Role of Inflammatory Monocytes in Vaccine-Induced Reduction of Helicobacter felis Infection

Abstract

cDespite the proven ability of immunization to reduce Helicobacter infection in mouse models, the precise mechanism of protection has remained elusive. In this study, we evaluated the role of inflammatory monocytes in the vaccine-induced reduction of Helicobacter felis infection. We first showed by using flow cytometric analysis that Ly6C low major histocompatibility complex class II-positive chemokine receptor type 2 (CCR2)-positive CD64؉ inflammatory monocytes accumulate in the stomach mucosa during the vaccine-induced reduction of H. felis infection. To determine whether inflammatory monocytes played a role in the protection, these cells were depleted with anti-CCR2 depleting antibodies. Indeed, depletion of inflammatory monocytes was associated with an impaired vaccine-induced reduction of H. felis infection on day 5 postinfection. To determine whether inflammatory monocytes had a direct or indirect role, we studied their antimicrobial activities. We observed that inflammatory monocytes produced tumor necrosis factor alpha and inducible nitric oxide synthase (iNOS), two major antimicrobial factors. Lastly, by using a Helicobacter in vitro killing assay, we showed that mouse inflammatory monocytes and activated human monocytes killed H. pylori in an iNOS-dependent manner. Collectively, these data show that inflammatory monocytes play a direct role in the immunization-induced reduction of H. felis infection from the gastric mucosa. Helicobacter pylori is a helical, rod-shaped, microaerophilic Gram-negative bacterium. It specifically colonizes the stomach of 50% of the world's population (1, 2). H. pylori infection induces inflammation of the gastric mucosa; however, only 15% of infected individuals develop clinical symptoms (3, 4). These clinical symptoms start with superficial gastritis and may evolve into chronic atrophic gastritis, peptic ulcer disease, intestinal metaplasia, gastric carcinoma, or gastric mucosa-associated lymphoid tissue lymphoma (5). Due to its high prevalence, H. pylori is a major cause of cancer worldwide. It is eradicated by antibiotic therapies, which are expensive and promote resistance (6). Hence, alternative therapies need to be developed to eradicate antibioticresistant strains in western countries and to reduce the prevalence of H. pylori infection in developing countries. From this perceptive, the development of a therapeutic and/or preventive vaccine(s) needs to be pursued.In mice, H. pylori infection can be prevented or cleared by prophylactic and therapeutic vaccinations. Some clinical trials have been conducted in humans and have shown that immunization with H. pylori antigens is safe and immunogenic (7-9); however, the elimination or prevention of H. pylori infection has not been achieved with this approach. To develop an efficient vaccination strategy, a better understanding of the protective mechanisms is critical. Indeed, the running of clinical trials without this knowledge is extremely risky (10).In animal models of the vaccine-induced reduction of Helicobacter infecti...

Divergent roles for Ly6C+CCR2+CX3CR1+ inflammatory monocytes during primary or secondary infection of the skin with the intra-phagosomal pathogen Leishmania major

“…Our observations also bear similarity to studies examining the role of vaccine-induced immunity in shaping the innate inflammatory response in the spleen and liver or stomach, specifically the activation of inflammatory monocytes as a strong correlate of protective immunity [38,39]. …”

The Immune Battle against Helicobacter pylori Infection: NO Offense

“…Therefore, intra- or extra-cellular pathogenic bacteria exhibit a strong resistance to NO challenge [51, 55]. However, H. pylori is more sensitive to NO and RNI, including ONOO − , than other enteric pathogens [56, 57]; moreover, it has been shown in vitro that activated macrophages inhibit the growth of H. pylori through an NO-dependent pathway [35, 58, 59]. This anti-proliferative effect may be mediated by the irreversible inhibition of H. pylori respiration by NO and ONOO − [60].…”

The frequency of circulating integrin α4β7+ cells correlates with protection against Helicobacter pylori infection in immunized mice

“…We next analyzed the frequency of circulating CD11b + Ly6G − inflammatory monocytes (Ly6C int MHCII neg ) using a gating strategy used by Moyat et al and found them to be upregulated after SL + CT immunization day 7 after the 1st immunization ( P < .05) and day 4 after the 2nd immunization ( P < .05). A similar trend was seen in the SL + mmCT immunized mice, although the data were not statistically significant (Figure D).…”