Pf bacteriophage (phage) are filamentous viruses that infect
Pseudomonas aeruginosa
and enhance its virulence potential. Pf virions can lyse and kill
P. aeruginosa
through superinfection, which occurs when an already infected cell is infected by the same or similar phage.
FOXP3+ regulatory T cells (Treg) depend on exogenous IL-2 for their survival and function, but circulating levels of IL-2 are low, making it unclear how Treg access this critical resource in vivo. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/- Treg have impaired stability and function in vivo, including the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their tolerogenic function in vivo. Together, these data identify novel roles for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.
Bacteriophages are abundant in the human body, including at sites of infection. We report that Pf4 phage, a filamentous bacteriophage produced by Pseudomonas aeruginosa, dampens inflammatory responses in response to either P. aeruginosa airway infection in a mouse model of acute pneumonia or bacterial endotoxin treatment. Pf4 triggers TLR3-dependent type I interferon production and antagonize production of anti-bacterial cytokines and chemokines. In particular, Pf4 phages inhibit CXCL5, preventing efficient neutrophil chemotaxis in response to endotoxin. These results suggest that Pf4 phages alter innate immunity to bacteria potentially dampening inflammation and neutrophil migration at sites of bacterial colonization or infection.
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