Ecto-5′-Nucleotidase (CD73) Regulates Host Inflammatory Responses and Exacerbates Murine Salmonellosis

Abstract

Food-borne Salmonella spp., are a major cause of hospitalization and death. Adenosine, an important immune regulator of inflammation, limits tissue damage during infection. CD39 (nucleoside triphosphate dephosphorylase) combined with ecto-5′-nucleotidase (CD73) metabolizes ATP to adenosine. We studied the expressions of CD39 and CD73 in tissues, and T helper cells in mice after Salmonella infection and evaluated the role of CD73 in regulating immune responses and bacterial clearance in wild-type and CD73-deficient (CD73−/−) mice. Both CD39 and CD73 transcript levels declined in the infected wild-type mice. Compared to wild-type mice, tissues from infected CD73−/− mice had significantly higher expression of pro-inflammatory cytokines and reduced anti-inflammatory responses. CD73−/− mice were more resistant to infection and had a greater inflammatory responses and a significantly lower bacterial load in the liver compared to wild-type mice. Thus, CD73 expression attenuates inflammation during murine Salmonellosis and impairs immunity, leading to increased bacterial colonization and prolonged infection.

Ecto-5′-Nucleotidase (CD73) Deficiency in Mycobacterium tuberculosis-Infected Mice Enhances Neutrophil Recruitment

“…However, the role of CD73 in infectious diseases has been poorly explored. CD73-deficient mice are more resistant to Salmonella enterica and Helicobacter felis infections and display a stronger inflammatory response than wild-type (WT) mice (23,24). These observations are in contrast to those obtained upon infection with Toxoplasma gondii.…”

“…However, CD73 deficiency does not affect mycobacterial growth in vitro or in vivo. In contrast, CD73 impairs bacterial clearance in the livers of mice infected with S. enterica serovar Typhimurium and in the spleens of those infected with H. felis (23,24). In fact, CD73 rather seems to play a transitory role in the early homing of innate immune cells, and notably neutrophils, to the lung parenchyma and to tissues damaged during M. tuberculosis infection.…”

“…Bone marrow-derived macrophages (BMMs) were infected with virulent M. tuberculosis strain H37Rv and stimulated with 100 M ATP, and cytokine levels were assessed 18 h later. Such concentrations of ATP are observed under pathological conditions such as inflammation (9,23) and may be reached in cases of tuberculosis. Consistent with results for human macrophages, in the presence of ATP, the secretion of TNF-␣ by M. tuberculosis-infected BMMs decreased, whereas that of VEGF increased (Fig.…”

Cell wall‐anchored 5′‐nucleotidases in Gram‐positive cocci

“…It was also shown that Ado can prevent the activation, proliferation, cytokine production and cytotoxicity in T cells after stimulation of the A 2A receptor and might also play a role in naïve T‐cell homeostasis, memory cell survival and T‐cell differentiation (Bono et al, ). Interestingly, infection of CD73 KO mice with Salmonella enterica Typhimurium led to increased production of Th1 cytokines and reduced bacterial burden in tissue, which further highlights the importance of 5′‐NTs in immune responses to bacterial infections (Alam et al, ). Readers with deeper interest in the purinergic regulation of the immune system are referred to the excellent review by (Cekic & Linden, ).…”

Surface Antigen Profiling of Helicobacter pylori‐Infected and ‐Uninfected Gastric Cancer Cells Using Antibody Microarray

“…Decreased expression in H. pylori-eradicated patients [39] 73 Increased expression leads to impaired immunity in mice infected with Salmonella spp. and increased bacterial load [55]…”