report that BALB/c interleukin-4 knockout (IL-4 ؊/؊ ) mice are weakly overcolonized compared to the wt strain but that the IL-12 ؊/؊ knockout results in a strong overcolonization (500%). Unexpectedly, in the C57BL/6J background the same knockouts behaved in diametrically opposed manners. The IL-4 ؊/؊ mutation caused a 50% reduction and the IL-12 ؊/؊ knockout caused a 95% reduction compared to the wt colonization rate. For C57BL/6J mice we further analyzed the IL-18 ؊/؊ and Toll-like receptor 2 knockout mutations, which showed reductions to 66 and 57%, respectively, whereas mice with the IL-10 ؊/؊ phenotype were hardly infected at all (5%). In contrast, the tumor necrosis factor receptor knockout (p55 ؊/؊ and p55/75 ؊/؊ ) mice showed an overcolonization compared to the C57BL/6J wt strain. With exception of the low-level infected C57BL/6J IL-10 ؊/؊ and IL-12 ؊/؊ knockout mice, all knockout mutants were accessible to a prophylactic vaccination and their vaccination behavior was comparable to that of the wt strains.

Vaccine-Induced Immunity againstHelicobacter pyloriInfection Is Impaired in IL-18-Deficient Mice

“…These authors used few animals (3-4) in each group and only two immunizations and evaluated the level of protection (day 63) 4 wk after challenge, whereas we performed several experiments, used larger groups and four oral immunizations, and assessed protection 2 wk after challenge. Although we used mice of the same genetic background, C57BL/6, derived from the same founders as Panthel et al, we arrived at opposite results (44). At present we cannot give a decisive explanation for this difference.…”

“…We believe our study presents statistically significant and reproducible results, whereas the limited data provided by Panthel et al (44) must be considered less reliable. Furthermore, the latter authors did not determine specific T cell or Ab responses; therefore, no conclusion about the role of IFN-␥ could be drawn (44).…”

“…Given that IL-18 primarily is involved in protection as a coregulator of Th1 development together with IL-12, it is not surprising that we found a strong dependence on IL-18 for the development of host resistance also against H. pylori infection. However, Panthel et al (44) recently reported that IL-18 Ϫ/Ϫ mice were as protected as WT mice after oral immunization with H. pylori sonicate and CT adjuvant. These authors used few animals (3-4) in each group and only two immunizations and evaluated the level of protection (day 63) 4 wk after challenge, whereas we performed several experiments, used larger groups and four oral immunizations, and assessed protection 2 wk after challenge.…”

“…The serum IL-18 level was significantly increased in patients with gastric carcinoma, which is frequently found to be associated with H. pylori infection (2,43). Moreover, a limited study in mice addressing the role of IL-18 found no difference in resistance to infection between immunized IL-18 Ϫ/Ϫ and wild-type (WT) 3 mice (44). It was then assumed, but not assessed, that IFN-␥ production was significantly reduced in IL-18 Ϫ/Ϫ mice, and therefore, the result, showing normal protection, would favor the idea that IFN-␥ is not essential for H. pylorispecific protection, in agreement with the report by Garhart et al (19).…”

Augmentation of Helicobacter pylori urease activity by its specific IgG antibody: implications for bacterial colonization enhancement

“…Actually, the H. pylori-induced chronic gastritis was significantly augmented not only in interferon gamma (IFN-γ)-defi cient but also in IL-12-defi cient mice with enhanced humoral immunity of Th2 dominancy when compared with the wild type (WT) (18). Also, a strong over-colonization was observed in the IL-12-defi cient BALB/c mice (23). In contrast, the chronic gastritis would not be enhanced, but rather weakened in IL-4 deficient mice with an enhanced cellular immunity to Th1 dominancy (1).…”