Yersinia pestis survival and replication within human neutrophil phagosomes and uptake of infected neutrophils by macrophages.
Yersinia pestis, the bacterial agent of plague, is transmitted by fleas. The bite of an infected flea deposits Y. pestis into the dermis and triggers recruitment of innate immune cells, including phagocytic PMNs. Y. pestis can subvert this PMN response and survive at the flea-bite site, disseminate, and persist in the host. Although its genome encodes a number of antiphagocytic virulence factors, phagocytosis of Y. pestis by PMNs has been observed. This study tests the hypotheses that Y. pestis, grown at the ambient temperature of the flea vector (21°C), where the major antiphagocytic virulence factors are not produced, can survive and replicate within human PMNs and can use PMNs as a route to infect macrophages subsequently. We show that Y. pestis is localized within PMN phagosomes, predominately as individual bacteria, and that intracellular bacteria can survive and replicate. Within 12 h of infection, ~70% of infected PMNs had PS on their surface and were plausibly competent for efferocytosis. With the use of live cell confocal imaging, we show that autologous HMDMs recognize and internalize infected PMNs and that Y. pestis survives and replicates within these HMDMs following efferocytosis. Addition of HMDMs to infected PMNs resulted in decreased secretion of inflammatory cytokines (compared with HMDMs incubated directly with pCD1(-) Y. pestis) and increased secretion of the anti-inflammatory cytokine IL-1ra. Thus, Y. pestis can survive and replicate within PMNs, and infected PMNs may be a route for noninflammatory infection of macrophages.
1.Rocky Mountain Laboratories, NIAID, NIH, 903 South 4th St., Hamilton, MT 59840, USA. justin.spinner@nih.gov.
Justin L
JL
Spinner
Seth
S
Winfree
Tregei
T
Starr
Jeffrey G
JG
Shannon
Vinod
V
Nair
Olivia
O
Steele-Mortimer
B Joseph
BJ
Hinnebusch
D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology*; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology*; D010930:Plague / Q000382:microbiology*; D014774:Virulence; D015010:Yersinia pestis / Q000276:immunology / Q000472:pathogenicity*
apoptosis; efferocytosis; intracellular; phagocytosis; polymorphonuclear leukocytes