HLA-B27 Modulates Intracellular Growth of Salmonella Pathogenicity Island 2 Mutants and Production of Cytokines in Infected Monocytic U937 Cells

Abstract

Background Salmonella enterica serovar Enteritidis PT4 KS8822/88 replicates rapidly in HLA-B27-transfected human monocytic U937 cells. In this process, Salmonella pathogenicity island 2 (SPI-2) genes play a crucial role. Our previous study indicated that 118 Salmonella genes, including 8 SPI-2 genes were affected by HLA-B27 antigen during Salmonella infection of U937 cells. Methods/Principal Findings To further investigate Salmonella replication in HLA-B27-positive U937 monocytic cells, two SPI-2 genes, ssaS and sscA up-regulated most during Salmonella infection of HLA-B27-transfected U937 cells, were mutated by using one-step gene disruption method. Intracellular survival and replication of the mutants in the U937 cells was compared to that of the wild type strain. Surprisingly, the two mutated strains replicated significantly more than the wild type bacteria in HLA-B27-transfected cells. Secretion of tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) was significantly induced during the infection of HLA-B27-transfected U937 cells with the mutants. The results indicated that the certain SPI-2 genes in wild type bacteria suppress Salmonella intracellular growth and production of cytokines in infected HLA-B27-transfected cells. HLA-B27-associated modulation of Salmonella SPI-2 genes and cytokine production may have importance in the persistent infection of the bacteria and the pathogenesis of reactive arthritis. Conclusions The study provides evidence that certain virulence factors of pathogens can reduce the intracellular growth in the host cells. We suggest that the limiting intracellular growth might be a strategy for persistence of bacteria in host cells, keeping a balance between pathogenic growth and pathogenesis.

Altered Regulation of ELAVL1/HuR in HLA-B27–Expressing U937 Monocytic Cells

“…Evidence exists suggesting that the interaction between ReA-triggering bacteria and HLA-B27 expressing host cell is abnormal [2], [4], [8], [26], [27], [38], [39]. We have previously observed that the presence of HLA-B27 HCs in monocytic cells modifies intracellular environment of U937 monocyte/macrophages in favor of the disease-triggering bacteria and we found that the regulation of several signaling molecules was altered in these cells [1]–[3], [26].…”

“…lipopolysaccharide (LPS) are shown to persist in ReA patients for an abnormally long time [4]–[7]. In fact, it is suggested that Salmonella is able to regulate its intracellular growth in the HLA-B27-positive cells and that might be a strategy for bacterial persistence [8]. Thus these observations suggest that the interaction between HLA-B27-expressing host cells and ReA-triggering bacteria is abnormal and leads to the persistence of the causative microbes/microbial compartments in ReA patients and to prolonged immune reaction.…”

Treatment of reactive arthritis with biological agents: a review

“…HLA-B27 has multiple alleles that may affect the host response and disease susceptibility; among these, HLA-B*2703 increases the risk of the typical clinical triad of ReA [19]. Other data suggest that HLA-B27 may contribute to the persistence of bacteria in the host, especially Chlamydia and Salmonella [20,21]. So how does the susceptible HLA-B27 gene participate in the occurrence and development of ReA?…”

The role of the gut and microbes in the pathogenesis of spondyloarthritis

“…For example, Granfors and colleagues have studied a monocyte cell line transfected with HLA B27 [20]. The presence of HLA B27 appears to affect the intracellular longevity of Salmonella .…”